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·GENETICS
IN ULATION TO
CLINICAL POIOINE

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·GENETICS
IN RELATION TO
CLINICAL MEDICINE
PY
F A E CREW
M.D D.Sa Ph.D. CRSFRC.P.ED.
arom o rana ILALTH AND POOLAL WEDDA
UNIVELETY OF PRODOOR
OLIVER AND BOYD
EDINBURGH TIYET.DDALE COURT
LONDON ORCAT RUSTIL STREET WYC
1917

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·TO
JOHN TRASER ROBERTS
ON HON I HATE LOVED
TAI MO TAL I IYA ATL.
A TODO Y ATTECTION and
MLATITUDE

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·PREFACE I HAVE been required to fer cousa of instruction In Genetla to medical student since the year 1919. For their ustunce I fashioned my lecture noten nto i book called Organi Inkeritance i* Wer which wu publlabed just twenty years ago This very rapidly lort its mefulness u the pubject of human genetlas grew and u my da concerning the methode of teaching changed. By 1938 I had dedded to bring out a revited edition of the book, but immersion in the affain of the 1939 International Genetial Congren and engulfment in the war prevented my doing so until now This book, liko ito predecesor is not meant to be anything more than an edited compllation of lecture notes It is offered u un aid to those who have listened rather than to those who have to learn their genetic rolely by reading For the latter there are for better boobs than thus, Of those publlbed in thu country the best b ) A Fraser Roberts An Introduction to Modice GANTA E B Ford. Gosties for Hidual Students is another unful one. The only cIcun for producing yet another which cannot possibly be better than there and which indeed annot be very different in respect of content u that it reema deurable in my view that the many students who in each year must laten to me whilst I strive to attract their eager interest to a subject which has given me such unbounded pleasure, should be able to check that which I said yalnxt that which I have written. I love my enjoyment and my audience if tu memberi maut scribble u I talk. This book to written so that they may not be forced to write If it remains the only genetical tert red by students of mine then my teaching will hare been most lmperfect, us imperfect u will be the knowledge of clmial genetla porcued by those wbom I have taught. To prondo ruch an introduction to genetics is by no man un cury tuk for anyone who has personal knowledge of the medial student and of the strenuous and havlly loaded counter into which belo plunged The student quickly learns that the quality of subject is to be used according to los relativo ·PREFACE importance in his examinations and to its promised usefulness in the job of earning a living or of guning promotion within his chosen profession One that is merely Intellectually stimulating or ethfylag annot be allowed to cum his rapt attention. Interest must be harnessed to utility The student is forced by circumstances accepted by his teachers and created by the most damant needs of saety to seek, above all else, the power to treat and cure even though this be gained without an understanding of what be does. So it is that the genctidst, cuger to share with others the foy of duscovery and to display the considerable attractions and poruble befulness of ho subject, encounters embarraxtment at tbe art. It has to be admitted that the gifts he praffas annot compare in respect of immediato usefulnce with those that bedeck the laboratories of the brochennot or the radiologlit, for example It is not to be expected that, to one whose conditioned ambition it ba to treat the sick or injured human indivdual genetia can exercise a strong appeal Fantly remembering the remote day when he wus reluc tantly introduced to the Intimada of the slimy frog and the rinking skate, and still wondering what on earth those thing had to do with matters medial, tho student in no mood to appreciate the attractions of the specul genetio of the fruit fly or of the mour. To call upon the vut store of genetial knowledge that has been accumulated through the intensive Kudy of forms other than man, knowledge well worthy of serious consideration by those wbo are concerned with programme of human and sodal amelloration, is 1 sure method of persuading the average student that the science has little or no Yuue to birozelf Heb not interested, he cannot afford to be interested In comparative genetia in the latter part of his curriculum. He a concerned with the acquisition of that limited corpus of knowledge and of that soall constelladon of skills that will enable him to find a place in clinical medicino with los dramatic episode it human contacts and its emotian-Atisfying rewarde. He Interated in the Individual not in the speaa in the prevent and not in the future. So that of genetia is to be made attractive it must be offered u tbe special genetics of man, a difficult task in itself doce knowledge in the field is so incomplete It rust daul mth individuals and very small groups ruch u the family ·PREFACE b and not with large population. If the student an be perpaded that the children yet unconceived are o much the patients of the phyida u are the moribund senescents on whom be la preparing to lavish his are that the population Deeda tpedical attention nok than do tho individual sbo in thar combin tion comprise it that the prctice of medidna 1 much moro than a means of achieving self-utisfaction, social security and clevation that it is in fact among the sport potent Instruments which mandnd bouing deliberately for purporn of human and social bettement, then and only then aan tho taucher bopo to reap utofaction from his worring To the dintauan, concerned with the treatment of individual patients genetic bar but little to offer that can augment skil or reputation, but to the diagnosticien und apecally to the doctor who in large or small measure to wishful to play a part In the grand adrenture of furthering the best interests of man hodu a whole ft hos much. It must be the purpose of this book briefly to illustrate genetical fact, to interpret this in terms of current theory and to invite the student to dream of a world to which medicine, u form of experimental and applied blology bagerly used in the marvice of our speda F A EC ANCORA 1946

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·CONTENTS M CHAPTER 1 IS A KOWLIDE OF GUITI LALLY CONTAI? VALLATION TE SLALO toa THE CALL OF GOITIC YATIO THE SD-CHON904D S 1 1 IS 19 CHAPTER II TM THOTY OF THE GA THE MADELINE OT OLGLASEC IURETAT பாடபM LAN TIL LAW OF SLOLLOATION MODEL'S SECOND LAY THE LAW OF THE IDDIT ART MOIT OT CLAUCTOS 10 20 19 CHAPTER III LOTLAOL SOL-LILAUL TOTAL SDT LINKAOL Tom GOD TOTAL SD LINEAGL Y DOLLE GOD PAKTLAL 80 LIIT AOL NOW-DISJUNCTION 43 44 56 57 60 CHAPTER TY MULTILI ALLILONOR ABO SD TUM AD N ATTHOLD THE RIDUI Aman 64 6 69 77 7+ TI CHAPTER V COMPLICATTOO Lroot LITT DOLOTUCI MODITUTO GA VAATIOON T THE DLOTT O Inox or A CHALACTO AND OT TILL PTIMUM OF A GOT DOID TAI Tha OF THE DAY OR A CHALCID MULTT ACTOR LOOITATTI MOTAL DOO NUOTAL DINDICT COOTTITUTO DLAT. bo IS 17 93 ·CONTENTS M DinOT CONS AND GOETIC AND EXTIRONMETAL FACTOUS YILDING THE SAME CHARACTE F2, on RICAU MUTATION THE POI ROOTE ETC or Eroon TO RADUATION 94 96 100 102 CHAPTER VI ON THE TAUTATION OF KrovIDOE DITO ADTICE AI AUTOONAL RICCHITE AL AUTOROVAL DOXILAIT A TOTALLY SO LIKTED ROOT WWDI PENETRATCI B Low CONCIUTO THE PROSPECTS OF SIN TIT TO I ConcuTED CORAXCUIXITY CHARACTERS CAULD AT THE INTERACTION OF GOIETIC AND ENVIODITAL FACTOP CONCILIO MIED MANUAL EPILOOUT 100 toj 104 104 TOS IOS 107 107 109 ·CHAPTER I IS A KXOWLEDGE OF GLETICS REALLY NECESARY ? IT - dow generally accepted it would seein, by those who rre responsible for the coostruction of medial curricula that the science of genetia has much of value to offer and that tberefore an introduction to genetical fict and to current geactical theory should be included at some pount. It is recommended for comple, that instruction in clerbentary genetia should be offered dunng the pre-registration or the pre-clinlal yer and that the beaning of genetical knowledge upon problems of bealth and diresse sbould be comdered at come length in the courses that lead to ruch diplomus u thone of public health and poychiatry It - the cure that the theory of the gene claims the place in biological thought that years ago w occupued by crolution theory The latter wus demonstrably of the very greatest importance to the proper understandog of the role of medicine u an instrument of mdal policy Concerning it there is today no disputation. It is part of the birthnght of every Individual. There is no longer any need in a University coun of medical zoology to affer evidence intended to abow that Durwin wu probably right. It is enough to buke the whole of oncs teaching upon the fundamental truths of the theory which is an article of one s faith and an ingredient of anc . hope and uplntion The theory of the gene b equally invigorating » . theory It is equally important in relation to medicine specially to thore upects of medicine that are concerned directly or Indirectly with the cell. But it to happens that its methods are cruentually experimental and that many of its techniques of analyals and syntherls which have been employed with ruch outstanding success in programmes of animal and plan Improvements are directly appliable to both dinaal and population medicine. Eampla are much u are concerned with the recognition of what is inborn and what is acqured with the mode of Inheritance of the abnormal and undered those which attempt to estimate the apected inddence of ·GENETICS IN RELATION TO CLINICAL MEDICINE abnormality in a given population of those that relate to the control of such frequency But there is no need for the geneticot to hawk his wires. It u sufficient for anyone who wishes to convince himself that there si place for genetia in medial education to consult 2 standard tardbook of medicine The dimomsons of this place will be indiated by the frequency with such ruch genetical termo u familial heredity hereditary genetic or inborn are mentioned in the accounts of etiology A rapid search in such a textbook much wed by student and practitioner alike revealed that one or other of these terms was included in tho discusion concerning the etiology of certaunly not less than fifty-ur different diseases This us a mall number 1 mere fraction of the list presented in the Nomenclature of Durosas Morcover the great majority of the diseases quoted are relatively rare The genetic element ID diense awution should therefore not be given too great a prominence The discasos clearly of genetic origin aro not unong ibose which are responsible for the greatest amount of gepeni morbidity and mortality in our population The L not wo in certain special fields of medicine, however For ciumple authoritative opinion presents the view that not las than 10-25 per cent of all dealnou a genetic la orlgla, wbibt genetic awe of partial and total blindnew account for about 10 per cent of the whole. Here are some illustrative cumples Acbolurk jaundice Hepatomegalima tlycogeole Tbo dien may be bereditary The relatirely high incidence of courin marragou umoty the parents of affected patients rugret that the coodution may poably be mbertted u Mendean rocco chunder La to Tory and coa famihal, prennby rosult of an ibon defect of the Har Curtom of the liver Pernom aconha Sickle-celled untola Hodophila There's hereditary prodirty It is bereditary and famhal, behering Mondeltan dammant. I Modellen terminology it ballaled Tocante It b. bertditary dbank. It tnnomted directly from geocation to generation and affecta fomula tince nofta omila (hance the term femalo homophou Hereditary Purpun Hemorrhagla ·IS A KNOWLEDGE OF GENETICS REALLY NECESSARY? 3 Btbedingu Madaban dominant. It is pouble that the coodhon ba duo to an Inborn 107 of metabolbem. Heredity to fuctor Herodhary Honorragia Toangiectada Gaucha dbou (Splenke ud bopatic colorfement) Tutty datinantan of the Hurt Angloe poctor Congenital heart discuro Angioacurotic andere Acuto bronctlth Asthan Pulmony tuberculo Rheumatoid arthritis Osoortaen mapafecta Osteopathyroads Heredity factor Heredky probably factor Heretit la un montant factor It s probable that some degree of bereditary prodh poddion cocon once talne od tho chart common in too fa Certalaly rns to famiha The houdity dot un direct, tho Dorroos mutability ometimes being endanced in other foerations by migrim, epilepay hysteria. It believed that no onduly trritable brunchal centro : the facto trummitted by bereday Children e mbert the tubercaka datbah It does not Pour that the docto barndary but seems lody that the han harttod dethode Tbo condition berdary in 17 per ceat. of u Ahlstory of borradon from foretation to generation is cogimon The dhouse may be tramited throogte the malo line. It Once in three rooan thoma bits been woorde Thero 6 pondbility of an lobortid onceptiblity or duathala. Hereddary in och uro of importance in the chunktion of congenital hydrocepbalus. Nothing to known of the cology of the de part from ta famill and putal inddence. Iodirect heredity be the most common for the Tuon that the subject of thb dooms and Dolly Affected to caldhood and toapucated by the temostat fetched w that they do not procitate Direct batdity , bomom by DO man uncommon os bos be rapponed and to ooo folly the dha hua boca nuncuted from fatbe to on for more mentions Tbe dann i romethods bereditary but s mon commonly full Achoodroplarla Ear Hydrocephalus Apenrodicadlocy Freddd dury Fotel pestic panely ·4 GENETICS IN RELATION TO CLINICAL DEDICINE Huntington . chorea * Further than brtedlty no cual (uctorit an berma Pero manlar atrophy Heredity plays an important part to us hotdorce Myotonia congela A Yery ran muddy which b bereditary and familiar Dystrophla myotoola The beredity is bampolopous, that is it tooda to appear in the anne cullak is number of spparaty uncopnected famibia at a CORDON datance from one and the Atde voortar med om med to be estir y corned to one childnok. Fazitul periodik paralysis Heredity to rery marted and the malady has been traced through five generation Trizmiraco may occur efther through the male or througti be female and not infregematy . deration to kipped Seven! rotteber of the curre fully un wreatly acted Putodohypertroztak Lo cartun incidences . fumiy bistory pariya obtained, always on the mother's side Caroly kve children aro attacked in each peneration Senil demonta Heradky " held rempartite fos abie wiele deferences to morotal banhh amony obaly people Affertit dborden Heredity in the most constant single cha la tho sayor Danske deprestro came the ropedic rotor la weekly dokonannt. Schizophrenia Stodiet of the loadence is and to the Berbers of. Aruly demonstrata bereditary factor in a majority of cakes If one of momorrotx pair of two b Khrohread the other sabo in 70 per coot of a The frequency of the ution among various relatives of putem badkaits that pot intratted .. simple dacínunt poc indeed at a simple recesine, probably more than otocol reo is responsible Obradood disorders Tbo bereditary factor i trong of the purests of obsession padets and a 6h their brothers and han hare the kresbou poudaltanice.** Certain of these statement aan bare little or no meaning to the student unless he already ha a fairly thorough koowledge of the simpler facts cod of the more firmly founded hypothea of genetics and an acquaintance with its terminology Athalind ·VARIATION 3 Geneto (Gk gouest descent) b that branch of the science of Biology which ha concerned with the study of the nature und and of the similarities and dissimilantia in charconation chibited by individuals and groupe related by a common uncenry This book will attempt to deal with certain uspecta of the spodul genetia of men and in particular with the au and mode of inheritance of certain characters regarded - pathological and dbtinguishing the abnormal from the normal the wek from the hale VARIATION The clinaan dealing with an individual patient u fint concerned with diugnou's the recognition of the aigns and symptoms which in the combination indicate the nature of the disorder from which the patient knuffering Then bo veets the awe of 1h disorder The value of genetics in clinical medicine les to the fact that it is concerned with problems of cusation, with the auses of the similarities and duunilarities in the characterization of related individual Since the precision and potency of therapeul must nccemarily be affected by the validity of the phyaam . concept of auntion genetic must perforce be of interest and of value to him In general it an be and that the commal agents of defect, derangement, disorder disewe ure of two kinds those that pertain to the lodividual and those that derive from the environment in which the indindual hu hu being Individuals und cavironments differ widely among themselves, among them there is much oration Genetics though necessarily Interceed in En Tironmental yarations 1 ospecially concerned with Inborn vanatoms ahibited by living organisme. Tbo raw material that dalms the interest of the geneticist is to be encountered in great abundance to any human congregation. All the component individuals present many characters (detuls of structure or of fiction) in cominon 11 uro namals al tre human Betten them there ! much fundamental similarity Yet no two are cactly allke. Erorywbere there is much distilartty much variation. A rullway compartment or curoom an include repre kentative of several of the geographial varletla (nuca) of manbod differing one from the other in raspect of alin colour huir texture and so on. There an be a polydactylos individual ·6 GENETICS IN RELATION TO CLINICAL MEDICINE un albano 1 diabetic, a Frenchman a continety, Waleyan methodist. It is a matter of common observation that certain of these disullarities eg differences in language, religion, political preferenca cultural tastes mines are acquisitions pertaining to the sosial skontand which one generation receives from its predecessors. The changing of bubia in their candles would change ul there. But it equally matter of common observation that other dissimilaritia are not acquisitions are not derved from the physical or social environment of the individual but ure innate inbort The offspring of a Chinese couple will be Chinese physiognomially whether born in Canton or Creff If his parents art negroa the child will be negro phywogromnically whether raised in Gambia or the Gorbals. Certain character ahibited by the parents and the parental stock are malfortly transmitted to their children and remain largely if not wholly onaffected by difference in experience It s recorded that a family named Little, now living in New Brunswick, us remartable la that many of its members have a white lock of hair This has been the case for six succcare generations Tbc funily u related to the Percys. The story is told that after Hery Hotspur wus slain at Shrewsbury to 1403 his wife gave birth to son bearing thu wbite lock It is no longer credited that emotional distres can be the cause of such morphological abnormality The really interesting fact that this character white forelock, suddenly appeared in a pedigree and there after he reappeared generation after generation, lving at different times in different places and enduring markedly different experiences. A child when born ahibits a peculiar abnormality poly dactyly for example. Io mother and a sister ure normal in respect of digit number but its father und another inter are both polydactylous. It becomes difficult to avoid the notion that these lodividuel of different generations of the urde family are chibiting the very une abnormality for the rason that being related they harbour in themselves the elfamo ause of the condition name that be costitutional and pure from one generation to the next across the bridge of reproduction. The affected mut differ from the normal for the reson that in the latter the awe be aboant. Vyhan apoved in the name circumstances to the name discus ·VARIATION 7 provoking agency-outdooal deficency bacterial thyunon, occupational hard-tome individual of a group but not all, ficoumb Con it not be that constitutional differenca muut dotiguoh those who becorte discared and those who do not? It would mean to be reasonable to upproach to matter of auntion by postulating that differences between individuels of the same group are indeed of two kodas (1) modificators acquired character the rault of the reactions of the living organism to the impren of mvironmental forces, to differences In aperience, in social tradition, education, occupation climate, rodocoonomic circumstances and the like, and () inborn, fooate bereditary genetic characters which are the apreolon of precare developmental impulses or tendendo which were present in the individual from its very beginning If there be such inborn tendende or inclination, then it be reuocable to look for their material busi If there bo ruchu bunu then It must be prosent within the fertilbed ovum in which the mdividual (the syrote) has ita ongin. If , genetic character is to be Inherited from, tran mutted by the preceding Generation to its muccessor and ff both parents shart in this trammation, then los materul precursor must be sought for in both spermatozoon and ovum (the gramatus) wluch in ther union gire no to the typote itrelf It is to be understood that in concentrating hls attention upon the constitutional genetic-causes of vrution the genetlost doar pot arume that the genetic cure openuto in a vacuun. The end repult of the development of the lndividual must rurely be the expression of innato tendence inbora capacita recting to the general environment or clse to specific ingredients of the An Inborn apadty to become a tall Individual, for oample must remain a potentiality so long u malnutrition faulty bygiene or frequent Illnen deny the individual the opportunity for ts premton Nature und Nurture are the forces which, in their interplay fushuon the chincteruation of the individual But quite commonly it is necenuary to dorogard much md to concentrate upoo Little In orda to advance knowledge. In order to recognbe the role that Nature plays in the fashioning of a chancterization It is Decemary to disregard Nuture u fur u la resonably powable This is done by considering genetic variations u they occur in un environment that has been made u uniform and constant ·8 GENETICS IN RELATION TO CLINICAL MEDICINE In these mar u poalble. Alternatively genetic similarity can be studied It is pressed in & vanety of environments. the roles of Nature and Nurture can be disentangled and the relative importance of the two an be usessed. A survey of the hereditary differences which distingubah related individuals suggests that whilst certain character, c.g eye colour the blood groups and in their developonent reemingly quite independent of the environment, bang the direct apremion of initul und Inborn ddferences others life pectancy for cumple, are expressions of bereditary tendencia more or les affected by environmental forca It u SOMI THE SEARCH FOR THE CAUSE OF GENETIC VARIATION It is establisbed that the sole phynal link between the generations consists of the two gameta Together they form the only bridge acron which the physical bass of organic inheritance can pan from one generation to the next. establubed further that fertilisation and conception conut not so much in the union of male and female fumetes u in the fusion of their nuclei. The nucleus is built up of a variety of protoplum alled chromat which b remarlable for its appetito for much basic dyestuffs u hematoxylin and gentan vlolet and which costs in the form of a number of discrete lumps or rodo known a chromosomas (GŁ chroma colour ·body) Tbe number of chromosomes present in the nuclei of the cells of 1 given anjinal or plant is characteristic for that particular pedo The number in homo sapiens a 48 Oning to the fact that these chromosomes are hetero morphic, differing among themselves in respect of nze shape und behaviour during cell drvuion it has been demonstrated that there 48 chronsonoma ure present in the form of 24 pain. With one major exception to be considered later the two member of a given par are idenbal in raspect of ruze, sbapo and behaviour For this reason they are know u komologous ckromosomes If the number of chromosomas # to remain constant und characterist for the species and if the Hipe gemete arria chromosoma units nucleu a do all the nuclei of Jl the somatic cells it would seem that the number of chrome in the mature gamete must be helf that in the fartilored ovum und ·THE SEARCH FOR THE CAUSE OF GENETIC VARIATION , in the cells which derive therefrom. Cytology that bruch of biology which is especully concerned with the study of the Loutomy and phylology of the cell has shown that this to ko and that thus half (haploid) number (0) s built up of one member of ach per of chromosomes present in the somatic nuclei. The number typial for the speda b therefore 1 double set of chromosomes. Thu diplad number (20) L atablished at the moment of fertition by the union of two haplold wet one of which wu received by the wypote by way of the spermatozoon from the father the other by way of the Ovun from the mother The delicate predalon of thu mechanism u such that it would seem to furnish the meant whereby the phyucul pre currons of genetic character if there be ruch, could be dbtributed from parents to offspring in an ordały fashion. There ! no structural unit other than the chromosomes themselves which behave in a way which ensures that they are reduced to one half their number in fametogruesus (tbo formation of the panetes oogmers and permatogeneses) and are restored to their constant and chancteristic diploid number u the result of fertilisation Purants Zygoto (diploid, on) x Zygoto (diploid, 10) Genelogocos Gamete (bapland, ) Goneto Fertilation chaplaid, awa Ourung Zygoto (aplard, on) Sunco it - intended to present the argument that the chromosoma uro in fact the vehicle of minute structural units the hereditary factors, the games which are the of genetic resemblanca and dissimilaritas among related Individuals, it is necessary to pay attention to tbefr bebuanour In testis und nor's weitos = thread MA - mode) lo a cell (with the diploud number of chromonomco) aboat to divide the nucles undergoes mitos i proces which for purposes of description to conveniently divided into five stages prophare, prometaphare, roetaphar, anaphase und telophax. It when mito la completed that the cell itself becoma Increurngly constricted about middle and breaka ito at the construction to form two new cells ·10 GENETICS IN RELATION TO CLINICAL EDICINE PROPAAL The best and the state alackot read The chromontots love water to become one Tha LIU Dow in a coddion to which they an be axed, sabied add theret med ently biblo, It bo on that each chromosomo has formed a replia of itkell. The origloal chromonome ud fts reptia are dor Koov bronchids Tho ntimber of these bodia is therefore the strooid (4) Erry chromonomo pouces A short reglou, the spadle attachment, which does not sain. In this region the two chromatids remain malted throughout prophant. The position of the spodle Attachment in the length of the chromosome constant for any given chromosomo bot purta from chromoworo to chromosome. POVITAPRAIL, Twardo ad the state taken their position There doablo maok the core which to outside the nocar membrase A to end of the peoplert is to parts separete and a to oppoute idea of the nucleus, résintoy connected by modified rtglon of the cytopla koown the suck At tbc optct of promctaphen tbo nuclear actor de diepper and the arba of the studio como to llo along tlm. Joining tho tro centropoma Each chromatid organa tho poclear ap into additional pada elements. ITA RASI The online ſhow chwili Thomo Lo in the form of flat plato og the equator of amten the palm of which in the centrooma and an attached to the spindlo at their spinele attachments, the Long 20 tretchlog out foto the cytoplam. The two chromanida dertred from ach chrotroom Dow De to come together that the division between thren aurtely decernible. They han med the form of a tightly coiled spring within thin pellico ANANAS Tasting of the third attackwds on the path of the chromtids Each ptodo attachment is into two parts and there repe Omo Another Thos the two chromulds are drugred apart in opports dredlons towards the polas of the pindle. The chromatids of propeo DOW become the daughter chromowotnes of anapha. TILOIHAIL The Au sew of the formation to determid Tho spuntad sets of daogbier chromosome come to rost and undergo a hosts of changes, the most of thout wakich happened to prophareA Quclear membrado fotos udood each oth to cw nocle, tho chromosome Imbabe nie to wwe and to becomo lacte dinghy dificult to fix and stan. Mitosus is the device by means of which cach and cvery cell having its origin la the fertilised ovun shall becomo poucared of An cunct replia of the chromosome content of this origłoal cell. Melonia is a modification of mitoars and is peculiar to gatpetogeneris faentially it canalata of two divisions of the nudes (first and second melouc division) with but co dirbsion of the chromosome The first malone division is divisible, us is an ordinary mitotic dission into prophax, prometaphore metaphase, waphore and telophan, but its prophus u further divided into four stages, the Leptotene, tygotere, pachytene and diplotene ·THE SEARCH FOR THE CAUSE OF GENETIC VARIATION 11 LOTTOTAL The curtosomo yppars to colled thread not get spit Lato chromats (the one of the frontion of the chromatiche dicken ilgilary from that to mitosa) A wies of duty talabag mundo the abwe co be detected along the length of the chromonopol The relative pourdo o there chromatera bacoortret for stor chromosome ITCOTTI. The barnatopou chromosomes come together pur a thu realt of an attraction between Wettal chromoneret As the autor the parts of homologoor droporto stond oomber lo tanto (double chromosoma) b formed that they do constat of double cromo como la proven by the fact that each binlett botro quado nuecht PACHTTOIL The member of bralen vood themsetre around aucha alber Then the cromorone ple lato chromated to form and Each other matted of two chromodo ach other chrom fond les tres rythm to two chromatida oo that there are four bodies, let, In the place of the original pair of chromosoma. DIPLOTUKI. Bet the two chronics derhed from the decat cabens of the chronour pets that appear A darba cror and suprueba day a breaking and stundoo ith interne of material of the churrids coccerned. Thla baterchange kom croman-ort and I ta thu that are the upper or wo As many * eight chata 20 Dot cotton. They do not accur very bear together became the chromasits as a moph to recht claro tubing The ocentace of one comme therefore potents the ration of other Derby After the chacotta ben forget the chromatics aborten, thuchmood rotat Spodle attinett Chaus AN TIM) Fra. -Dlou a Chine for Gold-petent crophodrodila Ipod - otro de la foto direct de Babp and main attor de chem best bon the perbed Broby od we theront proth the of the other la beat three teen More that pemul druod punde od wtb pomacround with of the dang Adat Hetken the ratio olyor bu mature ·12 GENETICS IN RELATION TO CLINICAL MEDICINE PLOXITAPRASI und ITAMAR art an mitoe AVAPAASL Tbo podlo thachments do not dirido o in metoda This father of the podle sttachments to dride fa pocullar to the first melobc drilon When those of bocologom chromosome begla to repal at anorber the one yout pain of chromode which contagocut upon crorting over cantan wetloos of both patermal and material origin. This then, in the enticant differepa betteen the emphase of mitoda and of tho ont rcotic dinero. la mitors the diploid number of undfulded chromon some more from the equator comanda auch polt la meloos o la tbt taploid oomber of chromosomes that a port, but not each other cromootba dirided foto a pair of chromatids bed together at the padlo attachment the number of bodla that more to the autho doplod in both cura Tulorian ba u in mitoda The word datur atian dufen from citoslo and from the hunt molot driekop In the following way. There an be no interphase betwote the teloplan of the int meat distoa rod the prophes of the scond. or the promotaphase of the rocood com, without pecs, follow upon tho dclophose of the fire PRONETAPAASL The chromosome art of the baptord mrobe They un plat troto chromod held together by their spindle attachment. MITATAL, AXAFRASE TELOTHMA AO in mitos Art that they rokult ta tho production of acel containing the haploid number of chromonama No now drosion of chromowotnes occany and all that happeos that the chronaldo bett togetbet at the first meiotle dirbtoo pee to opposito polas of the spindla 4 of the fint sod socond melotic divinions fous alle low spermatolce of Anoram and three abortir pour bodies formed, ach carrying the bapkold nomber of droom For further and fulla mformation the reader referred to a book on cytology for emplo MJ D Watte The Cross (Mabuen). THE SEX-CHROMOSOxes Male us to be distinguubid from female by reference to the chromosome content of the nuclei of their constituent celle The two so differ in respect of one pair of chromosomes known for this retrn u the ser-carremes The rat of the chromosoma are related to us ontosomes In the human farpale the rex-chromosome have the form of a pair of idential members One of the richromosome pair of the male is umilar to these The three art knom u the X-chromowotno The X of the male has an unequal partner called the Y chronome The (diplold) chromosome constitution of the human female therefore rutosoma 33 pairs of homologous chromosomas x-chromosomos a pair of borpologous chromosomDOS (XX) ·THE SEX-CHROMOSOLES 3 where that of the male tutosomas 23 pain of bomologou chromosoma k-chromosome * per of unequal chromosomes (XY) The baploid set in every mature ovum conut of 23 autonomo plus an X but of spermatozor there are two kinda and with 23 autosome and an X and one with 23 autocones and . Y The female is komogent elaborating but one kind of orum in respect of chromosome constitution, hereus the male L keterosomwho producing two kinds of spermatozoa, an X-chromosome beanng band and a Y bearing Any onum fertilsed by an X-benning spermatozoon will yield m XX wypote, a female. Any ovun fertilised by Y-bearing spermatozoon will yield an XY pute, i male. The Y-chromosome is the peculiar property of the male and it pater from father to son. The heterogansetic mechanism ensure the production by a mated male and female of both male and female offspring It is necemury to devote a few lino to an aplanation in genetiaal terms of the actual mi-determining mechanam. In 1 species in which male and female forms ocarr maler.com and femalenes are in the ultimate analys genetic characters, In the constitution of every Individual, male and female alke, there are a great many genes which are partly or wbolly concerned in the control of the ri-dimorphuc chancer Sorne ko male-determining, other are female-determining Both knde are kattered throughout the chromosoma autorompas and re-chromosomes alike. In a species like our own as the result of chromosomo fragmentation and recombloation the chromosome compla as we now know it came into being The X-chromosome in its construction came to indude a relatively large number of female-determining genes, while among the autonomes and in the Y-chromosome a proponder ance of male determining becamo congregated. The result t that there be a malo xet and a female set and between them there b. balance In the female, XX the relationship of the two is that the female wet bs greater than, stranger than the mele In the male, XY the relationship bruch that the male xet is predorninant. Quantitative disturbances of this autosome Y-chroro.ono and X-chromosome relation ship rould be aspected to lad to disturbances in rerual ·14 GENETICS IN RELATION TO CLINICAL MEDICINE chancterisation. An XY Individual beause it on XY Individual develops testes and becomes a functional male. A genetic female XX develops ovaries and therefore becomes a funcionei femnal. Aboormality In respect of the endocrine products of the gonado (testie and ovary) would be expected to lead to abnormalities in the final sexual characternation But these are matters which belong not to genetla but to developmental physiology If information concerme there to sought, F H A Menhall Pkysiology of Reproduction should be consulted CONCEPTION It is whilst the oocyte s umderpoing metosis that it be entered by the mature spermatozoon which promptly loves its tall As won us the spermatosoon has entered a membrane forms around the Orum which prevents the entry of any other mate gamete The nuclew of the ovom puna Into anephew of the second meiotic division. The haplold nuclei of opum and spermatozoon fuxe to form the zygote mith the diploid chromovone number This diploid nudeus neat divide in the mual mitotic fuhion to forin ibe first cleavage celb of the newly formed embryo ·CHAPTER II It hurt Hotellektual a from a The Ugly Duckling --Hun lodenoa. THE THEORY OF THE GONE This postulates that the inbented chancten, physcal and metal, normal mod abnormal, anatomical physiologial and pathologlal ure controlled by gends reddent in the chromon some of the nuclew. The geiles tre present in pairs and of ach pair one member to derived from the futher and the other from the mother The gumete contains only one member of each pair of genes present in the constitution of the individual wbo deborated these gumetes Each gezse has its own particular place (locws) in the length of a particular chromosomo and the genes in any given chromosome are utanged in a linear order Homology in respect of chromosome now uwume different meaning Homologota chromosoma Le Fuch u accommodate the same kerta of loc. Genes resident in the ame chromosomo will remain together linked in trumbanion po long as the chromokorne retains its Integnty Croacing-over between member of pair of homologous chromosoma aun darupt rach linkage. The number of groups of linked genelindege groups - the haploid number of chromosoma that chunctcriatic for the species. The gena in their action, presumably chemical in land, affect the process of development and depenention, in flucndog their timing rate und direction. In so daing they introduce forces which tend to mould the chanctatation of the individual For practical purposes It b often coarenient to correlate one gene with ooo character bence the notion of ochorurter But most, if not all characters are the product of the internation of several gene. It is pouble that may many gener, posubly Jl the genes in the constitution of the Individual—the genotypt play • part in the fubioning of any one character Nevertheless it is al for one pene to be the principal agent In the production of a gtven character and it I therefore convenient to rom this me u heino that which 13 ·16 GENETICS IN RELATION TO CLINICAL MEDICIKE cause which ytelds thic character If a gene has a discernible effect on several character its aid to be plolotropic When this is the as the name given to the gene is derived from its most striking effect. Any gene can undergo mktation spontacou alteration of its internal organpation which s reflected in a corresponding alteration in the character which it evokes Through mutation * new heritable variation comes into being The unutsted pesse prelda normality the Ame gee, mutated affects the uame developmental process of the une bave or organ but yields a different end result, something different, u vratton 1 devidon frorn normality a defect. The unmatuted and the mutated forms of thr rame gene arc for convenience akt spoken of u allelomorphs or alleles (different forms or states of the come gene) Mutation can occur at any time when the gene is producing copy of itself (the formation of the chromadde) It aan take place therefore during ordinary somatic cell dirbton-somath mutanon--and it can occur during gametogenealogowanie mutation. Each gene bas its own mutation frequency and the rate of spontaneous mutation ranges through a wide variety of anmals and plants from about i in every 50 000 to around 1 in 110,000 life-cycles The mutation rate can be greatly Increued by the use of Xsar and other high-energy radiation ultraviolet light certain charlal substances such a gustard FU and to a lesser degree by mblethal temperaturen in the aux of X-rays the increase is proportional to the douage u meanred by contation but is independent of the wavelength and of the intensity of the radiation There is no threbold of lonluation below whuch no mutaboru are produced Knowng the spontaneots mutation rate therefore i poulble to calculate the antyount of ionintios necessary to produce it It hu been suggested that cosmic radiation and naturally occurring nadioactivity may perhaps produce that amount of fonination which is necessary There is considerable dureeiDent concerning this matter For the present the arute of spontancou mutation remains un nom. To i chemat it kould not be surpriang to find that different internal organi tiory dlherent spatial arrangement of elements were asociated with different mutation frequencies Some would be in virtud of their organisations more stable than others Pahape this ·THL THEORY OF THE CENE 17 Is the explanation of some of the differences between the nata of spontancow mutation of different gena Random temper ture osallations within the nucleus may be another poedble ause of thu mutability The fact that outation can and does occur in both dlrection normaal allelo to mutant allele and mutant allele back to normal ulele show that mutation doa not involve a low of reno material Each gene it has been stated hw its own particular locus in a particular chromosome. By thua 1 maant that in thla particular locw one or other allclomorphic form of a particolar gere to be found. At a particular level, or point in their length, of a pair of homologous chromosorna there is a pur of loci in which the palr of genes for this or that particular chancter reuide. The two lod may be occupied by the sun allelotnarphic form. The individual l then said to bo komo syrous in respect of the particuler ulleke gerie, in question. On the other hand, there an be different allela in the two lod. The individual is then ald to be laterary rows (having two diximilar alleles). The states of homorypoalty and hetero wyponty result from the fact that two indivduals are involved m the production of tygotes, that in the genotypes of these Individuals there are many thowands of gene pain conting of Imilar or dlumllar mates and that in respect of many genas these parent aan differ one from the other The mutated gene may be a dominant or a roustor in relation to the allelo from which it arome. If It is a genetic dominant the chincter based upoa It will appear in tho neet generation If it ba gametoc recenive it will remain un suspected and unemprened until it happers that two individual uch beterosygous is sospect of it, bute and reproduce. Then and only then does it become powelble for the honorygous receive to appear and the indivdua cxhibitlog « roceive chincter must be homosypom in respect of the game lo question Recentre characters therefore the woully displayed ITETNI wypotic generation after the mutation hus occurred. In the ax of . dominant somatic mutation all the which ure denved from the cell which first received the mutated gene Il powers It and the character based upon the gene will be expressed If there to happen to be involved in the formation of the appropriate organ Menifestly a mutant gene affecting B ·16 GENETICS IN RELATION TO CLINICAL MEDICINE the colour of the eye will have no affect if it # 2 romatic mutation and has occurred in a cell which, roultrplying foros the two of the foot. Aromatic mutation an geld motalc or chimena. Heterochromia indis would seem to be an example of Inosalciom with a patch of a dominant character on a recoutre buclaround or viot veru. The gonade themselvo can be affected by 1 somatic mutation so that the genotypic constitution of their elaborated product the gardetesan be different from that of the bulk of the roma of the individual that produced them. The parent would be a monic, the greater part of his body being bult of cells in the nuclei of which there is the unmutated gene whilst in the nucles of the cells of the rest and of the goodic there there would be the mutated gene. The genotype is the genetical basis of the characterbabon of the individual The phonotype of the individual the son of ita chancer, ba the expresalon of this genotype this presion being suppressed, encounged modified by vano agences within the environment of the ling individual. The action of a gene an be affected not only by environmental agencies but by that of other genea in the unde genotype. Thin in duferent individuals with different genotype the character based upon the gee in question can vary in the snode or degree of its exprehlon To demonstrate the reasonableness of all these staternents by reference to illustrations of organic inheritance in manis not without difficulty The human subject o by no meani atisfactory experimental material from the point of view of the geneticist. He cannot be kept in a age or restruned by wire-netting his roate is not to be chosen for him he nature slowly and produces few offspring hla cbromosomes ut numerous and his mutation rate cannot be speeded up deliberatdy by the use of X-rayu So that for genetical studies of on methods other than those employed in the case of the urual laboratory animal material must be adopted Studios of pedigrees the comparison of the phenotypes of dental twins, the study of the effect of parental connnguinity upon the Inddence of particular characters among the offspring and the application of sophistiated statistial techniques to date produced by the occurrece of wwual and aboorma carcas in large population bave ku added considerably to our ·THE WENDELIAN LAWS OF ORGANIC INHERITANCE 19 Lowledge, and against the background of geen genetia und of the spedal genetid of other forma enough of human genetica bas already known for its value in application to be used It a but natural that our knowledge of the genetia of growly abnormal conditions should ciceed that concerning normally They re more emily described identified and traced Because of their ugliness and of tbeir affects opon vubility and functional efficiency they attract attention. But If abnormality binberited so abo la normality tf ugline 20 ako ba beauty und the mechanıma the Hume in both and THE MODELIAN LAWS OF ORGANIC IXHELTANCE At this point it is deainable and necessary to refer briefly to the personality and to the work of Johann Gregor Mendel (1821-84), for if we me for Into the nature of organic inhentunce u because we stand on his shoulden Mendel nu a member of the Augustinlan Moautary of St Thomas at Bro in Moravia. During some dght yeun he carried out experimental breeding work with the edible per (Ann sano) in the mooutery garden. In 1865 hle famous paper Experiments on Plant Hybddo Fus publlahed in the proceedings of the local Natural History Society where it lay unnoticed until 1900 when it rus brought to the Dotice of the brological world by three men independently de Vna (Holland), Trcbermak (Awtrla) and Corrent (Germany) Mendd wus by no means the first to find himself Interested in the problem of hybridization. He differed from his predeceron In that he did not think of the individual u the unit to be studied but of the nun detalls of structure wbuch in thetr combination make up tho indindul. He did not attempt to hybridisc representatives of different spece but made tue of the reveal varieties of once and the uume enly grown cultinted plant. He was able to construct a lot of contrusted chancton eg tall stem and short stem, that were to be foand in the different noriete and designed experimenta whereby he might hope to determine what for crample, the stern length character of the hybeld would be when one parent mu tall and the other short and thereafter to find out what happened in respect of these characters when there hybride in their ton produced another generation. Out of thu copennentation two “lam emerged.

·GENETICS IN RELATION TO CLINICAL MEDICINE MEDIL S FIRST LAR THE LAT OT SZOREGATION Thos uutes that chancen are controlled by pans of factors the menben of wluch reparate bregate from one another dunog the forestion of the gate cells and purs into different gameta The pairs of factors are restored at fertilisation which allow of their recombination in definite proportions The churactent controlled by these factors may abo segregate appearing in nubsequent generations with definite numrenal frequencies. The fort Wybord generation (F) derived from a cons of true breeding parents is uniform. in the second hybrid generation (F2) segregation of charactan occur in definite numerical proportion. Mende aplanation of the results be obtained postulated the crutence of corpuscular entitia the hereditary factory prevent in the tygote in paus but in the gamete only dngly In gametogenesu these factor paus regregated one and only one parang into each gamete To the new tygote ach guarte contributed one member of each factorial pair Nothing is simple or more reasonable than to translate these postulatas into the obscrved facts of cytology If the chromosome themselves are the factors of Mendel the genes us we now call them, or if they are the vehicles of the genes their behavour in mesosha futile all the requrements of Mendel, first law MENDEL S SECOND LAW THE LAW OF THE INDEPENDENT ASSORTMENT OF CHARACTERS If several pun of contrusted curracters enter into thy ime arou thene segregate Independently of each other The fur lax bs still undisturbed. It has been shown to be univerully valid. This not w in the case of the second It still holda good for character wbote genot tre raldent In diferent chromosoma As for genes reddent in one and the une chrotxoome the phenomenon of linkere the tendency for gone to be transmitted in blochan-diorupto this Independent portment of chucten The relation of chronosorbe distribution in mitosis and myclost to the distribution of inberited characten had not been revealed in Mendel, time He thought not of gends in ·HENDEL'S SECOND LAW INDEPENDENT ASSORTLIENT 11 chromosornas but of factors in the germ plamn. In the following Illustrators of Madeleinbarttance it will be cartaient to combine both Mendelian and gene explanations * Autosomal Donitor Plants of the cyelids be the condition in which the upper eyebd cannot be elevated so that the palpabral foure is much nanosed to give to the individual the appearice of a sleepy und indolent creature having been addenly rrperbed. This is a serious hindrunce and most detrendng embartiment It can result from injury to the cyeled from paralysis of the third nove or of the branch of thus which supplia tho looster palpebre superiors or of the sympathetic supplying tho knooth mucles of the musculus tersaks swTIC A weighty tumour can drag down the ld. The capio-frondalus muscle is used to compensate for the loss of the led-elevating murcles and the forchand is transverrely winkled In xrere cars thus procedure fails to incorer tho papū and tbe eyeball i rolled down wurde and the head thrown back to compensate for the deflection of the optal ords. When such causes are operating the ptor pt to be illateral. But there are instances of this condition to which there awe are abaent and in which the proata la bilateral. These can be use of bereditury ptos. For thos reson the diagnostidan will include among hu exquiria tho question Does any relative of this individual also offer from ptoain ? Tbc Information be collects enables him to construct a pedigree cg Fig 1 A study of this pedigree show that the patient (11) -the proposthu an affected dater and a brother and two datan who are normal that their mother (II) nus affected und that she married in unrelated normal man (1) und furthermore, that she had an affected brother (II.) unmarried brothers twins (11, and II) and en unaffected sister (11), whilst the first pregunty of her un affected mother (1) had repulted in a mocarriage (112). The grundfather of the propositus (1) had been affected. Tbe marriage of an unaffected unde of the propoultur (II) with in unaffected woman (II) had yielded a group of three silnys (brother and stero) all onaffected So that the condition had been exhibited by some but not by all the related indinduab of three soccepire generations and both males and femala ·GENETICS IN RELATION TO CLINICAL VEDICINE were affected. Every fected indindual had had an affected parent. The offspring of affected X normal included affecteds and normal and normals related to affecteds had produced when mated with normale none but normale. PTOSIS 1 1 , I D ayo .O E THO. 1-Pedigree of Ptoda, autosomal donnant - UM Eocted pele Updected fronke Afacted puel Abeched forlo Identical twtos Abortion . Bu nom Propoulos - Mero lar Copilo bar - Slenge III etc. The contre entor IL34, etc.- Indiktol corporis anthon Genta order of both, atat on the last These are the characteristic features of completely dominert Mendalian inheritance The genetic interpretation of this mode of inheritance is us follon. Hereditary ptoals bu genetke character It s awed by it is the exprentian of the action of a gene the gene for ptosis. This gene n in allele of a ·AN AUTOSOMAL DOMINANT normal gene which, in it action upon the process of development rields normality 20 abuence of aboormality It drome from tho normal gene through mutation. In an individual heterozygow for this mutant genc, banng this in one member of a particular pair of homologous chromosome and it normal Lelo In the same locus in the other the two compete for the matery Which of them shall control the process of development? That which to the stronger () that which comes into action before the other ) Sbould one exert Its action to the total action of the action of the other the one that prevzil ta uid to be dominant, the one that is rupprewed the recensire member of the par For convenience make the chancers themselves ptoab und normality are spoken of u being the dominant and receive members of pair of contrusted characters But in reality to the gene and not the character that dominant or recorre. It has come to be unul to distinguish between two alleles one dominant onc recensire, one mutant the other the unmutated form, in one of acteral way. The capital Initial letter of the name given to the dominant character la often med to designate the dominant gene which in its action has produced it, the corresponding small letter to indicate the recente alleke. P – the mutant dominant gene for ptoms, p = the recessivo Jele for normality or the symbol + or to be more precise +Pan be wred for the unmutated gene und P for the mutant dominant alele. It matters little what system u ured though it is obviously destrable that us much uniformity u ponible should be observed What « important is that the writer and the reader should se a chromosome and a locura und a gone whenever a symbol for that goe u encountered. The tranunsuon of genetic characters from generation to generation u depicted in a pedigree will have but little meaning until in the minds ye the chromosoma are seen dancing and manoeuvrlog paring and parting being torn and toured during meiosk ind mutotu. To the genetice the character but the glow of a trucer indicating the movement of the geno telf. An todividual with hereditary ptoals may be a bomolyrott. This to unlikely doce it is most anceptional for both of tho parents of the individual to have ahibited the condition, Horiyer ume that the individual (male or female) in ·24 GENETICS IN RELATION TO CLINICAL MEDICINE bomozygous. Then the genetic constitution in respect of the gene vould be pp The followog matings are poolble PPX++ homosyrots affected xoormal, PP XP+ bosticuygous affected x beterary got affected, PP X PP buenozygous fected x bornozygou affected. Or the individual with hereditary ptosis may be a heterotypote P+ when the following matings are posible P+x++ heterozygous affected normal, P+XP+ beterouygous offoctod x heterouygou affected, P+XPP beterozygous elected x bomozygous affected. Any of these matings can furnah the parental generation (the first pomial guration of P, in order to distinguish thu frorna grandparental generation, Po and so on) in a breeding experiment The offspring produced by such a P form the Fr the first filial generator those produced by inter-matcd individuals of the Fi produce the F, and no on. Since nether brother and sister nor parents and offspring intermarty in our soclety the sequence P, F, F, or the back crou the mating of an F, individual with one or other of the P, individuals will never appear in a pedigreo (are when Incest u inrored) The modified use of the symbobs in humın genetia la convenient, however Consider the maang P+ # Zygotet Heterosyrou affocted x homozygou Docol. Gametogencat Meodel. Fire Law Segregation Two forthy of puneto from the beterouyguts. Fertilisation Equal members of two pheno P+ + + types, heterozyou affectedy md porrus acquel chance of their appearance. P Uning the Amo tyttem the results of all the other posible matings involving the P gene can be predicted It will be bent however to make use of a pair of purely hypothetical genes A for a dominant character and 1 for the corresponding receivt in order to show that the scheme has universal application and does not refer tolely to prostes. AA hordotypow dorninant, Anheterozygow dorminant, u receivt.

·AN AUTOSOMAL DOMINANT Oleod Facts AAXAA = 100 percent. AA u Xu o per cont. u AAxu - 100 per cent. As AAXAL - 50 per cent An, 50 per cent. A Al xu - 50 per cent. At, so per cent u A XAL - 5 per cent. Also per coat. A 15 per cent u The caplanation of the fucts can be displayed in the following way (1) AA Aa x umetes A A progeny A A AL t gunetou from one purent I A AA A ramota from the other partit J 4 I beterdygow (A2) 11 rocedir (u) It will be noted that mating (1) the Pi of a typial Mendelion monohybrld experiment, an experiment in which the parents difer one from the other in that one u bomorypoia in rospect of the dominant member of pair of Jelas whilst the other bs homorypou ln respect of the recentive member This mating produce an F which, since dommance la commune plete, is remarkable for the uniformity of ita phenotype. This uniformity rests on the fact that all the individual bart the very name genotype (Aa) and here not como to diffes Among ·GENETICS IN RELATION TO CLINICAL MEDICINE I 1. themselves through the action of any other genes in their respective genotypes ar u the result of difference in cxponenc. Mating (1) In the typial Mendelian back-croor the mating of a heterozygote with the recenivo parental farm. It will be noted that segregation is more likely to be recognized among the progeny of a back-cross than amoog the F, produced by the mating of two F, individuals (se meting 3). The chunces of a recessive appearing in u F, oro im In the progeny of 1 back-cross they ure i in a Mating (3) 1 in Mendelian terms, the meting of two F, individuals to produce an F, consisting Ideally of the different phenotypes and genotypes in the proportion I AA, 2 A. Consequent upon the regregion of the genes (ooc member of ach pair into each gamete) there is megregation of the corresponding characters. The 3 i ratio of dominantı and receulve in the F, is due to the fact that the dominant gene, whether in the single dake or in the double ylelda tho dominant character The following points will be noted – Number of types of guetes in the gemetic series produced by anch of the parent - 2 Number of pooblo combinations of these gameto - 4 (4 compartments in the checker board, thereforo) Number of different phenotypes among the progeny - 2 (1 displaying the dominant, i duplaying the recensivo chancter) Number of different genotypo among the progeny - 3 (AA, A., u) It will have been noted that the wodation within the genotype of a beterozygote of dominant and receive alleles lends according to the theory to no kind of mutual con tamination The alleles leave the heterozygote fost u purt u they catered. There is blending of characten us will be shown but this to due, not to gene impurity conscquent upoo unoastioniugenotype, but to the incompletenem of dominance. It is seen that in a core of this kind in which thert u dominance and receivench and in which dorninace complete the iodindul exhibiting the recente character must be bomorygous for the recessive ele A phenotypially normal individual cannot be beterorygous for the gene for ·AN AUTOSOVAL RECESSIVE of this rene ptou aumot be a curie An muffected Individual in a pedigree of dominant abnormal charcter u In fact normal On the other hand in individual exhibiting a dominant chancter most carry the gene for it but may be homo- or heterotypous in respect of thus genc. It will be shown later thut dominance is pot an amendal feature of the Mendellan sberne. When complete bowever It a most useful phenomenon for the reuson that the track of the genre an be asily followed by the distribution of the character Within a grven pedigree a dominant abnormalty an be traced with the Ame care in the vertial direction o in the horizontal that u to ry the parents or chūdren of an affocted individual have the ame chance of being affected u have the ab. If a dominant geno bo videpread among the population an appreciable number of A4, bomorygow dowloants, will be mailable for mating AA Xu, AAXA. ΑΑΧΛΑ. But if a dominant gene b raro in population then it * mahly to be found in the heterozygow pale. Most fuffcren will be Ar and not AA Mating of rure dominants kro therefore ansout lanırlably of the AeXu typs, heteropow affected Xnormal. This win tho caso of the majority of the growly pathological character. In mort jostmooit ta not known therefore whether to fact two doncs of the gerie pould yield a greater degree of deviation from the normal than doen ono dose, and in human genetias the term dornin ot tured to signify nothing more than that the gene in question manfaat Itrelf in the beterozygous condition An Awtarmal Roasta Mutution can yield an allele that u recomano to the unmututed of previowaty Odsting gee from wb ch tt spring Allplaneta ba conditon in which, oving to the abecoce of a particular enrying, the affected lodindual excretes in the urido hornogratilac sad i derintive of aromatic untoondds poch u tyronin and phenylalanine. Honxogenthaic zad gives a dark brown colour to the orixe, teade to produce arthritis and blackening of the bona and cartilage Alkaptonuria reocuir character the expression of a gene that I recentre to the normal allele. It follow that the individual exhibiting this character mu bo bomoryfou (u), which means that thl gene must have been received by the propadtus from both ·28 GENETICS IN RELATION TO CLINICAL MEDICINE of the parents who could have been us or ta in genotyp. constitution, either exhibetlng the chancter or else arrying the gene in the heterozygous state it action bang suppressed by that of the dominant normal allele. Since the most wul mating will be that between two phenotypically normal but genetically heterozygous people since most marriage yield but few offspring and since the chances that a child with allaptonunu will appear are only i in 4 it is not murprising that I receive churacter such u this should slap a generation, should in fact commonly provide no ruggestion that it is inhented at all Only rarely aan one secure suffiaent information out of which to construct pedigree that includes three successive generations and so it is that an affected Individual aan have none but unaffected relatives (either homo- or heterozygous for the normal allele) No technique hus yet been evolved for the identification of the arter of this recentive gene (1) mo that ++ und ta indivduals are phenotypically indistinguishable. Consider the following pedigree ALKAPTONURIA X 111 Fro 3-Pedau of Alaptonurins, an toracal recor Uonfected into the porceber card of me interes ta por u the pedige coaced Chce ·AN AUTOSOVAL RECESSTVE 29 The propositius (111) & decorered to have one affected elder alster (III) and two brothers and 1 we unaffected Both parents and their jibs und all four grandparents are phenotypically normal. It is quite lmponsible from the single pedigree to reach my conclusion concerning the powdble genetic bas of lapton. The affected brother and deter (III, and III) could be suffering from the same condition not because they had shared a common partntage, but because they had been exposed to the action of the same non-genetic cnvtronmental disease provolong factor One feature of this pedigree would be noticed, borrever The dostribution of the condition is horizontal It b characteristic of a receive chancter to sbow preferential horizontal dutribution. The chance of being affected is much higher for the albe of an Ufected individual than it is for the parents or for the offspring of this individual. That this is not due to the prevalence of the Aa X An maung mince the u genotype is an aduction from an ancestry in whicb tho As is to be found and the Ae genotype yields phenotypial normality The diagnosilcian when confronted with a recesivt gene of the land must perforce turn to the literature, in which Information has been dutuled fron pooled pedigree involving tho Ame gene. But even that can be unestisfactory unco wually only pedigrees including kenal affected individuals are recorded Yet there must be many another full of beterorygotes and with but ono o no affected individual. There are not recorded and so fabe imprendons are readily guned He will learn that receive gene can be handed down through many generations amoupected and unexpreweed and that only when by chance two tradividuals auch heterorygows In respect of it, mate and reproduce is the necessarily homorygow exhibitor of the character likely to appear The vast majority of affected individual are the odspring of parent wo ere phenotypically corrmal but who are in fact heterozygou. There is a familial Incidence more than one Indmdual i esbahip being affected and the abibition of the character o significantly more common among the odspring of consanguinous marriage. The pheno typically normal obe or children of an affected person an be heterozygotes. Finally the odspring of affected xbomorygow sormal are innriably phenotypically normal those of affected x

·yo GENETICS IN RELATION TO CLINICAL VEDICINE
affected invariably affected. Here is a pedigree which includes
1 corenguous marriage
ALRAPTONURIA
I
11
5
IV
1
The 4-Pedigre of Abertoord, ebowting coomboy
0 - Heterosypoos
A Ø. Died to tnfancy
Here yg in there is the horizontal distribution and the high
Incidence among the vibe of the propontia. The parents of the
uffecteds were the children of two full brother The chancos
that both of the parents arry the name recenire gone ore
Increased when they themselves have received part of thes
genotypes from a cominon source, Thus if among the parenti
of individuals exhibiting e particular aboormality there is a
higher percentage of continguinous merruges than in the
population at large the possibility that the abnormality ba

·A DIHYBRID MATING 31 genetic recount is considerably increased. Groting that alkaptonunu in this pedigree u agenctie recetiro character then the parent (111) and (III) must be heterozygote The grandparent (112) and (II) must also have been heterozygotos There la no reason to suggest that their wives (112) und (II.) were otherwise than normal. But one of the great-grandparents (1) or (1) must have been carrier of the gene (IV) and (IV) can be either genetically normal ar elec beterozygous for the gene for allaptonun. So I IH itt (ar 1++ it) II 3++ IH ta 4++ III Ita + IV I++ 3++ 6 orto ate Through a long period of time and with the accumulation of many pedigree it is certain that ultimately records of the following madoga and approximations to the following rution will be obtained to prove beyond all reasonable doubt that u condition ruch us thus in fact « genetic receive In 1 constellation of varieties of environmental conditions and creumatances the one constant element u the genotypo of those who ahibit the condition. A storeboue of pedigrea la an entential requrement in dinical medicine. X 00 per cent affected (w) Affected focted + affected x Lected per cent. onaffected but boteroro (+2) bat batero 50 per cent afected (da) Tyrou. te 75 per cotomaffected (15 por cent. ++ ood Lected uncted so per cent (+) but botero bat bataro 5 per cent afected (2) Tyron Tyroa. A Mondshar Dekybrid Mendel . second law which states that when two or more factor (one) pain segregate rumultaneously the distribution of any one of them b Independent of the distribution of the othes an be instrated by the use of two other genetic curucten, syndactyly a condition in which most cormonly the third and fourth fingen ud toes are webbed or de moro ar les completely fused, and allodisn, the condition to which - -

·GENETICS IN RELATION TO CLINICAL MEDICINE
there is complete or almost complete absence of pigment in
the kan hair ind yes The following pedigrees show that
yadactyly is a dominant and albinigna a receive dancter
SYNPACTYLY
1
2
101
11
TIC S-Pedigree of Syedactyly outoral dominant
ALBINISM
I
먼
ITT
TV 2
to 6-Podgree of Albania, Dalmat

·A DIHYBRID MATING 1 Suppove that a child exhibiting these two chances como to the rodce of the physician who happens to know that syndactyly has been reported to be a domainant Mendellen chander and that albinism is acknowledged to be a receatve Being interested be will at once expect to find that imong the sibo of the patient there will be some that are syndicylow that one of the parents exhibits the condition and that in mo far as the albinbi concerned It will probably be found that in the pedigree to be constructed consanguinous manage will fail to be recorded. He will mume from the start that the patient is most likely to be the result of the mating of two individuals ach beterorygow for the gene for albintain and that one of those wu beterozygous also for the gene for syndactyly The genotypes of these parents an be represented 10 - to X to 6 +S +S +S с с Two pair of homologoun chromosome are involved-ach borisontal line represents such a pair The gerne content of the members of the patr is shown above and below the line It would be confuong to use the sign + to represent both of tho normal alleles of the two geno pain. To the + is therefore added the initial letter of tho chincter . apatal S(+5) In the care of the normal allele of the gene for ayodactyly rinco the mutant allele is the dominant member of the pair I onul c (+c) for the dominant normal allele of the gene for albtamin (- lack of colour) Alternatirely the genotypes can be shown as Se CcXn Ca For the sake of convenienco It propoeed to make use of this syatem, but again it is to bo emphucd that the student should wo train himself that when be see a letter be seen chromosome and when he see! chromorone hered a locus the gene in it. But for the purpose of malding the Maddian argumentos dar u pomelble it will be best to start with a grandparental genonton and to nuggest that there grandparente o SS CC and . o respectively bordorygon syodactylow Indindual (who would, in sality probably be non viable) and in borsa. It ratten not which i chibited which character с ·44 GENETICS IN RELATION TO CLINICAL MEDICINE P1 Normal digius albanodic Hamorygow syndacty lous Dormally pig mented SS CC D C A dihybrid buting m molring i palny of gena Guctos SC 1C F1 Ss Cc Syndactylow (heterozygous) Normally pigmented (heterozygow) Umformity of F the double beterosygote The gamedic verla produced by ruch an individual according to the second la of Mendel will bo C 6C svojo Sc VERY C 531 مرل In the pro- The distribution of the Sands patr of chromosomes (genes) la quite unmfluenced by that of the Cc patr duction of an F, two ach gumetic series will be concerned und these meeting will yield the following genotypes and phenotypes Spermatomo Sc Ort SC IC 1 SC SS CC 1 SS Cc J As CC clis Ss Cc 6 7 & Sc SS Cc SS cc S. Cc Ss cc C 9 SCC Si Cc NCC IS A Cc 14 13 Si Cc 15 o Cc 16 Acc ·LIENDEL'S SECOND LAV INDEPENDENT ASSORTWENT 35 Individuals chibiting the two dominant nynductyły und normal pigmentation Homayou for both S modC Square I Homorygow for 8 heterozygous for C Heterosy row for S homocyou for C 3,9 Heterozygou for both S und C +7 O, 13 9 Indivduals exhibiting one dominant and ane recensire, syndactyly and albinin Hanasgow for 8 Squere 6 Hetorozygous for S 8,14 3 Individuals exhibiting the other domloant and the other recewive, normal digits and normal pigmentation -- Homozygous for C Squero II Heterocygow for C 15 3 Ladividual exhibiting the two recesives Dormal digits and atheism Necemarily borporygown for both s and c Square 6 1 The 9. 3 3 I ntio to the mathematial combination of two 3 I rutron (35+12)x(3C+IC) SSC 3SC, CI * It ha ven that there is no tendency for the parental combinations of character to be preserved in the offspring nor for the two dominant and the two recesire to segregate together The reason for this is, of course, that at meronis the members of tho syndactyly and bino pain of homologous chromo Ordo spanate ooc from the other into different gameta at random in the sense that there is no tendency for the paternally a maternally derived clement of each par to per into the Aame ruote together Consequently the chances that the Sai chromosome becoma trclude la = pamete with the Carc chromosome are equal It prill be noted that in auch an F only one Individual in every sixteen an be apected to chibut the two receive characters in combination ·GENETICS IN RELATION TO CLINICAL HEDICINE The t{hybrid natio arising from a mating in which both parents who heterorygoro in respect of three pain of allelomorpha cod with dormancr lads to a combination of three 3 i ration independently yielding a ntio of 27 9,69 3 3 3 I (34+11) X(3B+1b)x(3C+10) Other natio have been obtained by computation und by aperimentation. tul X We kr ho p BE 2 But there are matter which, although of great interat eod practal aportance to the geneticket and to the creator of new vaneties of animals and plants cannot claim a value in clinial medicine Mendel . second law can more easily be Lustrated by the use of a back-cron of an Ss Cc Individual to n double recensive, bo X 84 Cc The double The double racerdo beteraryroto Donnal digits Syodactylow Lihootic Normally plgınented Gametas Ganctos Progeny SC St Cc Syodactylow Normally pigmented BCC S cc Syodactyloon Ripotic Cc CC normal het Normally pigmented pompa digits Anotk This moating yielde equal nusnbens (or pel choncus) of the two dominant one dominant, op rocesire the other dominant, the other recapire and the two recentivo The mating that we nuerested us the most probable origin of the ·VENDEL'S SECOND LAW INDEPENDENT ASSORTMENT 17 This would syndactylous albiconic child wu Sa CcXs Ca yield Ss Cexulc SC Sc C SC C gemotic Sc 3 Kerle C C St CC Salc CC IC 5 6 7 Sa Cc Cc IC I 8 Sac CC I Parwas Syndactylow end normally paymented normal digits und Normally pigmented J 47 Dormal digits and albino 8 8yodactylus and abro 6 There is thus I chance in 8 of each parents producing ruch * child CC There is a dimple method of alculating the probability of the appearance of a particular pborotype anong giver progeny The probabilities for the various unit chancter of which the particular phenotype Le bullt up are multiplied one by the other 85 XN Sa so per cat. 50 per cent. Ссхаси CC Со 5 per cent 50 per cent. 5 per coolt. Chance for offspring to be Syodactylows (94) Chance for odprlog to be abtooth (cc) 44 18 The Lawt of gene trenamion are thus wen to be the Law of chance, Chance it is that deada which of two alleles present in the genotype of a beterorypote will cater particular groete. Cherce decides which over will be fertilled by a given spermatogoon An Indtvidal has two gena of ach kind and there may bo albo or different. These were derived from two source, paternal and maternal repec tively To ach offspriog ach of these two parent transmita one, only one, member of each gene pair Segregation in the core of a beterozygote means the provision of equal numbers of the two kila und so there must be an equal likelihood for a child to recare dther of these. So for It hu not been necemary to refer to the son of an individual when dbcting ·38 GENETICS IN RELATION TO CLINICAL MEDICINE its characterisation It has not mattered whether the gene in question hus been recered from male or from female parent or received by kon or daughter the effect of the gene hu always been the same. Morcover the distribution of the members of onc gene puts from parent to offspring has not been affected In any way by the distribution of the members of any other genc par un so far as geng borte on different chromosoma are concerned Finally which member of a given palr of allelas u received by a particular child from its beterozygous parents not in any way affected by the distribution of these Am genas among prepous children born to the same permt. It will be recognised that the operation of Mendes second law provides the opportunity for mutant genes which have cruen independently to be brought together Advantage aan thu be added to advantage if the mutant genes concerned better than those from which they have antren Orun INTERNATIONAL PODIOREL SYNDOLA ure Samknown - Punt pot wanted, claren Illeghtonte Number od unboom - Coorgabecote risp Two children an A won thuria und - Sulon bale child - Freda Diked la boxy KI So I Embed penonaty - Identical tolar Eyubord mot per sally tot by capen pepa -Tot certain detal Various obbols for wb perly lo white mit derrot uncert len to Lorded, aber an de foto u model ·CHAPTER III LOIRAGE Ir the genes ure raident in the chromosome ind if the number of gene pato cuceeds the haploid aomber of the chromosome it follow that Mendel . Recood Law annot man hold. There must be many thousands of genes in the hurman genotype for more than 24, the haploid chromosome number la man, buvo already been recognised. Each chromosome must therefore auty more than one gene. If more than one gene lo rendent in one and the name chromosome thon so long u the chromosome remains Intact the gane group resident in it must trrel together from one generation to the next, must remgin linked to inbentance. Lankage is the tendency for two or more pain of good to umort together instead of obeying Mendel's second law because they are resident in care and the meme chromosome. The number of groups of unbed genes Himlage groups should be the Ame u the beplotd number of chromosome ff all the chromosomes any genes. The number of linkago groupe to man should be 24. Thus postulate has been shown to be correct in all instances in which the spedal genetics of the animal or plant has been raffidently developed. Moreover the relatire dia of the Inkage groups the luted genes to ach correspood roughly to the relativt size of the chromosomas the longer the chromosome the longer the list and the larger the group The facts of cytology strongly reggest that linkage will rarely be complete. The Totence of chlagmata mut surely man that interchange of sections of chromosomo material between chromatid derived from bomologous chromosomes take place during the prophase of the first meiotic dryshon of gemetogenas If this top then blocks of gend out be mutually transferred from one member of a pair of bomologous chromosoda to the other Linkage to disrupted by the runn- tbe Interchange of Inked genes consequent upon a reciprocal trumference of ·GENETICS IN RELATION TO CLINICAL MEDICINE Kections of material between chromatids derved from bomo logous chromosomes. As yet it is imponible to Illustrate at all atfactorily the phenomeu of linkage and coming-over in the autosoma of man. There are many Instances la which because of the behaviour of churracters in Inheritance linlage u strongly swpected, but it has not so far been confirmed. We must wait awhile. Lokage has shown itself to be so very useful un instrument in genetical enquiry that it ia to be hoped that it soon will be recognised in human genetical studies. If two genc are linked and of one corresponds to a deep teated character of considerable interest and importance affecting viability or functional efficiency for example, whilst the other yleldo a superfical character readily recognised but of no great importanco in itself then so long us the geno remain together tbo second chincter can be used as a trucer for the first The presence of the fort could be womed fron the dosplay of the second It la posible fortunately to illustrate these pbenomena by reference to genes roldent in the X-chromosome, but before doing so it is detrable to discum these matten in a general und theoretical way If the genes are raident in the chromo pomes, and of each gene has its own appointed place in the length of a particular chromosome, an individual heterozygow in respect of several of these gena can have a geryotype of the following kund ABCDEFGEIJKLMN palr of autonoma abcdefghTJETTE If it be uumed that two chromatids derired from there chromosoma stick, brak ind reunite with mutual interchange of rubetance at a point between the loci occupied by the genes E and e uod fuod f respectively the reconstructed chromosome will here the following gene content – ABCDEfghijklmn abcdoFGHIJKLIN The interchange hus broken down the spatial relations of the blocks of genes to the left and to the right of the level of croning-over ·CROSSING OVTR 41 Multiple crossing over an occur recombinations talding place dmultaneouly at everal kreds. Double croming-over In the case of the autosome being considered could give tho following result ABCDBfgbIJKLMN abcdoFGHIJETma Avrault of such croming-over combinations of character chibuted by heterozygous parents are broken down and rebuilt into different combinations in the progeny Manifly crowing over between two chromosomes containing identical gene companies (in the completely homozygous individual) would anto no much recombination place what each chromated gave up la interchange it would receive in return If coming-over an occur with oqual eaxe at any level in the length of the chromosome, and if crouring-over at arry one level renders synchronous crowding-over dearby difficult (c'om. ferenc) then it follows that the frequency of crowing-over an be regarded u rough measure of the distance in the length of the chromosome that keparates the two levels involved. There should be a chunacteristic crowing-over frequency or percentage of crowing-over a crossing oor now (COV). between each two level. If Ar Bb und Ce are three linked geno pairs their spatial relationship in the chromosome can ABC bo reprexented u points on = line. If the order to abc then the CO V between A and C abould be the man of the CO V.. between A and B and B und C Thound it means that the genes are atinged in lingur order in th chromosome. For this reason. chromosome map aan be constructed showing the genes in their proper order and the distances spariting themn. The method of map construction bu follo, The rena A and B are known to be realdent in the Hmo chromosome (linkage) The doubly heterotypo Individual . genotype will therefore be AB BA AB Ба ar Thls individual will elaborate four Hnds of gamta, not two ·GENETICS IN RELATION TO CLINICAL MEDICINE not-TOOTA gameta Core punctes А B b b B b в croping-ores and mated with the double recessive (ab) (ab) will yidd the following tygotas (AB)(ab) (ab)(ab): (AbXab) (2BXab) DOD-COT-ovet dana cronorer data The bracket representa a chrotdosane and the letter within the bracket the gene company in the chroponome The majority of the garnetes elaborated by the double heterozygote will be non-cott-over the proportion of crossover ganxeter will be determined by the dostance lo the length of the chromosomes between the levels of A and B Croming over in the case of the double receive will not affect the relationship of u and b and the recetarve characters annot confuse the freue. The relative number of the courover phenotypes among the progeny gives the C.OV If for nample, ach of the non-Tom-over phenotypes amounts to 45 per cent of the total progeny and ach of the Crossover roughly to 5 per cent. then choosing-over occurred in 10 per cent. of Instance in gametogeneals The C.OV 13 10 per cent and the levels of A and B for of course of a and b) are separated one from the other in the length of the chromosome by to units of distance. But i A to the left or to the right of B? This la a question that an only be answered by recouree to a three-point experi ment. A third gene C is shown to belong to the hoc linkage group It u found that the COV betireen A and C in 15 per cent, and beteten B und C 5 per cent Then the order must be с B lo 5 15 And so by obtaining the COV between any other genc of thu linkage group and any two of the genas already mapped the spatial relationship of all an be determined.

·SEX LINKAGE 43 Croang-orer u fected by temperature Xtar ndlur and certain other chanical and physlal igenta. It recms probable that these effect the frequency of chiasmı formation and that the CO V bu mesure not of the distance between two levels but of the frequency of chiama formation between these kereta Homeyer it be convenience to speak of the COV 41 a centre of distance, i per cent indiating that the two levels concerned are separated by one unit of datace. The case with which coming-oper occur diffen between the Kies to many species In certain forms there is no conung over in ane raz, Unkage being complete. But this annot mean that the chromosomno ha no phynaal length it merely means that for reunos u yet unknovo croning-over does In man crossing-over would seem to occur with equal ear in both kids not occur SIX LINLAOB The X und tbc Y chromosome like the automorne ure the relucles of gesle groupe. But ovog to the heterogametic nature of the human male and therefore to a I difference in rospect of the re-chromosomas the transmission of the X and the Y-borne genas differ from that of the genes reundent in the autosoma It l not to be understood that because a gene is resident na ku-chromovome It is therefore necesarily specially or mainly concerned in the production of sus or of the mount character They are called me linked solely because they are realdent in a pair of chromosomes in respect of which the sia differ and which are involved in determina ton. The male ruceiro his Y-chromosome from hus fatber bus X from his motha the female recetves in X from each plant. The cruential difference between the chromosomes ind the autonoma to that the X and the Y do not in their entirety constitute 1 par of homologou chromozoma. Only part of them are homologow being built up of the name geno material. The portions or sections per and between them coming-over But the greater part of the X and the rest of the short Yune noobomologous between there there be no pairing, no Interchange. The genes lo there rectioo remain completely take place ·44 GENETICS IN RELATION TO CLINICAL MEDICINE X-borne or Y boone, the genes of the non-borologova portion of the Y being the peculiar property of the male. Men de Fio. 7 --DX of the modernes, aborty the bordelooos mod do homologous portions Because there are (1) homologoua sections of the X and Y (2) a non homologous section of the Yand (3) a non-homologous rection of tho X there must be three lands of sex linked inberitance. J Tota-linkage Genres resident in the non homologous portion of the X und rostricted to the X. 1 Total sex-linkage. Gena roident in the non homologous portion of the Y and restricted to the Y 3 Portial sel-hinkage Genes resident la the homologous rections of the X und the Y partlal becaux croning over can disrupt linkage TOTAL SEX LINKAGE GENES RESIDENT IN THE NON MOVOLOCOUS PORTION OF THE X Red-green blindnem, the inability to recognise these coloun, IS I I-linked recenstve character the gene for which is rendent In the non-pairing regrnent of the Y-chromosome. It is to be found in note 4 per cent. of males and o 4 per cent of females of our population. Since most red and green colour med la dgoals and ruch like art not monochromatic the condition not regarded us i rrow disability to prost occupations. Scores of red-giten blind Individuals remain completely unawart of their pecullanty Since the gene i X borne and cannot be thered through arotsing-over to. Y und since it is a receive, the heterotygote aan bo none but female. A male an either burt this genc on his X when he will be red-green blind or ebe he an bave the normal allele on his , when he writt be normal dghted There b no locus for these popa In his Y ·1 green SEX LINKAGE 45 The follomng matings can occur Doameld aurier ? A phenotyptoully (RDY Х (RX)(rX) A phenotypically normal male with norm fomelo tho normal bat heteroty allcla gous for the gemeta (RX) ( RO) (r2 gene for red blind. DC 8 (R Y Square 1 Phenotypically and geno typically darom (RX CRX RX) (RX)Y Square 3 Phenotypically md geno typically poonal 3 Square 3. Phenotypically pocul 4 XXX) (XOY but heterozygous for the red-green Windach Squard 4 Affected : Expected, rutto of normals to affecteds 3r Equal number of do and , of sooral and curder 98 of normal and ectod 88 According to the scheme the child, to be a male muut receive ho Y-chromosome from his father From hb mother be receives his single X. The mother has two Ends of Y Should the son record the one canying the receive allele he will be fected. normal 3 affected (RV) (Y) (Y) gear (RX) ( X) (RX) ( X) (X) Y anda? uffocted & phenotypically doma Expected, equal mumber of parmak od doctode Eqou nombers of :: od 99, the formal affected, the latter all auder Male ospelog mot be affected since the foother an offer only and kind of X the one with the recenive gene. Note ·46 GENETICS IN RELATION TO CLINICAL MEDICINE that in this pedigree the sons take after their mother and the daughters take after their father Thos to an instinct of trus-Toss wherten It to keen that in dealing with sex linked genes it is necessary to state the rai of the individual u well as the character the individual display. uffcctado normal o (X) Y X (RY) (RX) (r) (RX) (RX) (rX) (RX) Y auder Darmola phenotypically normal Expected, al normal, but daughters are cupen Equal numbers of 85 od 8 Sons must be normal for the reason that the mother an offer only one kind of that with the normal allele Daughters must be carriers because the X they receive from their father arries the recensive geac, 4 affocted ama ( XY Х (RX)( X) 1 (RO (RXXIV) (TX) (RX) (9) (X7 Y Squarc i Camer 9 phenotypically portal (RX)Y Square : Normal 1 Affected 4. Affected (X) (rX(X) (XY Expected Equal umbers of pormals and affecteds. Equal numbers of 88 and go of aner und affected 99 and af pormal and effected 88 The motha bus tro land of tberedare there will be two Erode of oni The father's X arries the recente therefore there will be two kinds of dangutans, affecteds and aurrer.

·SEX LINKAGE 47 uratida actod ? (rX) (X) x (Y) (rX) (X)() (rX) Y fected affected Expected, all ufoctode Eqml xtmbers of 8 and Certain characteristic features of total per linloed inheritance are presented in these results Redprocal matings yield different results (matings 2 and 3). Segregation can deffer between the cores (mating 2) Segregation among malas 15 determined solely by the genotype of the mother independent of that of the futher A male abowing the dominant character und fernale with the corresponding recendre produce cons showing the receive and daughten with the dominant- Tw-crou inheritance-muting 2) A mile with the recepit character and female with the corresponding dominant in the honorygous condition produce affapring all with the dominant, but all the daughters aro heterozygotes (mating 3) An affected male transmit the come to all his daughters but to none of his sons A auer female transmit it-the gene to half of ber kon and to half of ber daughters when rated with a normal male (mating 1) and to balf of her more and to all of her daughters when married to an affected mal (mating 4) An Uffected femal truntomt it to aber offspring regardless of the persotype of her buband (matlag 3 and 5) Fig & abome a pedigree of red green blindnen. I must have been carrier once there are diected fanalas in II II, belog affected is necewally homorypote. 11 Lod II, are curren III, Lartier One form of hemophila furnlabes another cample of . character based upon i receptve gene resident in the non palning soment of the Y-chromosom. As long ago us 1803 Dr J hin Otto of Philadelphe had mrcorded of humophilla ·48 GENETICS IN RELATION TO CLINICAL MEDICINE that mulas only are affected and all are not llable to it Though femela we free they are apable of transmitting it to their children. Io mode of inheritance to czactly similar to that of red-green colour blindness but it is a much more KTHOU1 condition. The affected indindual bleeds profusely from the alightest cut the eruption of teeth become a dangerous adrenture and minor operations such as tooth extraction or tonsilectomy are attended with dread since clotting bs greatly retarded Slight contulop an give rise to store bruling and extensive subcutaneous abortbage. Effulons of blood into sound an incapacitate. The life expectancy of ruch RED-GREEN BLINDNESS LI 1 III 30 Fro. I-Pedig ked three bilodden totally ka Loked recent deterotoed by one in the more homologarent other individuals u graatly reduced On the arenage hemophilia produce only about a quarter u many children us do normal. AL ted males are wually remored by death before the age of twenty five. They beget but few offspring therefore. For this reuon alone female hemophillao must be rare since to be a bomophthac a female must have had a hemophilic for a father In pooled pedigree of haemophilia tbere b a significant deficiency of femalo and it would seem that the homozygous female commonly dies # xter It is of particular interest to note that in the Talmud anction b giren for the ombulon of the ntual of circumcision in the are of sons of worden regarded us being likely to produce homophilic offspring ·SEX LINKAGE It is the marriage of a normal mute with u arrler female that provida the overwhelming majority of hemophillea tot huden comuninity parmelo (HXY Х (HX h. ( HO (HX) (h ) d (HX) Y 1 (HX) (AX)(HX (HX)Y 4 (11) Axh)(x)Y Squrer Phenotypically and gamo typically normal Square : Phenotypically and geno typically Damas Square 3. Phenotypochly normal but boterorygow for the bomo phthe gene Square 4 Affectado Rano of damals to affecteds 3: Equal ntabel af & and PR, of normal and avotu PR and of normal and acted 88 It is important to note that in respect of the gene thero are three bads of fenila, normals, carriers and affected, and only two kinds of males normaba and afected The danger COIDA from the aurier in our midst. A fostalo s certainly 1 arrier if her father wu efected. A female i crtainly a carrier If she belong to a hemophilic family and produce in affected on if she produce no more it is impoelble to say that according to the genetic evidence the be carrier It now rems to be possible by the ite of techniques recently developed, to detect the heterorygow female by channcteristic mugulation time of her blood. If the frequency of hemophilhc males uong the male population is and the frequency of normal male bowhere (+)-I then with rhodom mating the frequency of bemophilus an und normal among the female population is an Queco Victoria wus heterorygow for the bemophilic gene. The mutation gtving nike to this gene wald appear to burve occurred during spermatogenesis in her father the Duke of kont Among her descendants there have been one hacmophic mon, at least three bemophilic grandma and ax hepsophilic D ·50 GENETICS IN RELATION TO CLINICAL MEDICINE great-grandions Edward VII m normal and since Aether he oor hos descendants married into families with a bistory of hemophilia the House of Windsor is free from this wex linked HEHOPHILIA I п. 5 ILI TO 9.Petter Hemophilie totally is linked tocentes, deteanlod bong for a thi co borrokgou poot of the IL aunier II ponudby pardal, her children are too few to make it certain that bo ho. U arrier 1 receive gene. The Taarevitch Alexis rus hemophiliac and it is because of this that the monk Rasputin came to occupy so prominent a position in Rusian court drcia. It w comed that he could control the process of coagulation pertapa by hypnod. The heir apparent to the throne of Spain is a hemophiliac and his mother . descendant of Queen Victoria, la carrier Thore genetical facta bere undoubtedly played the part in determining the destinos of monarchia since illness of the kind bro easily interpreted us the curse of a deity A dominant sex-linked gene X-borne in the non-pairing segonent, rlelds a character that is commoner in the female than in the male for the reason that sbe hus tiro X-chromosorbet to the male sonc and has therefore a much greater opportunity for receiving the gene from one or other of her parents Tho male gets his single X from one parent, his mother Dominant ka linked inheritance, lite dominant autosomal inheritance, Linbaltuace from one partat All affected bare an affected ·SEX LVLAGE ST parent (In pedigree that artial dutribution will extend up to the point at which the mutation occurred) The character is exhibited by approximately half the offspring of an ofected person. This dominant a linked inhaitance is to be db tngushed from dominant autosomal transmission by the fact that in the former fetted mala mated to unafected formula have only affected daughter and normal 1003 (AXIY X(2XXX) - (AX)(2X) (EXTY whilst to the latter all the odspring terpective of their sex, are affected (AAXUA) or if the father is a bete orygute, equal numbers of utesteds and waffecteds frrespective of sex (A. Xu - As ) Congenital absence of the indsor teeth would semn to be poch a dominant a-linked character Defective anard of the teeth would appear to be another CONGENITAL ABSENCE OF INCISORS 1 1 III 1 Ya. 10-P o Congol Abed the lechon totally abled dott, detrabby on the box below the X This pedigree by itself is not pufficient to prove that tho condition by linked document. I, ud I, did not produco Though children to bow that the mala of II were inrurlably normal whilst the femala were innnably affected There were only two individual one I make and the other a female. But ·52 GENETICS IN RELATION TO CLINICAL MEDICINE If this pedigrec i pooled with other of the same band then it gumas an importance for the reason that the evidence It provides supports the contention that congenital absence of incrors can, m certain instances, be aused by a dominant sex-linked gene. It is of Interest to compare this pedigree with certain of the matings that were considered in the case of the recesivo Key linked chincter red-green colour blindness Sar-linked Dominent (I-bane, Doa-putring regment) affected a Docmal (IX) Y (1X) (ix) (1X) (IX) (2X) offoctod ! (1X) Y nomul s Sex linked Roceso (X bors, Doo-palding regmant) affected s normal (TX) Y (RX) (RX) (TX) (RX) (RY)(rX) ardero (RX) Y normal o Lo the axe of red-green blindness crins-cros inberitance wus encountered in the mating of a normal malo (RX)Y with en ffected female (rXXXrX). Among the progeny tons vert fected like ther mother and daughters (phenotyprally) ·SEX LINKAGE 33 normal like their father In the car of the domnant Inked chander congenital abrence of Incison, the muting affected male (LX)YX Dormal female (Xix) gave clocross Inheritance of a different Wod for father and daughter were uffected and mother and son normal The mating normal male (IX)Y and offected (hetero ygom) female, (IX)IX) yidds resalts that are Indistroguish able from that of the back o. of an ordinary uutosomal heterorypous dominant, ptoes (Pp) for emple, to the receive parental farm (pp) Sex Inked Dominant affected $ (hetero you) (XY (LXX) х (1) (L) OX) (X) Y 1 (1XXIX) (IXY Square 1 Heterosyrow affected R. . Affected 8 Normal 4. Normuo Equal numbers of male and female, Equal trumber of pocul und wirectode 4 (LXXX (LXY Aatosomal Dominant Pp X PP Рp PP darninrat TOUT Equal pumber of the two phenotypes and equal tomber of 88 und 98 Gena rezident in the neo-bomologous part of the X chromosome ve lpled with one another Strice the female ·54 GENETICS IN RELATION TO CLINICAL MEDICINE han two such portions, one in each X crowing-over between the two portions is posible. Such condng-over annot take place in the male who has only ono such section of the X A female who ho doubly heterorygow in respect of the genes for red-green colour blindnes ud for hemophilia therefore abould provide the opportunity for the study of linkage and crossing over Ha genotype can be represented 10 th tr ar T th I +r (Hr)(RX or (HRX)(br) that is to say the tro mutant genes aan bo together in ono X und the two normal lelas in the other or there an be ane mutant gene had one normal allde in each of the Ys If the two mutant gene are in the same chromosome they show the tendency to remain together in transminion (the phenomenon known u coupling) If they are in separate chromosomes they show e tendency to retain apart (the phenomenon of ropulson) The two kinds of distribution of these four genes among the two chromosomo yield different results (A) Normal : +hts х т Xth Y th +r th +r MO +b +r phenotypically normal but b doubly beterozygous th +r th h h T Progerry ## r boda + (B) Normal: ++ +h+ +1 th I phenotypically normal bat h+r doubly beterdaygous th +r +h r h +r h + MO Progeny st PNL Post All thl of course, in the abuence of crowing-over between the Xs of the female This would digurb the spatial relationship ·CROSSING OVER 35 of the pena concerned and so yield different combinations of characters in the male progeny – (0) Croang-over affecting Cue A abort. Normal th +r th tr phenotypluly pormal but h doubly heterozygous th CROCS-over the х I 1 +1 r croatorer gatto th b +r +b +1 Ꮒ +r +h Progeny h +1 +1 75 г +r Brut (D) Cromag-over offecting Care B bort. Narmel th +r th tr phenotypicaly pormal but х h doubly beterdry th 1 +b I 7 tr th r h + + th +b + to h LL 11 The two roccanve gene on the X of the fernale are thus *parted with the rerult that cromoter dasses appear well u non-cron-orers unlong the male progerry The C.O V between the two lod hus been shown to be in the region of about 11 per cent. The two gene therefore lo close together in the length of the chromokome. More than this annot be und until ryeral more rend of this group hare been mapped together with these two The gene for One form of optic atrophy would weon to belong to this group ·56 GENETICS IN RELATION TO CLINICAL MEDICINE TOTAL SQ LINKAGE GENES RESIDENT IN THE NON HOMOLOGOUS SECTION OF THE Y-CHROMOSOne Such genas u tre arried in this non-puring segment of tho Y ure pussed directly from father to som holandric inheri tance). They affect characters that are restricted to the male Webbed too bus been recorded ve gene of this kind. Hero w z pedigree involving this condition. WEBBED TOES 1 II ILI 1 Tra 1 - Pedigree of Webbed Tou, totally rexnked dancer detendered by ob the noo-bopologoas portion of the Y Every mile is affected 2U fomulas are normal. Every male trusmit the abnormality to all his son and to none of his daughter. To follow the character through the genera trons is to trace the Y-chromosome and the gene to its non-pairing #egment. Manifestly ruch a c-linked character bas to be distin puuhed from what is known as a ses limited res influenced or re-controlled character Hypospadlus (the condition in which the urethra u the result of detelopmental imperfection opers on the under surface of the penu Inutead of at the dostal end) b a genetic chancter id gene being an zutosom! dominant The female annot exhibit this character ber unatomy make this imposible. It is therefore restricted to the male. Congenital dislocation of the hip is a genetic character that finds espression more frequently in the female for anatorical reuon. Gene if there be auch in the hann ·HOLANDRIC LNHERITANCE 57 Pubject, Affecting the quatty and quality of milk an find cpreson only in the female. Pattern baldoen arting at the crown and templos lo early manhood cod quickly spreading over tho whole of the top of the bad, ba genetic character Id autosomal gene must find itself It would reem, In a male internal (endocrinologiaal) cartroonent if it is to gain full cepresion. This gone is of interest in that the ki of its power affecting u it does the presson of the character destroy the dominance-receavenca relationship of this gone und it Dormu allele. One gene awa pattern baldoes in the male, two of them are required to produce eren sparrenes ar partial baldner in the fernale. If the male i heterozygous and the woman normal half the son of the marriage will dovelop the character If the malo is homozygou all his rona will do so If the woman is beterozygoto and is married to normal male half her fans will show the character If bo la homosyrote ahe will beve sparse hair and in later life partual baldness and all ber won will develop tbe chander Male and female differ one from the other in respect of hufr churructer but it is difficult to find any reason why the geno for webbed toes should operate only in a mule environment and to judge by the pedigree ita gene must be Y-borne. Sa limitation is restricted to re-dimorphic churchthon by which the kes are to be distingulobed and so is unlikely to be confosed with we linkage Thero ito several genes which find it correr to gain expression in the male rather than in the female internal environment. Multiple crostom (boay outgrowth from the surface of a boce) are found about twice u often in men u Its gene is an autosomul domtnant and affected father produce both afected roos and affected daughter. Ono form of oligophrenia (imbecility) and the Laurence- Moon Biedt syndromo (mental defraency obeuty hypo genitalum polydactyly and retinal degeneration) are both encountered for more frequently to the male than in the famule. Yet both are bused on autosomal recondito gena. in women PAITIAL SA LINKAGE Genes resident in the hormologoun or pairing sequent of the X und Y chromosome can become transferred ·58 GENETICS IN RELATION TO CLINICAL MEDICINE through crossing-over from the X to the Y or out OTSA This being so It follows that these gena will not always remain linked. Moreover rinco any one of these gend an be transferred from the X to the Y or from the Y to the X it can be possued by male and female alike Because of this coming-over these gena will give every appearance of being autosomal borde, und in fuct from the point of view of the clinican it is enough that they shall be po regarded It is only when an unusual xa distribution of the chancter being considered is recognised that the evidence for partul rex linkage is rercaled In some famihes showing . particular condition affected males will be found to be much rarer than us to be expected In othen there will be foyer affected females than there should have been if autosomal inheritance were concerned. It is only by the analysis of Individual family records that the adstence of partial rex linkage has been detected When pooled pedigrees of this kind 150 xamined the unusual x-letnbution of ons kind in certain femihen 1. balanced by an unwual xx-distribution of the other land so that in tuch studies the mode of inheritance would seem to be entirely autosomal and the genie autoromul bornc. A male wbo has received the recentre gene from his father 1 carry it in hu Y-chromosome and will therefore thenett it mainly to his song but u erault of croucing-over fow exceptional daughten will receive It 215. A male who has received the gene from hu mother will arry it to hle X chranouome and will therefore transmit it to his daughter, but u result of crossing-over it will pass also to a few exceptional sonu. The curentul difference between partially sa linked und autosomal transmision is us follom A male who recctva i partially box-linked gene froin his father transmits it to more than half of his sons and to less than half of his daughter, whilst If he receive it from hu mother he transmito ft to less than half of bus pors and to more than half of his daughters Thu umuual distribution of an and character in Location to the result, of cours, of croening-orer between the X and the Y Seven gena prevladly looked upon os autoromal genes ·PARTIAL SEX LINKAGE 59 Le pot suspected to be partially sex Unked. They are the gena for I recaro raturo Retirtis matom doodnent) Retinitie pigmento (althout daaroo) alloles fuccedre The heart form of spidermayda bu Long Spoetic panplate Itoire Opocht date form of night-windoom) recontro Xerodama pirmentor Decaro Achromatopers (total colour bited) Retinltó pigmentosa is among the commonest of genetic abrormalities. It takes the form not of an inflammation us tho name would suggest, but of 1 gradual degeneration of the retina commencing wually in infancy or childhood (although ciceptionally belog delayed until early adult life) The first symptom b night blodden, radily to be distinguibed from congenital stationary night blindness, an autonomal dominant character which be present at birth and not progrendre. There is progressive contraction in the mal field and finally blind no Ophthalmoscopic examination of an advanced can abom the venuels of the fundw to be reduced in size with Jet black spidery spots of pigment lying on them. The retina and chorad are atrophied nad the duak wary in appearance. Epidermolysis bullou la a condition in which later form w the result of injuries to trivial that they would produce no cffect whatrocher in the Daranal Indondoal. In the avereat form wholo kreu of skin may be abwent at with and Watering occurs In the mouth and larynz, bronchi and corophagus and the corner and conjunctiva muy bo affected. The teeth may be abaorma. Spastic paraplegla, a series of clinlal conditions dependent upon imperfection in derclopment or on degeneration of tho nerte cells of the cerebral carter, begl guagle or cerebellum, to remarkable for mukuler rigidity pure porrerte move ment, contracturer, lacreued reizas and located with mental deficiency optic atrophy and stary It is deplayed duzzog the first year of He. Oguchis decue a form of night-bllodness which is to be recognised by 1 2000 golden Apparance of the fundos when this is adapted to liebt Thila dappear when the fundin ba adapted to darkness Xeroderma pigmento e condition in which in un Infant a few months old there ha profuse reddening of the old ·IN 10 AEDICINE of party exposed to ordinary sunlight Freckle develop enlarge und deeper in pigmentation. Warts and patchy atrophy of the skin follow Cornical ulcer lead to opucoes. Bual-celled carcinomata are in the sida, conmctira and corner. The game bills the child just us aurely u doar the Lary of the igneumon fly destroy lus aterpillar host עע ם 14 1 t photos OS Fro. Il-Dragon of the boosolspoon of the Ishontoge the prema radical therea. The map of the booun X-chromonte Achromatopsia, congenital total colour blindoors is a sare conditlon in which the indivdual sees practically no color call Everything appear to be black, white or a shade of grey Unitely there is associated amblyopia, nyugous and photopbobur Thor disturbed proportions of the excepted phenotypes by the appearance of cross-overs within auch family exhibiting any two of the character based upon these poes makes it ponible to place them tentatively in their relative positions to the bomologous sections of the Y and the Y NON-DISJUNCTION Abnormal distribution of the X-chromosomes during the molotic derisions of ougerests of the mother an yield exceptions phenotypus umong the offspring Normally into each orm tbere passes one member of the XX pair of chromosome ·61 NON DISJUNCTION But occasionally during that divblon which yrelds the ovum and the polar body there XXs fuil to kepunate, to dajoin, und both per Into the ovum or else Into the polar body Tha pbevontenoa bown u savdisjunction of the so-chromno roma. In certain instances this non-disjunction result from the fact that the two Xs are actually attached and cannot spante. Such na XX orun is available for fatiliation by un X or a Y spermatopoon. Resulting from fertilation in XXY or an XXX yote aan uppear The farmer will be a female-It has two X-chromosoma and the Y doo not exert ufficient influence to disturb the result. The latter to tygote that apparently las not viable. Oozenou in en YXY female will be complicated by the Decondity for disjuncton to kparate the X and the XY or the XX and the Y In respect of i-chromosome content abo U elaborate for kunde of on instead of one. There w22 contalo the following ma-chromosoma X XY YX and Y respectively There an be fertiled by an X-banng or by a Y-bearing spermatozoon to yield syrotes with the following kinds of ki-chromosome constitution - On Zygae pocmal in respect of ex-chromo- 000 content XY -XXY & non-disguactional X -XXX poo-table Y Darmel Taspect of duomosome coordation but pote that the Y ano from the mother and the x from the fatbor Erooptood pheno types on therefore appar poral Esctptlooal an therefore XY XYY : non-defuncthoel. -XX IXY condo functional Both Xs from tho mother phenotypes apper ? non-viabie. If u man with a linked red-greco Toner Blades ·GENETICS IN RELATION TO CLINICAL EDICINE happened to have the sex-chromosome constitution XXY the two Xs being attached so that where one goa the other must, and produced children by 1 hoonorygous normal sighted man there would appear in addition to the usual normal daughten und affected sons (ch-crous inheritance) ciceptional normal cons and exceptional effected daughter non duometroul P with attached XX, affected. Normal & RXY X (XH QY Gameta Progeny (RY) Y (rXXXrX Y (RXX Dix) triplex female Ufected ) nonvable) (RXY Docmal male X from father Y from (XIX)Y Back YX's an affected female XXY from maker non viable, YY If the tnplo-X femalo and the YY cypote do not appear there will be equal numbers of males and females among the RED-GREEN BLINDNESS I '민 116 F. 12-Hedgwo Red Wide peculu by moud of the a Xuntected for progeny thamal vors like ther father and affected daughters Like their mother a mode of inheritance that cannot be accordo

·NON DISJUNCTION
63
dated by the normal chromosome dbtributing mechanism.
The uld of non-dojunction must be invoked
(RXY X 1 (XXIIY
1 (RXY . (XX YY 3 (XXXY + (
RY
5 RAY
7 (RADY
1. RY 2 RIRI)
Bern
ROY
CRIIT
RR (RV) L (XXX)Y 3 (Ryty +(IX-X)Y 5. (XIY QORX)
11
and 3 and III 4 mod sun directed beat they toured both their r
toodud mother
La tbc cake of dominant X-borne gene such u that for the
dominant form of retinitis pigmentou the attached XXs of
an XXY arbal could dosturb the ti indidence of the
condition among the offspring #mon of an affected mother
homozygous) (AXXAX)Y by a bormal father (exdY could
be normal by receiving his father's X and his mother's Y
The expected result of such a mating with non-attached X
Lo affected now and daughten (heterozygous).
(EX)YX(AXXAX) - (AX)(2X) (AXY

·CHAPTER IV MULTIPLE ALLELOVORPHS It will not have escaped notice that on the map of the noa pairing wegment of the X-chromosome two mutant gene were placed in one and the name locus those for the dominant and for the receive form of retalls pigmentowa respectively They were placed there for the reason that the COV. between either of them and any other gene In the group were identical. Unless they are reddent In lod to close together u to be indistinguishable there genes must therefore be allelomorphic to each other and abo to the unnutated normal gene from which they trosc. If the to so then a gene must be able to mutate in veral way to yield several allelomorphs Thu is so. A gene and its everal mutant forms constituto a mulnpla allalomory ku sortus of which not more than two members can be present in the genotype of any one individual Such a series wually controle a given chincter or set of character quantitatively so that they an be arranged in a cries according to the degree to which the effects diverge from the normal Usually also the unmutated gene lo dominant to all the rest When two different alleles are present together they wully yield an Interncdiate effect It u tho intermediacy of the compound that l characteristic of a multiple allelomorphic series and distinguisha itu memben from ordinary recauren. If u Individual displaying one recentvo character is mated with another exhibiting · different recenive the clopnog will be doubly beterozygous and will duplay the two corresponding dominants ko - P Asbb x UBB Gametos Ab UB Fi ABb ·THE ABO BLOOD-GROUPS This not the cure with the members of 1 muldple Jlelomorphic krla. THE A, B AB AND O BLOOD GROUPS The autosomal god which underlie the A, B O blood groups are member of coch 1 seria. There are four blood group reared to u A, B AB ind o respectively Thake group differ are from the other in respect of the antigen and antibodies present in the blood. The endgens ure known u the A und B antigers the antibodia u anti A ud antı B respectively Finally the genus responsible for the differences In respect of these antigers and antibodies have been given the symbols A, B and o No wonder the geneticlat reading tbo kterature on thus rubject commonly finde himself lo doubt us to whether the As und Bs and Os which he encounter refer to the blood groupe, the antigens or to the genen. And Dow that the nomenclature b in common uso in clinical mediane It is too lato po to amend it that it will conforın to genetial convention. But for the purposes of thu book It is caury to make the attempt The last yet The gon() now! Blood group A Prevence of antigen A in the red NA blood carpido. Presenco of antibody anti B in the Krum. Blood group B Presence of mtigen B in the HD R.B Co. Presence of antibody ant-A In the serum Blood group AB Prenet.co of antigen A und B in Hod the RB Ca. Abuence of att conjointly bodlea auti Aud Bin the DLL. O Abena dotigos A and B in the но RBC Protena of antibodia mt And ontl. Bintbo rerum Blood group In accordance with genetical convention one and the mone initial letter i med for crery allelo (H -humun untigen and untbody) and ano alicho k distingulahed from the others by the addition of reftir. It will be noted that where there is antigen A there is no anti A antibody where there b antigen B there is no and B intlbody and that wherever antigen A I ·GENETICS IN RELATION TO CLINICAL MEDICINE 1 abrent antibody ut A u present and wherever antigen B is abwent antibody unti-B is present. These are the important obecntions that have determined blood transfioa practice. In this the danger is in the Introduction from a donor of red blood corpuscles containing in antigen or antigens which will be attacked by the antibodies present the blood pluma of the recipleat. Blood group typing count of testing in individual RB Co gainst I of known antibody content An individual is placed in group A if hls erythrocyta ut ugglutinated by serum containing unubody anti-A but not by rerum containing untibody and B be belongs to group B if hu R.B Co are agglutinated by rerum containing antibody and B but not by unt! A verum he is classified as AB if en containing anti A und unti B respectively both couro agglutination. If nether of those in produce agglutination of his RBC then be la placed in group O Transfusion of wbole blood therefore ob crves the rules Indicated in the following table Recitimi A ont B B unti-A AB Detha 0 both antigos antibodie Det A + - + B - + + АВ + + 0 + + + + tranfudon permissible. transfusion not permimble doce uggluthation resulta The three autosomal geng H* H' and Hº form a multiple allelomorphic 14. As dominant to B and O B L recensive to A und dominent to O But dominance u not complete and the counpound AB tveals the effect of the action of both ·THE ABO BLOOD-GROUPS 67 gere Erery individual possesses tro out of these three goa. The following genotypes tre pouble Paraty Frewny () Genty A A ar clomo B н AB > <1900 0 Recently tho genc Hhas been shown to edirt in three alleomorphic forme differing in respect of the Intensity of the Action of the antibody anti A on the A antigen, stroog medium and weak, the groog being dormiunt to the medium and tho weak and the medium to the weak The multiple aIclomorphuc merlas consists therefore of fire members A2 A' A* B and o Powealng thb purely genetical information it is poolble to predict the possible phenotypes and genotype of the offspring to be expected from any given mating Plomarys 0 per cent. À 100 per coat. A दादा ciclo x - 5 per cont. 100 per cent A so per cont 승 승 - 5 por coat 3 per cent. 75 per cent A 15 per cent. O 35 per cont. od k on throughout the worles, t being rerembered that po more than two of the five alickas an be postered by any one individual and that A' is the top of the cria und O the bottorn.

·GENETICS IN RELATION TO CLINICAL MEDICINE Phenotypes of Postleguntypu Pirnatytus lacky Menus of frus RAY of AXA AO BAB AXB AB ABO AXAB A, B AB 0 AXO 4,0 BAB BXB BO A AB BXAB A, B AB 0 BXO во 4 AB ABXAB AB AB 0 ABXO 4, B AD O 0xo 0 А, ВАВ It w poalblo by the employment of specul techniques to demonstrate the presence of these A and B antigens in the uliv of about 80 per cent of the population This property is bused on an auto omal dominant genc, S THE M AND N ANTIGENS Human erythrocytes have been shown to contain two antigens to which the symbols M and N respectively have been attached Every individual has one or the other or both of these and they are never umultaneously abuent. But human terum does not contain (uave very exceptionally it now seems) an anti Mor un and N antibody so that these matters are of no concern in blood transfusion. The Lodbodies are produced by the injection of human RBC with one or other of the M and N antigo into rabbits Rabbit for thus prepared a then used for the detection of the Mand N antigen chancen in human blood The phenotypes M - the presence of M antigen N-the presence of N Rougen, MN = the presence of both antigens are based on a par of genes, RW and R* resident in un autonome other than that in which the ABO seria is found Between Mund N there is no dominance and the heterorypotc MN shows the effect of both Pirnaty Freyway ( Hend) Graniye in mulann MI 19 7 M N 111 MIN 490 ·THE VAND NANTIGENS 69 The following matings ure poulblo and they will yleld the following phenotypos abong the progeny Phoneypes of Puth bestys Phantys labor peren's anmy of sorts A of MXM M NMN LIXN IN H, N MXMN M, DIN N NXN N MUN NMN NHN M LINX MN MNMN Recently an allele of N No glring a weaker efect than N has been identified. It seems therefore that tho M N1, N, gena form yet another moltiple allelomorphic tenien Since the ABO werto and the MN patr of gene are oa dofferent autosomes tho mode of labaitance of the characters will bo in accordance with Mendel s second law of independent anordnent. In the course of this ent-M antibody work another unti body anti-P w db.covered which dclosed the presenco of another intrgen, P in human red blood corpuscles. Pb present in approximately 75 per cent of the population. It is based on an autosomal dominant gene, P So far there a no conclusive cridence that the P factor is of any importanco in blood trawion there is u yet no record of a hemolytic transfuelon raction due to anti Pantibodies. But there uro suggestions that there have been obatetrial disasters In cua in which the father wu P pouitive the mother P-negative THE RABUS AKTIONS By injecting the red blood carpices of the Rhenu monkey tato guinea pig and rabbit it vu found posable to obtain terum tha contained bodies which pjec into the human subject, revealed the presence in human erythrocyten of certain antigens the roaalled Rhenus untigers. Individanls wboue erythrocytes are aglutinated by there antibodias are Hid to be Rhens (or Rh & R) poutire thoue in whom the reaction does not our oe Rbow Degatire Eighty-fire per cent. of our population i R+ 15 per cent R-(with reference to the first discovered and still most important D antigen). The Importance of these discoveries les in the fact that in ·70 GENETICS IN RELATION TO CLINICAL MEDICINE about 90 per cent of instances of erythroblutous fcctala (incidence about 1 in every 200 pregnancies) the cause is difference between the parents m respect of those Rhesus properties the mother being R, the father and the infant R+ More than i Rhowus untigens have already been identified but for the moment only sts will be considered To these the rymbole CSDDE e have been given. Every human Individual carria at least three of these in hu aythrocytes some have four five or even all us. The corresponding antibodies unti-C anti-c, etc. are never spontaneously formed in any human serum. But an individual lacking a particular antigen moy develop the corresponding antibody if be receives u blood transfusion including erythrocytes containing that antigen. Unually one such transfusion is not sufficient to produce this reaction, keveral are necesary A pregnant woman lacking i particular antigen and artying foetus porschung it, having received it by way of the spermatozoon from his father may develop ia her krum the corresponding antibody This then may react with the eythrocytes of the foetus to cause erythroblastomy foalb The antibody develops slowly so that it may not be the first born but wubsequent factures that are affected. Tbck abs antigenic character would appear not to be based on single gena ach antigen apparently rest on group of three gene rendent in lod vary done together in the length of an autonomne. Because they He to close together m the length of tho chromosome coming-over between any two of them w]l be a very rare event. It may be that the rarer gene asociations are the results of such crossing-over There i no dominance among them ach genc and gene group producas its own effect irrespective of the action of all the rest. These di gene an provide the following gene group Sorologists E CDE R -1 CD R 3. CDE R, (Dot ret dentified 13 d R ·THE RHESUS ANTIGENS 71 Serologists rcler R E cDE D 6. De B. E-7 E R مت o odlo I Gene group 2 8 and 5 in this order are the commonat in our population being pormed by some 95 per cent of the whole. Every buman being has two of these elghut gere groups ood they may be the same or different. There are thw thirtyux ways in which these cight can be arranged in pan ro that there are thirty-tu poolblo Rheno constitutions CDE CD CDE Cdo CDE De de alo CDE CD CE ca Do CDE CDE CHE Coke DE CD. CE CDE Do CDE CD CDE Cdo cDE cDo Cae cDE clo CE CDE CDO Car Cda DE CDR cDe ado CDE CD CHE Cdo DE a CDE Cat CD. ME. cdo CDE CD. JE CDE odo There are mx antibodia unti-C, 2nd-c, anti-D indd (not yet encountered), ant E and antie. If an individual u hbs erythrocytes will react with antic but not with anti- CD- Il be to they will react with anti-e but not with anti-6 whilst if he do they will react with both antic and antla The mme is true in the case of the D and d E and o antigenus and tho unti-D anti-d and E und antie undbodia. So that there erd twenty-seven posible ways in which I given emple of erythrocytes can ract with the the antibodia.

·71 GENETICS IN RELATION TO CLINICAL MEDICINE Genty D I + + - + CDE CDT CDE CD CDE L + + - + + + 3. + + + - + + + + CDE Oil CDE + + 1 5 - + 6. + CDE CD CD + 7 + + + + CDE + + + + a CD. CL a. + + CD + + 3. + + + CD CDT CDC + + I CI JE + + + + + 15 + + + 6. allo CE CAE CDE + + 17 + + + + it. + + + + + CE DE Cd + + + + + CE + + + + + + + + CU cdr CH + + + + 5 + + + + C DE CH + + 4 + + + ·THE RHESUS ANTIGENS 73 Ger od + - + + + + + + + + CH al CA con DE DE DE De DE लट DE + + + + + + + 32 + + De 3 + + De y + + + + Da 13 + + + + E 14 + + d + + ode + ܬܘ Since the genotypes and a reduction by CDE ade CDale (5) I CDE (6) CE DE Cde (24) De CDe CDE Cdo JE Cde CDE M CDE 1 CDE SCH I DE de DE CDE CHE CDO de J) 3 9 ·74 GENETICS IN RELATION TO CLINICAL MEDICINE arc dental in raspect of gene content tho thirty-fix genetic constitutions in the above lhat are reduced to twenty-ever. The commonest constitutions in our population ere CD. CDo ado CD CDE ade (13) CDe (36) (11) ache 60) ato DE In thu order Together they account for about 87 per cent. of all Individuab Another gene has recently been identified C It ta nurc allcle of C and the three forming a multiple allelomorphic seria The crythrocyta of an individual carrying the rene 210 с POLOS un antigen C which reacts with the mau untbody containing serum. ERYTHROBLASTOSTS FETALIS 1 CD colo CD Il 0 CD Fiat-Peyrun bowling the mode of tabertunar of the Rbuvo antro ode All ova contain the gene group ade and all spermatozoa the gene group CDe All the oflspring will therefore hure CDe the constitution ther oythrocytes will react with antibodxes ant Cuntis, ant D Anti-d and antie. The only krum which will give . negative reaction # anti-e The mother hu no antigen D and so s capable of producing indíbody mu D In het rum. The father trimmits the gene D and therefore the antigen D to all his oårpring und ·THE RHESUS ANTIGENS 75 so If the mother produca antibody anti D tha will react with the qythrocytes of ber children. It will be noted thut the production in the mother's serum of antibody ant D is low po that the first born is not affected. It will also have been noted that the mother has no untigen C und ob apable of producing antibody anti-Curell us anti D How It then that it the latter that doa the damage? For the present all that an be said that of the tro the latter to the stronger ERYTHROBLASTOSIS FETALIS CI. I ale r ode O SA CD ܗ Tro. 4-Pedigree bort the mode of their of the the cathos The father I, I beterozygous for D be laborates two formu of perinatoros, CDe end ode, in cqual number The cde offspring an therefore be either The other acto ode CDO an be semitoned by the chuld. Any rubsequent child cdo CDe or cde can be either CDe ode ode or If the und Dandbody elaborated cde cole in the mother & krum in response to the intigen in the first child . crythrocyta will leave the pubsequent child unharmed but if the child should be CDe then the mother's ale anti-D antibody an attack the child, D untigen und so an aythroblastonla factalis. The medicolegul determination of the Parent-Progeny relationship by reference to the ABO MN R S and P anti genic constitutions of parents and child respectively to of ·76 GENETICS IN RELATION TO CLINICAL MEDICINE Courts, the presentation of purely genetical evidence. This an be reinforced by other information relating to other geno tical differences between pututre parents and the child, difference in respect of such aboormal dancters u have been wed in this book to flustrate the perious mode of inbertance or in respect of normal charactert auch u, for enample the ability to spprecate the bitter taste of pheryl-thio-tren in diludans u lov us one in a million The ability i bered on a cupovomal dominant goe T (for taster) waffected to its retion by environmental factor Tastest may therefore be home or heterozygous Seventy per cent of the population are taster If the mother and the putative father are non-steri and the child is a faster then the man in the cake is not the father (Phenyl thio-ure is alo known - Phenyl thio-carbamide PTC) ·CHAPTER V COMPLICATIONS It has been stated that the action of a gene o influenced by that of the other genes in the genotype v well us by environmental agenda po thuat one and the same genc It would appear does not almay yıld the unde end result It to the teaching of genetics that the gene itself does not wory save only through mutation, and that variations in respect of its effects are caused through the interference with its action by other geen in tho genotype or by environmental pendio It u desirable at this point to conuder the nature and the extent of such reubility The genes which have been used to dermonstrate the prin apla of Mendelin Inbertance have been ruch us in their action were not affected to any considerable extent by other renes or by forces of the environment They were selected for this very reason, It is legithnate us well us enable to begin an account of this bad with relatire almpllaties and then proceed to complexities. It has to be recognbed that the birth of the science of genetkos might have been postponed for a very long time had it not happened that Mendel clunced to choose u his operimental material plant with maven pain of contrusted characters showing no linkage, con of each par being a complete dominant, the other areondre and none of them lo their development dilected to 207 diacernible degree by any Influence other than that of the one thponsible gene Hud Mendel choren not Pkw setia bat Zea mays (maire) for cumple he would bare obtained an F, with a phenotype that wu intermedlate between the two parental ona and the 1bmcnce of dominance might bare hidden the dues to genetic purity regregation and independent asortment It is not difficult to fit such Intermediacy o wus scen In the cases of the A and B and of the Mund N blood group chincters into a general scherpe ! It # encountered after an understanding of the Mendelian iw he been reartd Having considered Instance in which ganze action hu been 77 ·70 GENETICS IN RELATION TO CLINICAL MEDICINE uncomplicated by any other lofluence it u now possible hopefully to canine cures in which the character based upon I particular gene 8 rubject to verlation in a pression. INCOMPLETE DOVINANCE The non-red her coloans are dormant to the red Tbc allela responsible are autosomal. The heterozygote an often be recognised by a reddih tinge to the hair and try harry freckling Brown eye colour is dominuent to blue but in many instances the eyo colour of the heterozygote would seem to be a micture of brown and blue. It know that all you are blue and that a brown cyc to one in which in front of the laya of blue pigment layer of brown pigment deposited u development proceede. It may well be thuat a difference in the douage of the dominant genie, one or two makes a difference to the time of or in the rate of the deposition of this brown płyment. Exampla of a difference in the phenotypes based on the double and on the logic dose respectively of a dominant gene art pienuful in forms other than man and are, of cours responnble for the 1 3 I ratio in place of the 3 I Among the progeny of the mating of two (monogenic) heterozygota. The heterozygote wbo are the recentivo gene for the Laurence Moon Bledl syndrome is often not completely without certain of the stigmata of the docum, obesity for emple, the heterozygote carrying the recenive gene for Icroderma pigonentosum u often freckled These observations mupport the contention that dominance and recessivenon are never complete. It is convenent bowever for purposes of docmion to pretend that they are, MODIFYLYO GENES Albinus has been presented un directer based on an autosomal receive gene. The albino a therefore necessarily a bomozygote. But the bur is not white the cyos pink and the general build and vigour boormal in lase. Sorbetimas m albino hus light yellow hair and pulc blue fos und k ucceptional in respect of vigour and body bulld. The most reasonable explanation of rome of this variation that it is the result of the action of modifying gents. As hu already been ested the sotion of the “unit character ·HODIFYING GENES due to the action of Angle gene in the simple or duplex stato has been dorearded It is now accepted that in the fuhroning of a giren chincter very many if not all of tho genes in the genotype play a part. One gene the principal yout, the rest play 1 secondary role. Most gena ciert plelotrople action. But there are not the modifying gena. A modifying genc, according to the commonly accepted definition, le one that, acting alone, yleldas no phenotypically detectable remult, but ben 10ociated with others affects their action in a definite and constant my greating or rupproaung thla It moditas the action of the geno ar genes lavolved in the production of given character Friedreich s abaxua l me monogenic autosomal receive character There be a progreatre degeneration of the nervous quem resulting in lon of power in the legs, trunk, um and bead Its onget i woully in early adult life mo that the reproductivity of affected individuals a considerably diminished Modrfying gena have been identified which affect tho manifestation of this character The albino gene can find itself incorporated in a wriety of genotypo come containing genes which modify it action, others not including soch genes. In the second the albino gone will find completo expression, in the first their action can remain incomplete. So also in the case of a dominant gene. Modifier can yled incomplete dominance, espedally in the heterozygote, and to lead to intermediacy in charac tertuation. If this is so then it is to be expected that the bonory vote will show lens varubility to the expremion of character than will the beterdrygote. The mort nariablo . character tan in its expression the more probable will it be that the gene for It us present in the simples tate. The Interrdation of gene und geno has not any that of principal and modifier of cours. Plebelling her awed by a dominant autosomal gens, but manifestly it can het only in a thotype which includes gee that yield a darkly plemented side. The plehaldlag und biabım gend in cooperation could not posulbly produce a piebald albino. That a modifying goro is not the carbon of the needs of . harmed geneticat an eady be proveo by an appeal to propriate mating. Principal pero end modifier an be diapoined dodated u an abo the dominant and receive ·80 GENETICS IN RELATION TO CLINICAL MEDICINE allele and then it an be seen that though characters in their expression are subject to much variation yet the gene are stable, discrete and specific in ther panos actions and are in no way thatoselves affected through their usociation with other gena or by environmental lofluences (here, of courte that certain environmental agenda an and do speed up their mutation rate) VARIATIONS IN RESPECT OT THE DEGREE EXPRESSION OT A CHARACTER AND PENETRANCE OT A GANE OF THIS OT THE The degree to which the effects of a geno are verlable : the manre of the expression of the chancter in question. Epilota with its neuroglial nodulas in the brun its mental deficiency its adenoma rebaceum on the fuce and along the nasolabial folds based on an autosomal dominant gene But not all suffcren from this condition present all these abnormalities that is to may the complete syndrome is not always exhibited The degree of the empresaon of this character vasia greatly in different chach Brachydactyly and phalangeul synostomu autosomal dominants, are lovariably displayed by the individuals who possee the corresponding gore but the degree of the abnormality vanzas widely in degree in different individuals, rmging from ser normality to grow abnormality Nevertheless whatever may be the degree of thu expression the chancter however incomplete and imperfect can be recognbed A gene an be known to be present in a given genotype und yet in the phenotype there can be no hint of it. Polydactyły based on a dominant autosomal gene, is very variable in oxpropioo, in some instances there a do doscernible manifesta tion of the chancter though it is known that the gene bo present In the genotype of the individual Dubeta mellitus endocrme disturbance of carbohydrate metabolon tulng the form of an insufficiency of production of insulin by the cells of Langubans of the pancreu la certain instances a genetic character bared on m autosomal dominant gent. But In only about 10 per cent of individuals postering the gene to the character displayed The frequency orth which a gene products any offect at al u the measure of its powthout The ·VARIATIONS IN PENETRANCE 81 penetrance of the gene for diabetes melitu is thu 10 pez cent. Possibly environmental agenda determine who among the portemony of this gene shall exbibit the character Diabetes inapidi due to an abnormality in the functioning of the posterior lobe of the pituitary and characted by an Intense thirst cod polywola, is in certain are the preston of Ra autosomal dominant gene present in the heterozygout uc and with low penetrance DIABETES INSIPIDUS IT 3 7a. 16 edgec of Babetes toutpide, showing the elect of lor penetrach on the part of the foot ou ben powered them they prodwond bected deprem brythmudru od pot cabut cancer Manifestly If Individuals do not duclone the presence of a dastant gene within their gerotype by the diplay of the corresponding character the interpretaton of a furuly pedigree con present comiderable difficulty and confusion. There aan bu skipping of generations, affected individuals can have unaffected parents and meaningicas niton of affected and undected an be obtained For more than one podigree will be required for the recognioon of the true genetic nature of the condition It will be appreciated that it is not ang 1 lmpke matter to distinguish between a donnant gabe mth a low perietrance und a recentire. The cotence of contenguinity to the parents an help towards a decision shoce a recentre texts to appear lo several member of an inbred stock bilet a dominant for its exprendon depends not at all on consanguinity 1 ·GENETICS IN RELATION TO CLINICAL MEDICINE In the case of totuly sex-linked X borne recensive gand it appears that in general the degree of the expropon of the character in the male possessing but one gene is equal to that in the female poueulng two whilstin the heterozypows female there to variability Instances are a record in which such a female bus duplayed the recewire cuncter though not to the full. For calmple, some 3 per cent of female heterozygous for the gene for red green colour blindness are affected So ato in the cix of hereditary nystagmu Thus receive gun expression in some 30 per cent of femalos heterozygow for It. The degree of the expression of the curacter does not vary but the penetrance of the gene doos in so far as the heterozygou fernale in concerned. A considerable number of farly common pathological conditions have been recorded us being of genetic ongin, being based on dominant gent having a very low penetrance. These Indude leukemia perniaou anemia, Grava Hukus, putnc ulcer uthma, parocytral tachycardia eunucboridiem, inguinal bernia cod congenital dislocation of the hip When daling with condition Puch us leukeemia which ha * penetrance of wound i per cent. it must remain difficult to perrunde oneself let alone anyone else, that the condition la in fact genetically caused It is because in the use of so many ducased conditions there is a wide range of expression and much vanation in respect of penetrance that it la un derinabło to Indude in a manual of this kind long list of dbenso that hare been recorded u being the expremion of genic action, To do so would be to mislead the dinidian. The fact ba thut in the present state of our knowledge the interpretation of the majority of human pedigree demands an cxperience and an acquired skill that are powered by few As things are there is a great deal that ts of considerable penctal nalue lost because there has no cary mechanim wbereby pedigreen constructed by indindual practitioners and apparently meaningles in themselves aan bo submitted to potre central bureau where they could be curated against the background of accumulated knowledge It is most unlikely that any one practitioner would ever be able to recognize Podetic auntion In ringle instances of lov poletrince and mortable presion The difficulties presented by a frolly history do not ui derire from deferences in chander oppression and in genic ·VARIATIONS IN TIME OF EXPRESSION 63 pentru ce to commonly they retult dureatly from fulty recording To obtain full and accurate information concerning the illness and abrormahtus of three generation of a family en mopowibility in the great majority of instances Lattle ar more commonly nothing is known by the propontos of the fans of the grand parental group Unca, aunt and cuina hamo pred out of her havt migrated or died. Nothing is recorded in the family bible of the individuub wbo died in Infancy are that they did wo die. So it is that a pedigree commonly has to be bullt by the physician largely out of caecdoto, which is pater & Athfactory foundation on which to erect 1 Kentific diagnok What are needed more than anything clue for the speedy advancement of our knowledge of human genetics in its relation to dinlal mediane wro (1) the country wide rystematic preparation of pedigree by gonetically Informed and interested pedical practitioners and (1) 1 starchowo where there an be received pooled and interpreted. DIITERENCES DS THE TOT OF THE DISPLAY OF A CHARACTER Yet another complication is pronded by the fact that different persen produce their effects at diferent pomto o the Life blatory of the indindual. The ample inually alted ta that of Huntington chora, the condition in which degeneratire changes to the cerebral cortex and corpus arutan ere responsible for involuntary and inco-ordinated muscular movement wociated with progrentve mental deterioration. The dicure b aused by the action of a dominant autosomal gbe which wifects not the processes of development but those of degeneration. The average age I which it effects are to be decerned b cround thirty-óre w that it possible for many in affected Individual whilst still normal phenotypially to marry and produce funity The pufferer is usually beterorypote so that, marted to a normal roman, he can be aperted to produce pormal and affected in qual number The beterorygow affecteds in their turn, distgarding their father's fute will roury and reproduce before they theranero mccumb. The feature of a pedigree showing this condition will therefore be determuned by the ag distribution upong the individual complaing it.

·84 GENETICS IN RELATION TO CLINICAL MEDICINE MULTIFACTOR INHERITANCE There the possibility that certain abnormal characters tons are theraxelves mxlmfactor in nature, thuat la to hy are based upon a number of gena ach of which make a small contribution to the end result these contributions being additive to that different combinations of these gena yleld different grades lo the preselon of the chancter Such variability would have to be distinguished from vanation in the copronion of . unit character It certainly la the ause that some normal characters have such multifactor baru. Stature slan colour and thickness Intelligence and dloeuse resistance would seem to be aimpla of this multa factor Inheritance The proper methods for tho study of such chincters are mainly btometrical, biometry being the science of the measurement of living things. It is outside the scope of the book to present and to discum these methods It must suffice to give a hypothetical Ilustration of the manner in which many genas acting together can yield e seria of end renulos differing one from the other quantitatively It is known that werenl gena art reponsible for tho differences in skin colour which distinguish negro from white. Ja group induding white black and their hybrid offspring from various matings it is pomible to urange the member in 1 sequence ranging from black to whito through mulatto quadroco octoroon and so on Each grade differs from all the rest in rupect of a difference in the amount of melanin (and also of a yellow lipochrome) If It l uuumed that these difference rest on two gene pain Aa and Bb without dominance and if the four genes have a different pigment produdng power A-6 B - 4 1-3 b 2 It an be keen that regregation among tho olepring of two AABb individuab can provide a whole ringe of colour type. AABD x 6644 ALBb wody the 634 Puro ubb 10 MABB ABC ABB A Abb At ABB Aubb M abb 1S 17 6 5 3 T 1 4 Trequency ·MULTIFACTOR INHERITANCE 85 Bodily stature, diaregarding the pathological glant and the darf the end renult of the interplay between genetic apadty uod evronmental oncourgement. It has been atablished that about yo per cent of the variability in respect of staturo lo a people like ourere is to be escribed to genetic a The fact that with improved outrition and general unitation the trenage beight of the people has increased that the present funeration bus an average beight which aceeds that of its predecesor does not disturb this statement. Several genes are concerned, each alonc producing a full effect. Dominance would appear to be fomolved since there a tendency for shortnet to be dominant to tallpen. It to be observed that all parents, medium and short perents produce tall medium and abort offspring but that tall haro note the then do medium and wharts On the average, therefore if the offspring of a large number of parents of the tall and short dana ke meuured it will be found that the offspring of tall parents are not mo tall u were the parents, though taller than the odspring of the medium and shorts and that the offspring of short parents are on the average caller than were thetr parents the phenomenon known u regression to the mean, direct consequence of the operation of the land of chance METAL DISORDERS Examples of mental diseases which are the direct exprenion of genetic action uninfluenced or only alightly influenced by environmental forces have been considered. Huntington cbara is based on in utorocnal dominant gene, me urotic family kocy on an autosomal recemure. This latter deux b found more frequently in Jewish furnilles than in others The child, appareatly quite normal at birth, begins around three to w months of age to exhibit + programire mental Imperment which ends in idiocy There is alvo a progressive paraly of the body ui wale, Vhikt vuual cuity pro grenalvely dimini ho to end in blindnes. The average ago ut death is dghteen months, all rufferers being eliminated before the end of the third year of life. There are pathognomonic retinal change taking the form of a large cherry-red spot in the region of the macula whilst the cells of the whole of the nervous system lo their degeneration become cuttended with abnorind lipaid material.

·GENETICS IN RELATION TO CLINICAL MEDICINE MULTITACTOR INHERITANCE There in the possibility that certain abnormal characteria tions are themseloea mwHfactor in nature that is to my are based upon a number of gena ach of which makes a small contribution to the end result, these contributions being additive to that different combinations of these gener yield different grades 10 the expression of the character Such variability would have to be distinguubed from variation in the exprension of a Unit character It certainly by the are that some normal characters have much a muldfactor begu Statur skin colour and thickness intelligence and drcase resistance would seem to be cumplas of thus muld factor inheritance The proper metbode for the study of each characters wo manly biordetnical biosnetry being the deact of the measurement of living things It outuide the scopo of this book to present and to discus these metbode It must ruffice to give a hypothetical illustration of the manner in which many genes acting together aan veld a ferla of end result differing one from the other quantitatively It is known that several genos are responsible for the diferences in skin colour which dostinguoh negro from white In a group Including whites Wecks and their hybrid oferpring from vanou matings it is possible to arrange the memberu in 1 sequence ranging from black to wbuto through mulatto quadroon octoroon and so on Each grado differ from all the rest in respect of difference in the amount of melanin (and also of a yellow lipochrome). If it ba mumed that these diferenca tot on two pene purs Aa and Bb without dominance, and if the four geras have a different pigment produang power A-6 Bm4 1-3 bm 2 It can be seen that segregation among the odapring of two A.Bb lodinduals aan provide a whole range of colour types. ABB x Deto ubb 6044 10 1 ABD bolforakty of the F, 6341 AALB MO ABB Abb Abb ABB Asts but $ 17 16 13 1 1 1 J 3 t TAYY ·MENTAL DISORDERS 57 Io Lostances in which both genetic and environmental facton ire concerned in clology the twin method of Investigation is of particular usefulness It w Galton, us long ago u 1883 who firet alled attention to the fact that the blology of monozygotic u contrated with that of dirygotic min uffarda a means of dutinguishing between tho effects of Nature and of Nature respectively Moporygotic twins share common genotype dirygotic twins tre no more genetially Almilar than tre brothers und dlater born at different times. The quotation concerning achizophrenu on page 4 refer to areful and crltal evaluation of the nature autort problem on the banks of « clar mono- und di-rygonity Out of u comderation of these and dmilar finding it powible to reach the following conducos Genetic factor are not always involved in the cathology of the schipophrenic psychoses but u. general rule they play an important part By therselves they do not ruffice to produce the condition and in their action they are not highly specific. For the present we do not know what the environmental *geota 20 which play a part in the production of chipophrenia. Thu in lowelf be mufficient explanation of our lack of knowledge of the genetic factors that are concerned All that can be maid is that the relatively high incidence of the condition Amongrt side of affected Individuale, the uurual frequency of couunganous merrieges among the parents and the differences in the incidence among mono- u contrasted with dlzygotic twlos most stroogty suggest that a rocceive gene ar ganes undates the condition that the expressivity of the porno ba varlable uod that certain u yet undefined environmental draumstances are required if the coprentice of the character I to be at all complete. The findings concerning manic-depresive porchodwo Very similar uod the name explanation has to be offered. The georetic component would seem to be an autosomu dominant, the dominance being incomplete in many tetance. The movironmental agendos concerned are as yet unidentified. MENTAL DITIOCY This condition bu already been encountered in the dexcription of epllola Phenylketonuria (oligopbren la pbenyt- Pyrotria) the condition in which the individual excretos ·& GENETICS IN RELATION TO CLINICAL VEDICINE phenylpyruvic acid (darative of the amloo-add phenyl Hanine) in the urine and which is encountered among low grade mental defectiva Ao utosomal recessive gene is raponible not only for the metabolic abnormality but also for the wodated mental defect Thu variety of mental defect can therefore be identified by an analyals of the urine. These two conditions account for about i per cent of the whole. But there is i mental deficiency which not in ingredient of a syndrome in a butun population there are individuals who are to be distinguished from their fellow by reference to the relatively low grade of their general intelligence 15 measured by means of suitable testo It is commonly accepted that the quality b determined by goodc factors to the extent of tome 50-75 per cent. By appropriato psychometric terta the mental age of an individual an bc uscertained Yoo LQ intelligence quoticat) Asental 150 Actual 40 x If u representative sample of the population is no reasured It is found that the variation uong then nga between two extreme The whole range o broken down arbitrarily into aumber of categorias Those with an IQ of low than 20 are classified u idiots those with an IQ between 0 and so u imbecka and those with an IQ between 50 and 70 m feeble-minded or mentally defected (50-55 low-grade, 55-63 moid-grade 63 70 high-grade Daroo) These pride ispper cepúbly into normality u fudged by these tandards. An IQ of 70-80 - borderline 80-90 - dull 90-110 - normal 110-120 - superior 120-140 - very ruperior 140 and over genius. No one can ry where coactly stupidity cads and feeble-mindedoch begins or when feeble-mindedness become mabedility Mental deficiency is divided tato primory and secondary The primary the genetic group is said to constitute some three quarter of the whole. In certain pedigrees a single autorul receive gene would seem to be responsible. Among the des of defectivos about one fifth are ukerise defective when both partat ve phenotypially normal und nearly all are defectiro when both parents are defective. The onronmental care of mental deficiency we mtra uterte Mongoloid idiocy) birth injury hydrocephalin, ·LENTAL DEFICIENCY 69 cerebral syphilis, meningoencephalita hypothyroidom and certain congenital malformations of the cerebral tissue and odlom (microgyrie, porencephaly and syncephaly). It has been rarested that general intelligence to graded cancter multifactor in origin It reasonable thatfore to regard the high-grade mentally defident u being thou who are poorly endowed in respect of these gend. They tre at the one end of the sale ut the other end L the exceptionally Intelligent Individual. The difference between the two is like the difference between the best and the worst banda In a gome of bridge. There is nothing tho matter with the arda but everything wrong with the band that the dealer hu delivered. But it he probable that, u the scale s descended towards the imbeelle and Idiot categories, low-grado mental defidency when genetic an origto is caused by specific genes by genes that do not belong to the constellation of genes in the multifactor seria In other words the greater divergence from the mean of Intelligence the more probablo It is that tho auk a specific geno When the comme not genetic It is an environmental agency of considerable potency provolding largo reaction It will not hurt escaped notice that the geneticket conddering the problems of heredity and disense depends entirely on the chinidan for the definition of the character tho modo of Lnbentance of which he is studying Thero Lo do difficulty when the character is un anatomical detall that to cury of recognition and unchanging in apropion. Ptonds is alway ptout. Stmllarly dlabetes insipidus or neurotic family blocy Le labels that cannot be differently losed by diferent dinidans. But when different labels are given by different authorities to me and the ame condition or when one and th humo label la tried by different authorities to identify different Montal condidons the genctides tuk becomes hopelem deficiency for the most part be grade of an attribute rather than an attributo Itself It be action of the curre which Within the depicts the range of tatelligence lo • population Top of mental defectire there b ugain i graded vulety fron high to love Thus cren If environmental egendo in stiology are diraguded to truce its inheritance and to identify to genetial boss still remains difficult Furthermore whilst the offidet definition of nental ·50 GENETICS IN RELATION TO CLINICAL MEDICINE deficiency is a condinot of arrested or incomplete development of the mind before the uge of aghteen, much more than the intellectual function can be impaired the emotional and contive functions abo have to be considered and there are not to be menured by the tests which yield the lo In the case of that mental defiaency which retults from a genotype poorest in torpect of the genes for general intelligence und which therefore is the one extreme of the range that extends from dul to brillant, it can be seen that if it tend to marry like ther offspring wil, judged as a group tend to be dearer the ineen than were their parenta The most intelligent individuals of one generation will possess the terme equipment u the deverest of the mucceeding generadon and the dollest of one generation will be u dull as the dullest of the next, but brillance will not beget only brilliance and dullness only dulines. The shufiling and dealing of the multiple facton anderlying general Intelligence will repult in the production by the brillant of the quite ordinusy and of brillance by the ordinary and the dull. Only two individinis ench completely bomozygous for all the genes concerned and therefore identical m respect of them could yleld offspring all equal to their parents, and then only if environmental factors counted for nothing in no for us this character is concerned. Neverthelew the mating of well above the mean by well above the mean wil sield of *pring who on the average will be above the mean whilst the mating of well below the mean by well below the mean will yield offspring who on the average will be below the ein The question thus unses which group is producing most offspring Evidence has been presented which strongly suggest that there is in fact a negative correlation between the intelligence of a child (w meatured by the present-day testa) and the simo of the family to which the child belongs The explanaton of this father frightening fact would seem to be that the more Intelligent people marry later and produce ferrer children. Manifestly the evidence must be examined with the greatest care for it is indeed difficult to disentangle that part of an indirduals intelligence that the presion of his genotype from that which pertains to her social inheritance education, home and opportunity If the lower intelligence of the members oNuge families is genetic phenomenon then ·VENTAL DWICIENCY 91 ophy . differential birthrate in the opposite direction the more intelligent produang more offspring-could avoid the Stendy dedine in the intelligence of the popwation us whole. It the lower intelligence of the member of large familla i in en vironmental affect the social melioration rould elunloate the difference. Undoubtedly both genetic and environmental caure are operating but at present it is impossible to contrat them at Jl accurately in respect of their relatiro importance It is unclou to compare the spembers of large family of ano 000-cconomic group with the member of woull familie of Inother Differences in the uterine environnent mcm to effect the IQ tince thba vartos with the birthrink. The later inenbery of a large family tend to have an older mother than do the member of 1 mall family and the IQ of a child wers to be Influenced by the age of the mother On the whole the 1Q of city children is higher than that of the coumtry children. The different socio-economic danes tend to show different levels of intelligence u mesured by the standard test tho higher the can the higher the IQ The children of a group of parents with a high IQ tersd to have higher IQ than that of the children of a group of parents with a low IQ Sadnak mo para Anillo children Unalled Labourer 60 Partially slod 280 Serolod OS Sulled OTS Seni-profeumol und nenugerial Profondoval 160 When children are reared in mstitution apart from their parents there tend to be a correlation between their 1 Q und that of their parents. According to other lavestigations thr I Qs of farter children accord more closely with those of that forter parents than with those of theft actual parents. The Ils of children transferred from bad eartropment to food hare, in cetun studies moved up a potats. The Ils of Identical twins often differ though us a rule not markedly (reared togabes 59 rared uport 17 aceptionally by u many - fifteen point) but uually they are much neuer then are those of fraternal twiny (8 ) and soy douch Dearer than those of brother wd uiten born t different Iro ·GENETICS IN RELATION TO CLINICAL VEDICINE timet (15) Malnutrition does not seem to affect buric mtelligence The removal of tomats und adenolds doo not Influence the 1l Deafnes and che defecto mutt necemurlly offect the performance of a child in so far u many of these texts are concerned There is no es difference in respect of IQ soren. In Amena Chinese and Japanese children score juxt u highly u do American and European children fudged u groups The children of Jewish immigrants judged v. group secure the highest scores Negro children bave a lover average than do white chudren but the children of Dorthern negro score wont reven points higber than do those of southern negroe. In 1917 18 when exposed to the American Army Alpha test, negro recruit from the cities of the north obtained a higher median score than did white recruits from curtain of the rural areas of the south These and dozen other complications make it difficult to recognize the role of the gene in the progrehive decline of the intelligence of the population as a whole which, in the considered opinion of certain students of the matter would kem to be taking place It is of the utmost importance that wce bould know whether or not this is so. If general lotelligence an be compared with mature both being the product of the Interplay of nature ind nurture and if us in the chxc, tbe average belght of the population has increued as the result of improved unitation, it would be expected that nith improvemeno in education the average intelligence of the people would lo here riten If it b declining then in its catabllohment the initial genetic endowment must be the more important agent. Medicine annot be mistaken in supporting all measure that tend to improve the conronment that the uterus the home and the school. Of particular medical interest are the maternu! coaditions that are brocated with congenital defects and derangements ance it is reasonable to entertain the view that the cand of these, operating to a len artent could lead to damage wuch, though not exprensed us recognirablo anatornical abnormality could yield a lovered iQ Further more medidnt could not be wrang in presenting the view that the more Intelligent unong the populabon should fa the interests of our stock, reproduce pufficiently to ensure that But they are adequately represented in the next femtion It must not be forgotten however that in our kind of society ·CONSTITUTION DLATHESIS 93 there o plentiful room for the dull and buckward, creo for the high end middle grade moron. We provide appropriato anvironment and tuls for them. CONSTITUTION DLATHOLS So far the disasten hus concerned trelf with character that were referable to particular genet the gene for syndactyly and so oor with chancters that were based upon the Interection of several genes--multifactor inberitance, tho gena for nature, for de se rastance of . general kind for Intelligence of a general land and so on. But there are attributes which would seem to be referable not to a particular gene or group of genes but whuch are the reflection of the genotype a whole, of the genetic make up of the individual of the Individual constitution. To rutest that this is nou not to stretch genetical argudent beyond reasonable limits surely It bas merely to say that wereu in multifactor inhentanco the genes concerned an be identified by appropriately planned Investigation there are other truta characten undoubtedly genetic and certainly referable to the interaction of very many genes whose canct genetic bubu u yet hidden from w For the present therefore we must be content to prevent the view that they are genetic and are trustworthy indications of agnificant differences between the goaletype of different Individual, types, ethnic group Rheumatism in childhood with its folat pain fever and endocardito affecta about 2 per cent of the population at rak and is responsible for some 80 per cent of all destha frorn heurt douxe of persons under forty yean of age It is the au ubo of rery great deal of inulidlam. In the present state of our gnorance it wu inevitable that a genetic aun should be bought It has been suggested that a reces ve gerie lie at the root of aceptability or dlatbasis and that thb gene (In the dupla state) deinands for its expression « cortato constellation of environmental conditions. It u indeed difficult to accept such i pogretionIt muxt remnan exceedingly difficult to demonstrate the role of the gee in the amution of the condition unti nature and in partiace of such eartron mental factory u poverty and climate hare been defined Edence of a definite familial Incidence of crophthalmic ·94 GENETICS IN RELATION TO CLINICAL MEDICINE pene in goitre has been presented uffected by occur far more frequently than do affected parents or children It hus been suggested that an autosomal receive gene is concerned and mental sbook, infection and other non-genetic agences provoko the expreson of the chanster in each u pon the the duplex state If there i tuberculous diathesis what does this mean genetically? It would seem that every indindual can become tuberculous but not always with the samne car. Some are more prooc than others some more routant. Mott authorita are of the opinion that such differences are due to in acquired Immunity but its undoubtedlythe car that different genotype In virtue of the gends they indude, equip their potersons with different characterization and that certain genotype may include genes which in their interaction yleld this quellty of resustance to tuberculous. If yo this resistance would be expected to be of a graded kind, the grade being determined by the actual genotype The evidence that genotypic differences are responsible for differences in reautance and rusceptiblity must be regarded u inconclusive The name is true of the role of the gero In the actiology of cancer in the human subject. Genes and genotypes are involved, it would rem, but to what extent and in what way are not yet knoom DIFFERENT GEND AND GWEIC AND ENVIRONMENTAL FACTORS YIELDDXG THE SAME CHARACTER Then there is the difficulty that urbes from the fact that one and the name defect of derangement can be awed by ach of number of genes quite distinct one from the other For crumple epidennalyn bwlosa lo recognized by the dinian to do in three forms the simple, the mild and the tevert. The first two are autosomal dominants the third partially my linked recenlve Sputic paraplegia ia in certain instances a partially rexlinked receive in other it in an auto omal dominant, Retiutus pigmentosa in dofcrent pedigreer is partially rexlmked dominant a partially ra linked recerute 1 totally was linked treeniva, in autosoma! dominant and an autosomal recesire the last being distin fuisbed from the rest clinically atace it adds deafness to the conditions in the eye. Of keratosis follicularis, Darrier s dlucose ·DIFFERENT GENES YIELDING SAVE CHARACTER 95 (oregrowth of the epithellal layers of the skin, hyuline degeneration to the hair follido specially on the bad, cboste kam und extremitos plus subnormal sature and mental deficiency) there appear to be two geoetic form, me in agtoromal dominant and the other a totally ma-take dominant. Atheroma and polydactyły in different tince behare o tatoomal dominant and u autosomal recem. Defective ename of the teeth has been reported u 20 autosomal dominant and about totally a linked dominant. That there should have been I certain confusion between autosomal and partially ka-linked genes i canity under Rundable. The impreunions obtained from pooled pedigrees o be corrected by the results of the thorough study of . combination of family pedigree studied separately and daturbances in the nation of affected and normal males and fernalo an indicate that what wu regarded u an uutosomal gond a really a partially nox-Inked one. But there surely is nothing surprising in the fact that different genes an und do yreld the aume abnormality in charactertuation. Normality is the outcome of a number of integrated and co-ordinated developmental proceeds in which the various moulding influences must be of cactly the right kund, must come into play u the right time and be of tho proper strength. If the nature of the genetic stimull becomes altered u the result of the mutation of coe of perhaps quite a large number of genes, if the tmning to altered or the freogth, abnormalty becomes the end result. But to the varieties of abnormality that can rosult from interference of this ruture there must be a hmit. If two quite different genes whould reader ! particular step to the development of character abnormal and aboormal in the amo kod of my affecting the timing of the entrance of a particular stimulus for comple it is not The Burpring that in the end they held the name character Anlaun of all people, annot be surprised that different agencies of the manne general kind an evoke the same reaction con he be purcled when he learns that an accident of develop ment or un environmental force coming into play at 1 attial the of development aan produce an ad rerut that w Identical with a chancter that b in other hastances purely genetic That diabetes insipidis can be in certain care the requel of ·6 GENETICS IN RELATION TO CLINICAL MEDICINE pituitary tumour in other the result of a syphiliti meningitis and in mll other the expression of a dosninant autosoma! gene merely means that the pituitary can go wrong only in a limited number of nan la so far # its effective endocrine contnbution is concerned and that one and the Hume reaction in cooked by a variety of agencies somne genetic and others environmental The fact that one and the same clinial muty an be curred by both genetic and environmental factor con lntroduce much difficulty into the interpretation of a pedigree. Daar mutim, for example, an be the proprion of an autosomal recruive gene in the duplex state also be the sequel of infectious disewe in early infancy Denf mutes tend to fann an wolate in the population and mutuage between them not uncommon It often happens that the odupring of two daf mutes are all normals Thc planation is that the deal-mutim of one or both of the parents ms not the genede variety but we an acquisition It CD FRESH OR RECURLINT MUTATION Manfently of the propontus is the first of his line to athibit an abnormal character a study of the pedigree will yield no Information whatsoever If the character be doplays to known to be due to a dominant with roo per cent penetrance then * pumetic mutadon must have occurred in the germ-tract of one or other of the parents If it in a graightforward recerAVC then, unless the parents whare a common ancestor zaprtic mutation must have taken place lo the maternal and paternal pedigrecs vorne generations back and the propositus in the first homozygoun rective to appear Recurrent mutation mut occur in the case of certain genes at least, for otherwise they would disappear through time u they destroy their possessions. The severe form of hemophilia Terbove the great majority of its exhibitors before they transmit the gene to progeny of the human X-chromosome two thirds are posessed by the female part of the population one third by the mal. It sure indeed for the gene for hemophilu In the male X to murrive the male that bean it. It is cren rrer for those on the Xs of the homorrow beemophilic fernale to per from ac gtation to the next. The only hemophilic genes that are regularty handed on are those of ·97 FRESH, OR RECURRENT MUTATION heterotygou femala So that unless the genes continually reinforced the disease pould die out. Epiloia, when fully aproved slays o mfancy it is only became the expresslylty of this dominant autommal genel variable that it can be handed on it all. The birth of an affected child to normal parents has been recorded oo kaal occanons and there an be no reasonable doubt that this gene too o reinforced from time to time by fresh or recurrent mutation, If it is mumed that the proportion of iodividuab poskuring • gene that day, a lethal gene, among the general population Tenure steady throughout many generations, and of the proportion of those who carrying the gene, are eliminated by It can be opened then it becomes pouble to otimate the amount of recurrent mutation that will be required to maintain the postulated equilibrium Exercices of this kind indicate that the arenge mutation rate for the human genes lo unilar to those which have been obecrred in very wide rinety of animal and plant forms. It is rappored by many genetidote that tho mutation frequency has become establohed through a process of natural selection of genes which affect the mutation frequency Huels, acting over thousands of milenia and allowing the proment spontaneous frequency to be us high u can be handled by the type of Ketective processes that operates In the auto of the human subject the ngour of selection has been lovered with the result that the spontaneous mutation rate bu got out of step and a higher than is required for tho maintenance of an equilibrium between mutation frequency and allmination. When an equilibetum b provered by recurrent spontaneous mutation It follows that different penes have different mutation rates since the lethals and the gerxes that lower the chances of trunarntion through the exerties of the reproductivo function will demand a more frequcat reinforcement through frab mutation than will gones that scrantage rather than handiap their posterior Asha Rady been stated the ause of spontancow mutabon bu not yet known. It is well-known that all type of short ware radation strongly augment this tendency on the part of gende to mutate, but In ddition to proroking point" mutation, the mutation of a particular gene theme yenda auk frag mentation of the chronomes and roaldistribution of chrono ·38 GENETICS IN RELATION TO CLINICAL MEDICINE come material. A fragment, 1 mall section of a chromosome is lost excluded from the nucleus (deletion) 1 piece of chromnouomo rejoins the rest of the chromosome to which it belongs but upside down (Inversion) piece of one chromosome joins the other member of the une horoologow per (duplication) piece of one chronxovome join a chromosome of another bomologow patr (translocation) a whole chromosome is lost to the nucleu of one daughter cell and gained by the other (heteroploldy) the pobole chromosomo ket becomes multiplied (polyploidy) Most of these phenomena have not yet been observed in man. It can ufely be assumed that they occur horwover The urtifiau induction of mutation evoka nothing that does not normally occur it merely increases the frequency of the occurrenco. It can be imagined how linkage relation can be durrupted by much event u translocation, an autosomal gene become a KOX-linked gene and so on It u fortunate from the geneticist's point of view that spontaneow mutation und chromosome maldistribution are so rare. Wero it otherwise the building of the edifice of genetic theory would have been a hopelou tak Is this tendency to mutate an advantage or a dudvantago to the species? It is conventional in genetia to gtve to a gene a name that at first sight would seem to suggest that the gene hus but one action the evocation of the one character the beneticist waign to it--the gene for poosis the gene for albinism and so on. This suggestion to partially shattered When the gene standa for a syndrome, for example, the autosomal Secessive gene for the Laurence Moon Bledl syndrome or the autosomal dominant gene for blue klerotia und for bone fragility The great majority of gends are pleiotropic it la merely a matter of convenience to name then according to their most obviou or most teriam cffcct Genos interact with one another large number of thein are involved more or kers in the production of any given chincter Fortunately there is usually one that more responsible than the rest and this is the one the genetiart picks out us the gene that correr ponds to the character In doing so he dog not deceiro himself he love that many others are concerned There is a whole genotype lying behind a stole characterisation, od that conceration b in harmoony with the conditions ·VUTATION 99 of the indinduels external world There is hormony between genotype phenotype und environment. If thus be so if thus be normality than mutation mut destroy it. Mutation manc locus affects the whole genotype in action. This must change more or less the phenotype and this become out of harmony with the external world. No wonder that most mutations yield allela that are dlaadnanbigcow to the individual in whom they find coprension. Yet without mutation bow could there be change? How could the genotype como into harmony with m altered cvironment ? Mutation is the means whereby our evolutionary development has been made poolble, It being uwumed that we are the ucendants and not the descendants of 1 for more primitive stock. The varubullty and adaptability of a species depend on gene und chronxccome changes Adaptabihty to achieved through the resolution of conflict between organium and avtronment. The latter is in a state of flux and its changes fart or slow tend to make tho genotypes of bygone generationis no longer fit for survival The conflict between species and habitat aan be resolved ether through the extinction of the species or through reorganisation of its genotype, Manifestly what a needed for crolutionary change to intrequent mutation and the opportunity for a mutant gense to find belf in various geno compania in which it can hide itself until it becomes mmodated with auch gene compenlans - will suppress to deleterlows actions and encourage its beneficial ones (it, ke all the rest, being pleiotropu ) Obviously of a mutant gene is dominant and deleterious It annot be hiddless, it will be apressed and we wipe itself out. But if the receive it aan alat for many generations and in variety of genotype before it b expreased A mutant gene in the beginning is ongle gere Il will therefore akt only in heterorypow individuals for com riderable number of generations. During this twoe it can find itself in penotypes in which other geng modifier an act In concert with it. If it gields an improved phenotype then it will be to the adnntage of the species that thu aleke shall be 1 dominant in relation to the gene from which isprang If It should yteld in inferior phenotype then it will be to the advan tage of the speca that it shall be a recendre The modifying nation of other gena an yield the dominance and receiveness ·IQO GENETICS IN RELATION TO CLINICAL MEDICINE A survey of genetic abnormalitia in man show that many of the rare disorders are simple recentives and that such u ure not have a verlable expresivity they are us it were, on the way to corapleto recensiveness. Then there are many po-alled dorninants werowly diadvantageoro-Huntington, chorea and epiloia, for example—which are only encountered in the heterosygous Arte. It bo not know whether the homozygous Individual would chibit the condition to an even greater degree it is highly probable that they would. Being heterotypow there individuals sbow considerable vurlability m rapect of character expresal00 and also of gene penetrance. Thus it is that environmental agencias con cierta Kelective action upon the character and through this upon the frequency with which the geac is to be found in the population If the characterisation of a specia lo accord with the conditions of a static environment then mutation is underable, If the arcumstances within the environment change--and we have changed those of oim profoundly during our social evolution-then mutation is desirable but it must not be frequent otherwise the enential stabillty of the gene would be lost. Mutation u not purposeful but ruador. It produce allelas of 201 lands good bad and indifferent w judged by their difects upon tho vital processes of the Indivdual. The must majority are detrimental corde are lethal they eliminate themselves and are maintained only by recurrent mutation. For every fully lethul gene there are two or three which aro rublethal yielding lowered vlability and efficiency The former slay the latter constitute a severe handicap A very few coofer undoubted adrentage immediately and the selective agence of the environment encourage their cad 20100g the population and the development of the attribute of dornin- Most normal genes in our genotype arome through mutation presumably and they are in the vast majority of instuces dominants Others yield effects which are . murture of advantage and dindrantage. The modifying action of other geno ci ruppress the latter and low for the gradual cultivation of dominance by an alele which later through selection will replace the gene from which it sprang Multiple alleomorphic solas can be regarded us the pronsion through mutation of a muriety of uletos of different ment and demerit wluch are anailable for testing and approval by the selectiro Occ.

·REMOTE EFFECTS OF EXPOSURE TO RADLATION IOI ystades within the genotype (modifier) uod the external atvironment TaE POSSIBLE ROOTZ ETECTS OF EXPOSURE TO RADLATIOX Muny patients are much pored powdays to Xray in diagnoda und theripeuca In industry large number of pooplo ut cipared to the action of pbylal chemial agents known to be mutagenic. Smce it is established that empowurt of the Hod doa in forms other than man lead to murdan (gene mutation, chromosome fragmentation maldintribution) the question as to whether or not such a po uro in the cake of the human subject yrelds the Ame results at once urmes. We do not know for the matter hu not received sufficient attenthan But if to this respect man s like the mouse then it lodeed probable that mutation has not commonly been produced There is good reason for the display of monety Tho trbuting evidence for an adverse effect of therapeutic pelvic redudon on the foetus is conflicting Microcephaly hat been reported. The can be the exprension of a recen ve gene but it difficult Indeed to suppone that the radiation of womaa koown to be pregnant and therefore of a foetus already wel formed) can produce mutation in the two members of a particular pelr of genes It certainly might directly disturb developmental procesas already in progres But there is no wife donc and all radiation of the goruda is genetially objectionable. The testes and onine must alway be protected, it being remembered that the frequency of mutation is directly proportional to the total dome of Irudiation received regardless of how dluted protracted, Interrupted or concentrated the opposure may have been. There is no thrabold dare ud the effecture cumulativo over an Indefinito period througbout the whole of an individual. lifetime. It seems probable that a total accumulated dose of about 357 ypplied to gunetes or about root applied to the gonada would cause a doubling of the natural mutation rate As most mutations tend to be recente their efects will not be disclosed for many generations which means for hundrede of yan.

·CHAPTER VI ON THE TRAXSNUTATION OF KNOWLEDGE INTO ADVICE With the background no pronded it should be possible for the cliniclan to proffer round advice besed on scientific fact and reasonable interpretation to tuch us reck it concernmg the genetic nature of the abnormality which they themselves chibit or which their ancestors of near relativa have displayed and which they fear may reappear unong their offspring That which follows will consider the nature of ruch advice To know is one thing to advise be another To matyba not recently to procreate. Advice based on genetical knowledge to not concerned with the cohabitation of an adult heterosexual pair it deals with the powibility that girai mated pair day produce an abnormal child Advice derived from a knowledge of genetia alone must remain incompleto it must be based also upon a knowledge of the personalities of the partners and of thetr eico-economk circumstances It is the offenng of an understanding sympathetic, obec fnend and not the overpowering instruction of an authority It w for the recipients to make decbiom, it is for the adviser to ud then to ensure that their decimons are webwe. The clinician, though dealing with the problema of particular couple is in fact playing his mall but important part in shaping the future. He is influendng in anull measure the frequency of . Bere in the genetical constitution of a people. The family doctor is often thr physician of the future To offer advice of general kind us of no great value. Every aux must be dealt with on its own merito There are certain broad principles that can be stated bortre which an form the nucleus of a more detalled consideration Ax culosomal nessa corresponding to a pathological chricter and the partully rex Inked recove). It be imponible to eliminate such a gene from a population merely by denying parentage to much u exhibit the corresponding chandter To do so would be to leave the far more aconcrow beterozygoter untouched in the aute of a recente autosomal ·ON TRANSMUTATION OF KNOWLEDGE INTO ADVICE 103 gene, auming random mating the number of beterozygotes (As) in a population is twice the square root of the number of the two bormorygous case (AA and 2). Thus If the number of indivduals in the (AA) phenotype is and of those to the (u) phenotypo is go the three genotypes A4, At and u are distributed in the proportion 2 g Thu f. particular autosomal rectaire chancer in chibited by one in a million of the populatioa the frequency of phenotypically normal individuals heterozygous for this gene i sround one to five bundred. The me the gene in question the greater the proportion of heterosypotes (12) compared to individuals homozygous for this recentro gene If as many u coe in a hundred of the population chibit particular receive character (mn) then the heterozygotes (Aa) will be only eighteen times more numerous than those who chibut the character If both prospectire parents exhibit the character oo also will all their offspring If one of them is affected and the other is unaffected the latter may be a beterorygott. A pedigree may provide the evidence. If bo or sho ba heterozygoto then the chance that the child will or will not ahibit the character are equal (A.Xu - Az u) If he or she is not a heterorypoto l the offspring will be phenotypically normal but genetically heterozygotes (AAXU - Aa) If both of the prospective parents are pomalble beterozygotes the respective pedigrees showing the ume defect then the chance that the a spring will be abnormal ero one in four (ha XAR - I AM 1 A2, 12) Ax autosomal dominon (including the partially sex-Imked dominant). The pathologlal characters of this bod that matter are ruro and are those that are worlovaly deleterlow and uro aprened in the beterorypote. There is no point in denying parentage to the chibitor There are remarkable for u diminbhed viability and reproductivity The recurrent) mutation nte is bully poch us to maintain the low frequency with which the gene a found in the population. Short of devsing (chemial?) means for the overwhelming during development of the action of such a gene we muat wait until it has become a recente If on the other hand, the dominant rent doa mot equip the exhibitor of the character rith lowered viability and ·104 GENETICS IN RELATION TO CLINICAL MEDICINE reproductivity and if the mutation rate is lopp non-propagation on the part of the ahibitori an be expected to dimloush the frequency of the gene in the genetical constitution of the population But en earnest couple deeply conscious of a responsibilty toward their umconceived child will not be interested in these matters. They want to disco the chances that a particular individual the child they wish to bure will be abnormal If one parent cxhibits the defect half the offsprlog an be expected to do so or there is an equal chance that a child will ahibit the character or will not (As Xux Aa a) It is most unlikely that the affected parent will be homozygou If Aether parent be affected though tho character u present in their pedigrees they are normals and their offspring will be normal (in the aboence of mutation which is very raro) A Totally Sex lonkan Rocession The much either normal or else affected he cannot be a The female can be normal a carne or affected. The only real difficulty is the identifiation of the carrier A female certainly a carrier of one or other of her parents wu affected and the other normaal (AX)YX(2XXX) - (AXX (2XXY or (EXIY X(AX)(AX) - (Axa (AX)Y She may be a carrier of her mother was a arrier and bet father normal. (AX)YX(AXXX) - (AXXAXI (AXXadt) (AX)Y (2X)Y She may be carrier of her mother nua arrier and her father affected (X)YX(AX) (EX) - (AXX() (2XXX) (2X)Y (4)Y A murrey of the close relatives of the partnts and of the tibe of the female concerned my furnish con siderable und Reference to the red-green blindnem mating will provide the raw material of advice. CEITO WHIN PENETRANCE IS LOW Low penetrance introduces a serious emburnament to the offering of firma advice. To Ay that leukemi base penetrance of only about i per cent does not mean in the least that in the child under desciaion the character will not be fully expressed There is no telling Tbe prospective parents want to know what the chances are that this particular lodrvidul will be affected. They cannot be expected to listen to a keurned doquisition and to pro admiration for the profundity of coc a knowledge ·PROSPECTS OF SIBS YET TO BE CONCEIVED 105 Coordder for example the care of a young man roffering from kevert otosclerosis who whes to me ty His father daf but the nature of hu dafnes m not recorded. There b do hlatory of otosclerosis in the prospective bride a family What likelihood is there of a child of this marriage chibiting thla defect? Otosclerods can be genetic or non-genetic in adigen. When genetic, an auto ornal dominiot gene with Yanablo penetrance la responsible In hause therefore the question as to the nature of his father a deafnem urmes great importance. If nothing can be learnt about this it becomes nccouary to usure that it mu the genetic form of otooclerosis Then the prospect of a child of the proposed marriage developing the condition would be one in two if penetrance were complete A careful crimination of tho medial hatories of the wide of the propositus end of those of his father might show whether penetrance wus varuble. If it were the prognob would be Improved CONCERNING THE PROSPEITO O SIBS YET TO BE CONCETYLD If a phenotypically normal couple have prodo.ced a child exhibiting a lethal or Kalously irreparable dandvantageous chincter of undoubted genetic origin towards the etiology of which environmental gence have contributed little or nothing they should be advised to have no more. Whenever Dan-propagation I recommended the question of the adoption of a child of different parentage should be dlocumed, particular attention being paid to the question of the IQ This is advice derired dot from genetical bowledge but from the teaching of the paychalogiat CONSANGUINTTY The degree of blood relationship now being conndered is that which displayed by individuals whose mamice is potuitted by our lan. It not that degree which wociated with mating regarded by our soclety and its lan u incestuou. From the purely genetic point of view there to do nential difference betreen these two in kind bart only a difference in degree. In the case of father x daughter mother X10, brother X skuter mating the genetic constitutions of the individual ·100 GENETICS IN RELATION TO CLINICAL MEDICINE concerned include very many genes in common. One hall of all the genic material of 2 daaghter has been recared frown her father one half of all the autosomal Daterial und hu X-chromosome have been receired by a son from ho mother it b highly probable that the genotypes of brother and sister will be for more nearly alike than will those of an unrelated mule and female. If it is accepted that the genotypes of the rust majority If oot of all human beings are haviy fonded with undetrable recessive genes which remain impotent so long as the meting of heterozygote Xheterozygote does not provide the chance for their capratsion then mcestuous matings must be condemned It must be remembered, moreover that in our soclety those who indulge in this form of Degal activity are trually such as are unable to accept the current social standards by rauon of ther mental or moral subnormality innate or acquired Even although thar genotypes happened to include no common growly pathological receptore genes it remains pomblo toat they would be deficient in respect of the genes for high grada of general intelligence. In any are the individuals concerned are commooly quite incapable of providing in the horne the kind of environment which is essential for the proper develop ment of the child. This matter of consaguinity is wually related to the quation of the desirability of the martuge of first cousins There share in common coosiderable amount of chromosome material received from the ame pats of grandparents. It is therefore anirently possible for each of them to be heterozypona in respect of the same recessive gene corresponding to character of a pathological kind. Its for the reason that Inbreeding that breeding system which involres the deliberate mating of pour blood relatives has been so ful an instrument in general enquiry and in anual and plant improvement By means of Inbreeding the undainble that hidden becoma revealed end ko rock an be purged of its unwanted receiver In the case of man it is highly probable that when the pedigree of an affcated child suffering from a very nit recepire character by searched it will be found that its parents are near blood relatira. This is apecully so in the case of a female child who exhibitor rire receive sexdinked choicter The frequency of couem marriages in our society is of the ·GENETIC AND ENVIRONHENTAL FACTORS TOT order of o 5 per cent Progpective parents who share i cormon mcortry to which a seriou receive defect has appeared should be Informed u to the bearing of conungunity on the produc tion of homozypote If in the pedigree there is no record of goetic aboormality It will be difficult to find mufficient awe for advising non propagation On general grounds, however the advice must be that the marriage of Dear relatives is hazardows and not to be encourged. In the construction of pedigree it bas to be remembered that there do great profit in attempting to work back to the P and P, generations. It b Infmitely soort important to collect fall and accurate recorda of the parental generation and of the ribe of the couple Coccerned. A great deal aan be made of these. CHARACTEIS CAUSED BY THE EXTERACTION OF GENETIC AND ENVIRONLLATTAL FACTORS There ba mtofaction in the knowledge that many abnor malities are of this kind since the control of the environmental factor roaden tho genetk fuctor impotent. There undoubtedly La genetic factor powibly wo autosomal dominant with a low penetrance, involved in the strology of Mongolur, but the genes) that les at the root of this character requires spedal intra-uterine environment of it is to gain premion. The repair of the environment in attempt to eradicate Mon golian would seem to be a far more hopeful took than to ende pour to control the action of the gene or to eliminate it from the populabon So abo In the case of tuberculoans. If the environmental awal factors ure mastered the genetic factort an be disregarded. But it has to be noted that by doing there will remain in the population large numbers of Individuab genetically prone and that should the environmental factors ever come into operation through wormening of the standards of living tuberculoos aan become 1 Konge. The prevention of dbeurt of this kind through the control of the avronument demands that this control shall never be reland. Concmno MDI MALAOS By mbed is meant the mourage of indindual belonging to different geographlal prieties of kome spins Of these po-alled nica there are three main stens recognized by ·108 GENETICS IN RELATION TO CLINICAL MEDICINE the anthropologust, Whites Yelor Browns and Blacta (Caucasoid mongolod and negrord) There are subdivisions of each of them. Of the Whites there are humitic, remitic, Mediterranean Alpine and nordic of the Yellow Browns there are the mongolic, the Malay and the American of the Black there are the negrito the negrillo the bohman and Hottentot and the negro Polynesin and mongoloida would wem to be hybrids betereen the white and yellow browos Australians and Papuans hybride between whites and blacku. Each geographial parlety differs from the others in respect of it genotype and therefore of its phenotype. They are to be detinguabed one from the other by reference to nich characters u skin colour hair colour torture and distribution, head shape und so forth. They differ in respect of gene content and in the frequency with which certun gends are to be encountered in the population All art mutually fertile. Whether or not it u demorable or undesirable on goetical grounds for representatives of any two of theto varieta to marry and reproduce to be determined by the effect of the pooling of the genotypes. These varieties evolved as isalata. That is to my auch, bang separated from the rest, evolved it own genotype through mutation and kelection Each may have come to ponto mutant genea abuent from the genotypes of tho rast. Each, as the repult of mutation and selection, came to be in harmoony with its own pecuur external world. It hus to be noted, however that in recent time there hus been much inter breeding between most If not all of these venetian so that in respect of gene content and frequency all are much more alike than they were when auch wu an lolate. None of them u puro in the genetical wenke any longer for pooling of genotypes hu ready occurred There is evidence which seems to show that the offering of certun varietal crosso do ahibit certain anatomial and other duharmonia. On the other hand it ctablished that many intervinietal hybrids are biologially quite efficient If man s, in this respect like other annat it would be expected that In much offspring would be remarkable for hybrid vigour Yery wirley there is the pare wide range of vurdon In raspect of phytal perfection and mental ability though the main may differ from variety to rariety ·EPILOGUE MTMnct There certainly is no genetical problem in the Intermartlagt of representatives of subgroups of any of the malo stes, of en Alpine uod a Mediterranean, for example There would Keem to be done in the mtermaruage of white and mongnload or of white and yellow brown. The fact is, of course, that trually the different rurieties bure developed different cultures and art comiponly to be datinguished one from the other lo respect of ethic, habit and Intermarriage to far more than a purely biological ad renture it farala tho clash of cultura diferenco in Handards, habits valoen The mamago of black and white, for emple, urually means that one or other of the partner nut become a member of 1 soocty in which he or she must remain teringer Off spring of the marriage, besides being half-costas can bo social outcuts for whom there o no place The problemus created by the marriage of Scots gui to a negro ure of the name kind those produced by the marrluge of 1 Roman Catholic and an agnostic or of a Jew and a gentile. They differ only In degree. The dannbility or otherwise of such marriages to bo determined by coosiderations of the social arcunstances which will curround the mated pair and their offspring EPILOGUE Medidoe to the means used in the establement and re-establishment of harmony withm the todividual and between the indivdunl und his external, phyrlal and model world. It attempt to establush hornogy between the individual and ble environment by rerroving from the latter all wences Inimlaal to the well-being of the Inhabitants and to congregate within it all those sendes which promote the development and maintenance of bealth. By means of education concerning bealth and disease, and by nuccination and doculation or by ruch mauud u palodrido administration, medidde attempo o to modify the character bution of the individual that he finds hoxe adjusted to the condition of the environment ind so is enabled to flourish therein Through the duscovery of a booledge and its incorpora tion in practice, medicine bus gained great pover. The futuro ·110 GENETICS IN RELATION TO CLINICAL VEDICINE will see these greatly augmented. There is no hint u yet however that it will soon become possible to to control mutation and to modify genic action of an undesirable nature that it effects during development will be checked or reversed. All that we an hope at pretent is that in Increasing meaning surgal, biochemical or other means will be discovered that will reper the abrsormality aused by the gene Surgery can repair polydactyły Insulin can control diabetes. The prevention of purely genetic abnormality must take the form of the extirpation where this posible and dearable througte non propagation of the genes concerned from the genetic constitution of the population. It must remain imponible to advocate nors propagation until our knowledge of the retiology of many of these conditions is far more exact and conclusive We have learnt that ennironments differ in respect of their ingredients. We have learnt abro that in a hurrian population there are many different phenotypes based on different genom types No environmat u optimal for all genotypes, no single genotype can provide phenotype attwed to al environments Diversity in characterimation - der ble in a human racfety In the ideal haciety there should be both environmental and Terrotypic variety Medicne should him at the dimination of all norronmenu which prevent or binder the expression of tborc genetic qualities which use biologically mod nocially valuable and at the eradication from the population of those genotypes which render their pontessons incapable of Bourishing in any of the varieties of environment that art propitious for the manifestation of stologically worthy genetic endomment. There may come a time when in our programme for the achievement of buman perfection we may wah to treat gessetic doente by genetical therapeutis For this ration It is deinble that even now every effort should be made to expand our Inowledgt of human geneties in order that If required the #ppropriate instrument of therapy muy be found sharpessed and ready in the medical anmamatasiun One purpose of this book has been to enlux the cooperation of its readers ·LPILOGUE The student's advised to make use of the folloorin for further reading BLACIN, C. P (1994) The Cherrs Natu Inkrutane Laris COCATE, E A. (933). Intro Arnalutis e SH* Adidas Oxford University Press, Loodon. Car TAE (190L So Driwrnation Methuen, Loodoo. DAUDOTOX CD (1997) Racos A HOKA in Cytatng Ch London. Fan, RA (1990. The Geneticed Thury of Neund Selector. O Ustrentity Press, London FORD EB. (19401 Woudelism and Emotim. Hethorn, London. Forn, EB (976). Grudia for Medikal Studios Hethren, Looda GATE, R. R. (1976wwwa Gontics Macmillan, New York GOLDSCHMIDT R. (1934). Physiological GT cGraw HAI, York and Londoo. Gyurma, L. (1947) Asima Gentics and Hodkin Hant Hamilton, London. HALDATLJ B. S. (199) Th Canses Ambient Loogman London HALDAIL, J BS (1995) Horndauty and Politics Allen und Uowi Loodon. HALDANE, J BS (1941). No dis de Graetics Allen md Unwia, London HALDAXL, S BS (1946). Tbc Formal Genetia of Man Croonias Lectare, Royal Society of London. Pros Hoy Sa (British) HUL BRADFORD (943) Principles of Maliaal Statuta, Lone London, Home LT (9991 New and ww Allen and Vann, Loadoa. Homu LT (1947). An Introduction National Genetics WW Norton, New York MATHI, L. (9) The Answeat of Links Handy Metlen. Punon, LS(9) The Internet of Herndly m Dewass Laris, London, Purya, R R. (1946). Fonsbad Sumowy to Twierwhests Harnard University Prem Roniti, I A. Fu (1970) A* Introduction to Main Costa Oxford Ustrersity Press, London SCHUTTLLD A ( 999) You Ilmaty Chutto med Hodon, Loodon. WADODIOTOX CH ( 9 An Introduction to Nodern Gratis and Uma Loodon. WRITI, MID (937) The Clers Ketbaren, London Attention abould also be paid to the following fourmak The ſurnal of Grands (British) Comix (Amalan The formal Hornday (Americal Hernaty (British) The 's Y Express (Britbl) Esms low (Brithibi Bitra (feat. Am