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The hereditary defects: congenital dropsy of cattle and atresia ani of swine Irwin, Robert Edward Thomas 1951

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THE HEREDITARY DEFECTS CONGENITAL DROPSY OF ATRESIA M I  CATTLE AND  OF SWINE  by ROBERT EDWARD THOMAS IRWIN  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN AGRICULTURE in the Department of Animal Husbandry  aooept this thesis as conforming to the standard required from candidates for the degree of MASTER OF SCIENCE IN AGRICULTURE  The UNIVERSITY OF BRITISH COLUMBIA October, 1951  ABSTRACT  Two hereditary defects. Congenital Dropsy of cattle and Atresia  of swine, are investigated. The introduction makes ref erenoe  to the evolutionary significance of lethal and sub-lethal oharaeters and compares i t to the importance of such faotors to the practical breeding of livestook. Some reviews published on the hereditary defects of farm animals are listed.  Part one i s oonoerned with the congenital dropsy defect which was observed and studied in the Ubyssey herd of registered Ayrshire dairy cattle owned and bred by the University of British Columbia.  The history of the herd and the breeding practioes employed sinoe the herd's foundation are outlined.  A single-factor recessive genetic hypothesis to account for the occurrence of the ten defective oalves i s formulated and tested. Genetic analyses of the pedigrees of 153 of the 501 oalves born i n the herd up to September 30, 1951 indicated the average theoretical probabili t y of the defeot oc curing to be 0.0853. A test for the ''goodness of fit'' was applied and showed that the sample studied f i t s the hypothesis.  The etiology and pathogenesis of the defeot are investigated under a working immunogenetio hypothesis based on the two assumptions: l ) that the defeot, congenital dropsy, i s the counterpart of the hereditary disease of new-born infants, Erythroblastosis f e t a l i s ; 2) that the Rhesus isoimmunization theory which serves to explain the familial; incidence of the disease i n humans may be adapted to the genetics of cattle populations. The immunogenetio studies undertaken to test this hypothesis are described and an explanation of the results, aberrant to the hypothesis, i s offered.  Part two deals with a more complex hereditary defect. Atresia ani of swine. The literature i s reviewed. The histories and pedigrees of three abnormal l i t t e r s born i n a local herd of registered Yorkshire swine are presented. Two explanations of the possible mode of inheritance of the defect are put forward and tested on the sample available for study.  The recommendations made to the breeder which would enable him to r i d his particular herd of breeding stock of the defect are quoted.  The conclusion i s a brief discussion of the problems confronting the breeder of registered livestock i n whose herds or flocks a hereditary defect occurs.  The appendioes inolude explanations of the methods used to calculate the coefficients of inbreeding and of probability. The ohi-square test f or''goodness of f i t ^ i s outlined. The procedures for the serological reaotions employed in the immunogenetio study of cattle are also presented.  ACKNOWLEDGEMENT For suggestions and guidance i n undertaking the genetic studies included i n this thesis, the writer i s greatly indebted to Dr. J. C. Berry, Professor i n The Department of Animal Husbandry, The University of British Columbia. Special thanks are due Dr. S. N. Wood, Professor i n The Department of Animal Husbandry, The University of British Columbia, for his invaluable assistance i n the immunogenetio phase of the work.  TABLE OF CONTENTS PAGE ACKNOWLEDGEMENT INTRODUCTION PART I I  II  III  Edematous Calves i n the Ubyssey Ayrshire Herd A The Ubyssey Ayrshire Herd B Congenital Dropsy i n Dairy Cattle C Erythroblastosis fetalis i n Humans D Immunogenetic Study of Cellular Antigens i n Cattle 1) The Antigen Theory; Agglutination and Hemolysis 2) The Number and Interactions of the Cellular Antigens i n Cattle E Hypotheses to Account for the Occurrence of Congenital Dropsy 1) A Genetic Hypothesis 2) An Immunogenetic Hypothesis  1 2 3 5  7  Formulation of a Genetic Hypothesis A Pedigrees and Calving Records B Formulation of the Hypothesis 1) Basic Assumptions 2) Heterozygotes i n Pedigrees C Testing the Hypothesis l ) Probabilities of Homozygous Recessives D Discussion of Results  16  Formulation and Testing of an Immunogenetic Hypothesis A Formulation of the Hypothesis B Testing the Hypothesis C Discussion of Results  19 20 21  9 10 13  PART II Atresia rvni i n a Yorkshire Swine Herd A Review of Literature B History of Atresia ani i n "the Local Herd C Pedigree Analyses D Genetic Hypotheses 1) Single-factor Recessive 2) Two-factor Dominant E Recommendations to the Breeder CONCLUSION APPENDICES LIST OF REFERENCES  23 24 25 27  i IHTRODTJC'i'ION Variations i n the form and function of organisms enable populations to meet the foroe of selection, whether i t be natural selection or the seleotion practiced by breeders* If populations lack sufficient variation to meet changes i n the environment they become extinct* No environment is static The governor of the evolutionary process, seleotion, continuall y makes use of variation i n evolving the forms best adapted to the environment. If an individual form exoeeds the limits of variation allowed by the environment i n whioh i t must l i v e , i t i s unable to reproduce and the germ plasm which i t carried i s eliminated* This i s seleotion* Nature's passive seleotion has, for many speoies, been superseded by man's active selection. Though the living entity i s not immutable but rather prone to vary, man's seleotion i s based on the static concept of the gene* For the practical breeder, the statio concept suffices. To the b i o l ogist the dynamic conoept i s neoessary to aoeount for the variations i n heredity* In the practice of seleotion breeders assume that the offspring of the parents selected w i l l receive a sample half of the parent s heredity. 1  If the progeny vary from the expected beyond the limits allowed by the breeders' standards i t i s usually right to assume that one or both parents carried undesirable germ plasm. If several offspring deviate greatly i n form there i s extremely l i t t l e ohanoe the genetic control was altered by a mutation. Though natural seleotion i s passive, the forms i t has allowed to evolve are well adapted to existing environments. Deviations from the normal  ii are for the most part less adapted to survival and are therefore deleterious* The abnormalities are referred to as hereditary defects and said to be under the oontrol of lethal or sub-lethal genes. Natural seleotion has largely eliminated the single-factor dominant lethals and sub-lethals. There are s t i l l large numbers of single-factor recessive lethals in each population* The genes controlling the latter are capable of phenotypio expression only when they ocour in the homozygous state. Sewall Wright (1931) has shown that a large population mating at random can support a large number of recessive genes. But with the domestication of species, the creation of the races known as breeds, and the division of the population into isolates, true random mating i s non-operative. The number of recessive genes that may be carried i n the population i s much reduced. Inbreeding which of necessity must occur in isolates inoreases the inoidence of the homozygous recessive genotype and the lethal or sub-lethal phonotype. As the practive of breeding within closed populations oontinues, more and more homozygous reoessives w i l l be segregated* Individuals of reliable pedigree, high individual merit and good breeding worth may be developed by the application of inbreeding i n a line breeding program, but the breeder must be willing to risk produoing a greater number of homozygous reoessives* Not a l l , but most homozygous recessives are deleterious. The ease with which a population can be r i d of the genes causing a deleterious phenotype varies with not only the basic mode of inheritance but also with the fecundity and prolificacy of the animals. The seleotion pressure that may be applied i s governed by the reproductive rate as well as the eoonomio value of each individual. The hereditary defects of livestock were reviewed by Hadley and Warwick (1927). Later reviews include those of The Imperial Bureau of Anim-  iii al Genetics (1931), Butt (1934), and Eatfcn (1937). Lerner (1944), and Rioe and Andrews (1951) have compiled l i s t s of a l l reported lethals and sub -lethals of livestock and man. The mode of inheritance of most defects i s known. Of the thirty-four characters for whioh the hereditary control has been determined, only two are of the dominant type. The more reoent l i s t includes only nine characters of unknown heredity. Hereditary defeots i n animals are either anatomic or physiological alterations manifested as ohanges from the expeoted either i n appearance or i n function of body parts involved. Aberrant embryologioal development may cause similar defeots, but they may not be hereditary. Breeding tests must be conducted, or family histories must be seoured i n order to determine whether or not a given defect i s heritable.  1 PART I I  Edematous Calves i n the Ubyssey Ayrshire Herd A  The Ubyssey Ayrshire Herd The University of British Columbia Ayrshire herd of dairy oattle  has as i t s foundation, twenty-four head imported from Scotland i n 1929, The present herd of seventy-five head i s linebred to three foundation imported cows. These oows weret Rainton Rosalind V  -130259-,  Ardgowan Gladness II -130282-, Lochinch Lassie-130269- • A l l animals i n the herd trace from two to six times to one or more of these cows. Three recent herd sires are sons of these cows. These sires are: Ubyssey Rosalind's Admiral -226521-*, Ubyssey Governor's Spitfire -246791- , Ubyssey White Cockade -269047- . Admiral i s a son of Rosalind and a grandson of Gladness, While Spitfire i s a son of Gladness and a grandson of Rosalind, White Cockade i s a son of Lassie and i s by Spitfire. The present herd sire i s Ubyssey Admiral's Commodore -307558-, a son of Admiral out of a daughter of Spitfire. The junior herd sire, Ubyssey Cockade's Senator -339650- i s a double grandson of Lassie, by White Cockade and out of a daughter of Admiral. Commodore has sired eighty calves. Eight of his calves have been abnormal at birth. A l l eight, four males and four females, suffered from accumulations of body fluids i n the subcutaneous fasoia manifested as aocute edema. Only two calves born i n the herd previously had shown somewhat similar abnormalities. They were sired by Admiral. The high incidence of abnormal calves amoung those sired by Commodore led; to the undertaking of a genetic analysis of the problem. I t 1  seemed more than coincidental that Commodore, the half-sib of two abnormal olaves, had sired eight similarily abnormal calves* B  Congenital Dropsy i n Dairy Cattle The anomaly observed i n the Ubyssey c&ives i s comparable to con-  ditions reported to have been observed i n certain Scandinavian dairy cattle herds. In his check-list of the lethal genes of cattle, Lerner (1944) has included 'Congenital Dropsy*. The condition i n Swedish Fresian cattle was studied by Larsson (1935) and has been reported by Johansson (1939) to the International Congress of Genetics. Korkman (1940) has described similar oases which oocurred amoung the Ayrshire cattle of Finland. The f i r s t oases he observed oocurred i n the progeny of the bull Dunlop Talisman, imported from Scotland. Johansson reported that the congenital dropsy shows wide variation i n manifestation, some fetuses being greatly enlarged through accumulations of fluid i n the subcutaneous fascia and i n the body cavities, while others are only slightly abnormal. He states that gestation periods i n oases of fetal dropsy average 226 days, with a range from less than 150 days to 277 day8. Early dropsical degeneration i s followed by early abortion, wher<aoj& the gestation period may be normal i f the degeneration starts late i n intra-uterine l i f e . Johansson reports further that pronounced dystocia i s the rule i f pregnancy exoeeds 200 days. The dystocia results from the enlargement of the fetus to more than twice normal weight. The slightly defective animals are born alive and may live for several days or weeks. The extremely defective are stillborn or die shortly after birth. From a study of Johansson's descriptions and from observations of the oases i n the Ubyssey herd, i t would seem reasonable to assume that the disease i s the same as that occurring i n Scandinavian herds. The nomenclature adopted by Lerner, congenital dropsy, therefore seems applicable t© the oases observed at the University of British Columbia.  s Though Lerner (1944), and Eioe and Andrews (1951) have listed oongenital dropsy with other defeots controlled i n heredity by single, recessive factors, there are not, aooording to Johansson, sufficient oases on record to establish the mode of inheritance. Johansson notes that the cases he observed occurred only amoqnc the progeny of some oonsanquineous matings and suggests the control i s by a single recessive gene. Korkman*s analysis of the oocurrenoe of the abnormality indicated that a single recessive gene oontrols the inheritance. No investigation into the etiology or pathogenesis of the disease has been reported. C  Erythroblastosis fetalis i n Humans The disease erythroblastosis fetalis i n humans has a marked fam-  i l i a l incidence, but the mode of inheritance governing i t s expression i s not known. The study of the disease i s further complicated by the manifold c l i n i c a l manifestations commonly observed. In most instances the disease, takes the form of an edematous condition i n the new-bom infants. According to Weiner (1946) there are two clinioal syndromes* the f i r s t , congenital hemolytic disease with anemia and/or hydrops; the second, ioterus gravis (acute yellow atrophy of the l i v e r ) . Davidson (1945) states that a l l c l i n i c al entities of the disease are related genetically and etiologioally, but none of the syndromes are pathognomonic (peculiar to the disease). He has outlined a principle for the pathogenesis of erythroblastosis f e t a l i s which i s based on the isoimmunological reaotions of the Rhesus (Rh) group of antigens which ooour i n approximately 85 per cent of Amerioans. The Rh-positive husband of a Rh-negative woman transmits, as a mendelian dominant, the Rh faotor(s) to the fetus. The Rh-antigenic substances pass from the Rh -positive fetus through the placenta and incite the production of Rh antibodies i n the mother. The latter pass from the mother through the plaoenta to the fetus where they act as hemolytic agents and initiate a sequenoe of interlocking pathological changes. Similar explanations have been offered  by Weiner (1946), Levine, et al. ( 1939, 1941 ), Potter and Wilson (1945), and Irwin (1947). The Rh isoimmunization theory of erythroblastosis fetalis oan explain the familial incidence of the disease. While the above authors aoo* opt that the human placenta i s permeable to agglutinins and antibodies, at least i n the later stages of pregnancy, Ranstrom(l947) regards a plaoental lesion as an indispensable prerequisite to an isoimmunization. He advances the theory that the primary element i n the disease i s anendocrine dysfunction i n the mother which induces a plaoental ohange. Any resultant plaoental lesion paves the way for an Rh isoimmunization i f the appropriate serology i c a l conditions are present. Potter and Wilson (1945) suggest that an abnormality of the plaoenta permits fetal erythrocytes to esoape to the maternal circulation. Ranstrom's theory affords explanation of the low incidence of the disease. Erythroblastosis fetalis has an incidence of one i n 300 to 400 births while one i n every eleven pregnant women i s Rh-negative and i s carrying a Rh-positive fetus ( Potter and Wilson, 1945 ). Irwin (1947) states that approximately one i n 50 of the Rh-negative women involved i n the c r i t i c a l mating becomes sensitized. There i s nothing to explain why antibodies to the Rh group of antigens should primarily be involved. On the other hand, Levine (1947, I'j 1948) proposes that there may also be an interaction between the mother and the fetus of the A and B antigens. Crew, et al ( 1947 ) state there have been obstetrical disasters i n oases i n which the father was P-positive and the mother P-negative.  '  The Rh-isoimmunization theory raises a number of questions for whioh there i s no satisfactory answer. Ranstrom has questioned the absence of Rh isoimmunization i n many cases of the disease; and the presenoe of Rh isoimmunization without manifestation of the disease. Levine, et al  5 (1941) state there are oases of hemolytic disease i n infants when the mother i s Rh-positive. Davidson (1945) has listed the conditions whioh influence the severity of erythroblastosis fetalis. i ) The age of the fetus when the Eh antibodies become active i n i t s blood stream. i i ) The length of time during which the fetus i s exposed to this aotion. i i i ) The strength of the Eh antibodies of which the titer of anti-Eh agglutinins i n the maternal blood may not be measured ( there being no relation between the titer of these antibodies i n the mother and the severity of the disease in the infant). iv) Permeability of the glaoenta, there being quantitative differences i n different women or the same woman at different times. He concludes that hemolytic anemia due to the action of Eh antibodies i s not only the i n i t i a l cause of erythroblastosis fetalis, but also i t explains the genesis of the oomplex manifestations of the disease. D  Immunogenetio Study of Cellular Antigens i n Cattle The term immunogenetios was proposed by the Wisoonsin immunol-  ogists to designate studies i n whioh the technics of genetios and immunology were employed jointly (Irwin, 1947). The term indioates the study of genetio characters as yet only detectable by immunological reactions. 1  The Antigen Theoryi Agglutination and Hemolytic Tests Basio to the study of immunology i s the antigen theory. This  theory presumes that the production of antibodies i s inoited when foreign antigens are introduced into an organism. Findings in.the f i e l d of immunochemistry have proved that antigens reoognizeable by immunological techniques are definitechemical compounds. Difference between antigens involve their ohemioal structures and not simply their physical states. Landsteiner (1951) discovered that substances of simpler form than proteins could be antigenic i f attached to proteins. These substances have been  6  named haptens. The application of serological reagents led to the discovery that the proteins i n animals and plants are different and specifio for each speoies. The antibody i s specific for the antigen which incited i t s production. The presence of these antibodies i n the blood serum may be demonstrated. If the red blood cells of a cow possessing the threeantigens, A, B , and G are innooulated into a second cow whose red blood cells contain none of these antigens, the production of an isoimmune serum containing three highly specific antibodies to antigens A , B, and C would be expected. The antibodies are as qualitatively distinct as the antigens they define. When this isoimmune serum i s tested, while fresh, with the washed corpuscles of individuals having antigens A ; B , and C, or any combination of the three, the eorpusoles are agglutinated into dumps visible to the eye. If the fresh, immune serum i s heated for one hour at 56° centigrade, or aged for several days, i t loses i t s ability to agglutie4£fc the cells having the antigens. This i s due to the loss of a third oomponent called complement, a heat-labile, non-specific substance i n a l l normal sera. The addition of fresh, normal beef serum, containing complement, w i l l restore the ability of the isoimmune serum* to agglutinate the cells. A more sensitive test i s possible i f fresh normal rabbit serum i s used as the source of complement. When immune serum i s mixed with cells carrying any of the respective antigens i n the presence of complement serum, the cells are hemolysed. Hemolysis of red blood cells i s easily observed i n vitro because of the free hemoglobin pigment liberated from the cells. Complement combines with antibodies only when the latter are absorbed on the eells by virtue of their union with their specific antigens. Thus the three essent i a l components of a positive hemolytic test are: antigen, i t s specific antibody, and complement.  7 2  The Number and The Interactions of Cellular Antigens i n Cattle Over forty antigens are demonstrable i n the cells of cattle.  Most of these can be detected singly, so the number of different oombin40 ations possible i n the bovine species i s at least 2  . If each antigen i s  a chemioal entity, biochemical individuality i s possible i n the cattle species. Although the antigens may be detected independently, many are linked i n inheritance. For example, of the antigens called B, 6, and K, B and G may occur singly or together, whereas K i s not found except i n combination with B and G. There are genetically two kinds of animals possessing B and G together, namely those i n whose offspring B and G segregate as i f o  the parent were heterozygous, and $h#s« whose offspring carry either both or neither antigen. There must therefore be linkage of the causative genes of these three substances or they are controlled by genes i n an a l l e l i c series. Analyses by the Wisconsin workers (Ferguson,1941; Ferguson, et a l , 1942; Stormont and Cumley, 1943) indioate that the causative genes are located on ten of the thirty pairs of cattle chromosomes. There appears to be at least two sets of multiple allele each including several faotors. This reduces the number of looi involved and i t i s s t i l l possible that most of the antigens, eaoh determined by a dominant gene, are independently i n herited. The breed differences i n the frequencies of the genes responsible for the control of the cellular antigens  offer the most detailed informat-  ion yet available for the genetios of cattle populations. Owens, et al (1944) found the breeds Holstein and Guernsey differ only i n the frequencies of the thirty antigens studied. B  Hypotheses to Account for the Occurrence of Congenital Dropsy 1  A Genetic Hypothesis Acourate pedigrees of a l l members of the population under study  enable a reliable analysis of a genetic problem. The pedigrees of registered  8 livestock are highly reliable and are complete i n most instances for several generations. Complete records of ancestory are available for each individual i n the Ubyssey Ayrshire herd. These records enabled genetic analysis of the edematous-oalf problem. A working hypothesis was formulated based on the assumption that the heredity of the defeet i s controlled by single-factor recessive genes. The pedigree of each animal i n the herd was examined and analysed. Probability coefficients were calculated to establish the likelihood of certain events occurring i f the hypothesis was correct. Comparison of the theoretically expected with the observed results by application of a test for goodness of f i t offered a f a i r l y reliable test of the working genetic hypothesis. 2 An Immunogenetic Hypothesis A second hypothesis to explain the etiology and pathogenesis of the disease was tested. This hypothesis was based on the similarity which exists i n the manifestations of congenital dropsy i n cattle and those of erythroblastosis fetalis i n humans. I f the Rh isoimmunization theory, accepted i n eugenics as an explanation of the familial incidence of erythroblastosis f e t a l i s , has a counterpart i n cattle genetics, a hypothesis based on the knowledge of bovine cellular antigens would serve to explain the occurrence of congenital dropsy i n oattle. Concurrently with the pedigree analysis undertaken to test the genetio hypothesis, immunogenetio studies using the techniques of Ferguson (1941) were made to test the isoimmunization hypothesis. Breeding tests which might conclusively establish the mode of inheritance of the disease have not been deemed possible nor practical. Statistically significant results which would establish the mendelian seg-  9  regation could be obtained only following large numbers of test matings. Breeding tests with oattle are of necessity long-term experiments. To obtain sufficient data would not only be costly but would reduce the average breeding merit of the herd. The deleterious gene would be diseminated throughout the herd i n the heterozygous condition. Subsequent matings of the heterozygotes could cause inoreased inoidenoe of the defect. Several generations of breeding would be necessary to reduoe the frequenoy of the gene to i t s present Value. The low viability of defective oalves would i n crease the difficulty of not only the actual conduct of breeding experiments but also the interpretation of the results.  II  Formulation of a Genetic Hypothesis As related previously, the edematous oalves born i n the Uby-  ssey herd were close, collateral relatives. This familial incidence together with the reports of Larsson (1935), Johansson (1939),and Korkman (1940), led to the assumption that the oondition was hereditary. Pathological examinations at post mortem gave no conclusive evidence that the disease might be caused by a specific infection. Also there had been no alteration of feeding methods. Feeding practices dur- ' ing the pregnanoies, which resulted i n the production of edematous oalves, were substantially the same as followed for a period of several years. It seems unlikely therefore that a nutritional deficiency was the predisposing factor* A P&digrees and Calving Records The pedigrees of edematous oalves born i n the Ubyssey herd are presented i n figures 1 to 9, inclusive. The oalves have been assigned Roman numerals, being enumerated i n the order in which they were born. Calves I and II were by the sire Admiral, and Calves III to X, inclusive, were by his son Commodore. Calf X was a f u l l sib to Calf VI. From extended pedigrees of each of these calves, arrow type diagrams to show lines of descent from  10  Figure 1. Arrow diagram drawn from pedigree of edematous calf I» ' Admiral-  ,Galahad -  Gaiety. 'Chaplain  Jessie'  11  Figure 3* Arrow diagram drawn from pedigree of edematous oalf III, Commodore  Admiral Natalie  III Chaplain  Joanne  Man of War  Figure 4. Arrow diagram drawn from pedigree of edematous oalf IV, edeni Commodore _  Admiral——Galahad -  Gaiety  Man of War Eunice  Mainspring •  12  Figure 5 . Arrow diagram drawn from pedigree of edematous oalf V e  Figure 6. Arrow diagram drawn from pedigree of edematous oalf VI*  13  Figure 7 . Arrow diagram drawn from pedigree of edematous oalf VII.  Figure 8. Arrow diagram drawn from pedigree of edematous oalf T i l l *  14  Figure 9 . Arrow diagram drawn from pedigree of edematous oalf IX* Admiral  Natalie  Jezebel  White Cockade  Lucretia-  Rosalind  vemor  • Heather  ^ Morven  15  Sir*.  Gam  I.C.  21/9/41  Admiral  Jessie  12*5  Bom dead, enlarged with fluid  M  27/10/43  Admiral  Eilyi  20.3  Born dead, enlarged with fluid  III  P  16/6/49  Commodore  Lucy  19.5  Head and legs edematous  IV  M  3/7/49  Commodore  Ophelia  18.2  Edematous  V  F  22/11/49  Commodore  Quaker  7.1  Edematous  VI  F  8/1/50  Commodore  Regina  9*8  Edematous, died at birth of suffooation  VII  F  7/4/50  Commodore  Primrose  16.4  Stillborn Edematous  VIII  M  4/9/60  Commodore  Ramona  17.3  Edematous, living, active  IX  F  31/12/50  Commodore  Rennle  7.8  Aborted at six months. Snaquinous edema, hydrops  X  M  15/1/51  Commodore  Regina  9.8  Clear edematous f l u i d i n subcutaneous fascia — gaseous edema.  Calf  Sex  I  M  II  Date  Description  I.C. — Inbreeding Coefficient (per oent) Bote: Galahad, not Morven i s believed to be the sire for Jessie. Both sires served the cow during the same oestrous. Table Ix Data and Records Sonoeraing the Edematous tfalves Bom i n the Ubyssey Herd*  common ancestors were drawn. These diagrams are presented i n figures 10 to 18, inclusive. The coefficients of inbreeding were calculated ' using the arrow diagrams; and they together with other data and records concerning each edematous calf are presented i n Table I. The calving records, dating bask to the founding of the herd were examined and revealed the following information. There have been 539 calves born to 146 dams. There were eight sets of twins. The names of 12 sires and the number of calves sired by each are presented i n fable II.  SIRE  NUMBER OF CALVES  Auohenbrain Royal Chaplain -130252-  64  Grandview Man 0* War -159659-  i«  Gr andview Mainspring -165506-  39  Ubyssey Royal Gaiety -165532-  18  Fintry Morven -178672-  37  Dbyssey Gaiety Sir Galahad -202516-  53  Ubyssey Rosalind's Governor -202521-  14  Ubyssey Morven Gladgowan - 218123-  7  Ubyssey Rosalind's Admiral - 226521-  93  Ubyssey Governor's Spitfire -246791-  38  Ubyssey White Cockade -269047-  66  Ubyssey Admiral's Commodore -307558-  79 501  Table l i t Sires Used i n the Ubyssey Herd and the Number of Calves Sired by Eaoh.  B  Formulation of the Hypothesis 1 Basic Assumptions For purposes of the analysis, i t was assumed that the pheno-  17 typio expression, observed as edema i n new-born oalves, was possible only i n genotypes carrying both recessive genes. That i s , there are three genotypes possible in the population: the homozygous dominant ( AA ), the heterozygous ( Aa ), and the homozygous recessive ( aa ). Because only two phenotypes have been observed, namely Normal and edematous, we mustassume complete dominance. The genotypes AA and Aa having the same phenotypio expression, Normal; and the genotype aa the phenotypio expression, edematous. From an examination of the arrow diagrams prepared from the pedigrees of the edematous calves, and considering also the breeding practice and resultant lines of descent most common i n the herd, certain ancestors of these calves oome under suspicion of being heterozygous for the character. In a population of Normal animals there are only three types of matings possible, v i z . i ) homozygous dominant Z  homozygous dominant  i i ) homozygous dominant Z i i i ) heterozygous  Z  heterozygous  heterozygous  The frequency of each type of mating i n a randomly mating population w i l l be a function of gene frequenoy. The mendelian segregation from matings of these two genotypes w i l l be as follows: i ) Parents  AA  Gametes F  a l l AA  i i ) Parents  AA  Gametes  all A  '  i i i ) Parents Gametes F  x  AA  all A  x  Fx  X  Z  Aa £ A, £ a  £ AA, £ Aa Aa  Z  Aa  g A, £ a £ A, £ a i AA, £ Aa, £ aa  Iff Only under experimental conditions would matings involving a homozygous recessive individual be likely to ooour. 2  Heterozygote8 i n Pedigrees It i s therefore possible to obtain a homozygous recessive indiv-  idual only when two heterozygotes are mated. In mating two known heterozygotes, only one of every four offspring i s expeoted to be homozygous reoessive. The probability of obtaining a homozygous recessive offspring from the mating of two animals of unknown genotype chosen at random from a population i s extremely low. To increase the probability of suoh an event occurring to levels suitable for practical breeding experiments i t i s necessary to mate animals of known pedigree and genotype. Sinoe a l l matings i n the Ubyssey herd were of Normal phenotypes, those matings which produced edematous calves were matings of two heterozygous animals. The sires and the dams of any'edematous oalves were heterozygotes. The names of these eleven known heterozygotes are inoluded i n Table I. Further, by examination of the pedigrees of these animals, certain other ancestors of the edematous oalves can be assumed, within f a i r limits of probability, to have been heterozygotes also. The line of descent from Chaplain, to Gaiety, to Galahad, to Admiral i s common to a l l the edematous oalves. The line expends from Admiral ~bwo  to Commodore i n a l l but two of the pedigrees ( I and II ). In a l l but^of the pedigrees ( VIII and IX ), one or more of these sires i s a common ancestor. It i s therefore /yobable that the five sires i n this line of descent were heterozygous. Because there are at least two lines of descent from at least one of these sires i n a l l pedigrees except VIII and IX, the single recessive hypothesis i s acceptable. To account for edematous oalves of pedigree VIII or IS i t i s necessary to Incriminate as being heterozygous, animals other than those on lines of descent from any of these five sires. Though Admiral  IS i s heterozygous, and having assumed his sire to have also been heterozygous, the genotype of his dam, Rosalind, may be assumed to have been heterozygous at a probability of one-half. Assuming Rosalind to have been heterozygous, i t i s possible to account for the occurrence of edematous oalves of pedigree VIII or IX. Rosalind i s a common ancestor i n a l l but pedigree I. Calculation of the probability of the recessive genes being passed down both lines of desoent i n each pedigree from one or more of the heterozygous (assumed) ancestors serves to test the hypothesis and allows a test for goodness of f i t . The hypothesis formulated from examination of the pedigrees of the edematous oalves may be outlined as follows* i ) assumed the character to be under control of a single genie pair. i i ) assumed complete dominance. i i i ) assumed a line of desoent from Chaplain, to Gaiety, to Admiral, to the edematous oalf; or from Admiral to Commodore to the edematous oalf. A l l these sires assumed to have been heterozygous. iv) assumed Rosalind to have been heterozygous. C  Testing the Hypothesis The pedigrees of a l l animals born i n the herd were oheoked to  determine which calves had Chaplain, Gaiety, Galahad or Admiral as a common ancestor. There are 153 pedigrees i n which one of these sires appears as a common ancestor. Chaplain i s a common ancestor i n 123 pedigrees; Gaiety i n 13 pedigrees; Galahad i n 26 pedigrees; and Admiral appears i n 27 pedigrees. There are 37 pedigrees i n which two or more of these sires sire common ancestors. Arrow diagrams were constructed from eaoh pedigree and the probability of each offspring being homozygous reoessive was calculated.  20, 1 Probabilities of Homozygous Recessives The average probabilities of obtaining edematous oalves together with the assumptions under whioh they were calculated are presented in outline form. i ) Assuming Chaplain was Aa, ignoring that the oalves have other common ancestorst -ignoring that Gaiety, Galahad, and Admiral were Aa; average probability — 0.0132. -assuming that Gaiety, Galahad, and Admiral were Aa; average probability — 0.0526. (based on 123 pedigrees) i i ) Assuming that Gaiety was Aa, ignoring that the oalves have other common ancestors: - ignoring the Admiral, Galahad, and Commodore were Aa; average probability — 0.0189. - assuming that Galahad, Admiral and Commodore were Aa; average probability — 0.0697. (based on 13 pedigrees) i i i ) Assuming Galahad i s Aa, ignoring that the oalves have other oommon ancestors: - ignoring that Admiral and Commodore were Aa; average probability — 0.0396. - assuming that Admiral and Commodore were Aa; average probability — 0.0865. (based on 26 pedigrees) iv) Assuming Admiral i s Aa, ignoring that the oalves have other oommon ancestorst - ignoring that Commodore i s Aa; average probability — 0.0549. - assuming that Commodore i s Aa; average probability — 0.0914. (based on 27 pedigrees)  7) Assuming a l l the sires, Chaplain, Gaiety, Galahad, Admiral, and Commodore were Aa. ( This follows naturally from the basio assumption that a line of descent from Chaplain was common to a l l calves by Commodore.) average probability — 0.0772. (based on 146 pedigrees) vi) Assuming a l l the sires. Chaplain, Gaiety, Galahad, Admiral, and Commodore were Aa; assuming also that Rosalind was Aa; average probability — 0.0853. (baeed on 91 pedigrees) 2  Goodness of F i t The ohi-squared (%**)  test of''goodness of fit"was applied to the  data obtained from the pedigree analysis. From the formula:  i n whioh f  0  i s the observed frequency and f i s the theoretioal frequency,  the value chi-squared may be obtained. By reference to a table of ohi-squared (Snedeoor pi90, 1949) the goodness of f i t may be evaluated. In the tables of ohi-squared, the values indicate the probability of obtaining a f i t , due to chance alone, as poor as or worse than the one obtained by calculation. If this probability i s small, the likelihood that the disparities between the observed and calculated data are due to chance i s also small. I f such i s the oase, the hypothesis underttest i s probably applicable with f a i r aoouraoy to the solution of the problem under investigation. The average probability of obtaining an edematous oalf i n any one of the 146 pedigrees analyzed i s 0.0853. On the basis of the hypothesis, i t would be expeoted that of the 153 calves born, 13 calves would be edematous, the actual frequency of the edematous calves i n the pedigrees under analysis i s ten i n 153, or expressed as a probability, 0.0653. From these two frequencies, the value of ohi-squared can be calculated. Entering the tables of  22  chi-squared under one degree of freedom (one less than the number of classes) a value for P may be obtained by interpolation. When ohi-squared i s 0.00469, P i s 0.9325 under one degree of freedom. In other words, i n approximately 93.25 per cent of similar oases, as great or greater deviations from the theoretical probability would be found, and the present population f i t s the hypothesis. D  Disoussion of Results Though the observations and data drawn from this f a i r l y large •is  sample support the working hypotheses i t was originally formulated, the hypothesis i s not confirmed. More evidence to support the hypothesis could be obtained by test matings and back orosses i f i t were possible to raise the homozygous recessive to reproductive maturity. The maintenance of complete calving records and accurate pedigrees, as required with registered oattle, w i l l however enable further analysis to test the hypothesis. The types of matings possible i n a population of Normal individuals have already been outlined. There are three similar types of matings possible i f the population contains edematous individuals. If the mating of two homozygous recessives was possible, the hypothesis would receive an absolute test, sinoe only edematous offspring could be produoed. unless a l l the offspring from two homozygotes are themselves homozygotes, the character i s not under control of a single genie pair. There are at present only six animals of proven genotype i n the Ubyssey herd. These are the sire, Commodore, and the five dams of edematous oalves remaining i n the herd. The cows to which Commodore aan be mated are either homozygous dominant or heterozygous. The descendants of Rosalind and especially the descendants of Admiral are more likely to be heterozygous than homozygous dominant. Mating Commodore to collateral relatives increases the likelihood of obtaining edematous oalves. The probability of the homozygous recessive occurring i n eaoh case would be at least or greater than 0.25. If a female edematous oalf by Commodore i s born alive and i s f e r t i l e  23  at maturity, she could be mated to her sire, i n which case the probability of obtaining an edematous calf would be 0.50. Such a mating would be of genetic interest only. Such a female oalf would not ordinarily be raised. She could however be used to test cross other bulls of unknown genotype. Such test crosses would not likely be warranted. Because of the long gestation period and the small number of offspring i t would take several years to prove the genotype of one bull. The number of sires whioh could be test crossed to one female i s very limited* If a male edematous calf was f e r t i l e at maturity and was successfully mated to the cows known to be heterozygous, the probability of obtaining an edematous calf i n each oase would be 0.50. One other method of testing the hypothesis, the least likely to become available, i s to mate two edematous individuals. The l i k e l i hood of obtaining two calves of opposite sex whose periods of zexual maturity and f e r t i l i t y would coincide i s very small. It has been assumed that the condition observed i n the new -born calves and named congenital dropsy i s due to the presence of a single pair of recessive a l l e l s . Also i t has been assumed that there i s complete dominanoe, that one recessive a l l e l i s overshadowed completely by the phenotypic expression of the dominant a l l e l . The condition of the fluid balance of the immature bovine i s then assumed to be under control of a single genie pair. If one or both dominant allels are present the individual i s a normal phenotype. If both recessive allels are present the individual i s edematous. The f l u i d balanc of an organism must, by the number of factors exerting influence on the balance, be under a complex control; but, because of the delicate nature of this balance, i t may be upset by a single, simple change i n the physiological processes whioh control the accumulation and distribution of body fluids. If but one step i n one of these processes i s dependent on the  8fc  presence and phenotypic expression of at least one dominant gene of an a l l e l i c pair, the abscence of both dominant genes w i l l prevent the i n i t i a tion of the series of events necessary to produoe a system of oontrol for the f l u i d balance of the organism. Though pedigree analysis has shown the heredity of congenital dropsy to be very probably under the oontrol of a single recessive gene, the wide variations in manifestation may  seem to contradict this assump-  tion and to indicate rather, a complex mode of inheritance.  Since i n  eaoh individual the genes exert their separate influences at equivalent stages of development, a single genie pair would be expected to produce the same syndrome i n a l l individuals possessing i t .  However, the intra-  uterine environments may be of sufficient variation to cause the various degrees of severity i n the defect observed at birth. If a linkage group, or a number of genes, were responsible i n part or in total for the controls of the f l u i d balance, i t i s possible a weakness in this group i s that which would be inherited and the weakness could be affecting different genes within the group in each individual. Again assuming that each step of the physiological processes i s under oontrol of a separate gene, that step i n the process which would be deleted would depend on which gene was affected by the hereditary weakness. Ill  Formulation and Testing of an Immunogenetic Hypothesis A review of the literature on the congenital diseases of  infants makes evident the similarity between the manifestations of erythro blastosis fetalis i n humans and those of congenital dropsy in cattle. The R h e 8 U 8 - i s o i m m u n i z a t i o n theory, accepted by many as an explanation of the disease erythroblastosis f e t a l i s , has already been outlined.  The  immunogenetic studies of the cellular antigens of cattle have been reviewed. Considering the Rhesus-isoimmunization theory and the information available on the cellular antigens of cattle, there i s a possibility that the  :2S explanation of the human disorder oould serve to explain the disorder i n oattle.  One. or a group of cattle antigens may function, as the Rh anti-  gens are thought to function in humans, to produce an edema of the new-born. An analysis to determine the antigen complement of individuals i n the families producing defective calves would show whether or not an isoimmunization theory could explain the incidence of the edematous oalves. A working hypothesis based on the following assumptions was formulated. i ) Assumed that the erythroblastosis f e t a l i s i s the counterpart of congenital dropsy i n cattle. i i ) Assumed that the Rhesus-isoimmunization theory explains the incidence of erythroblastosis f e t a l i s . i i i ) Assumed that a similar isoimmunization theory applies to the inheritance and interaction of the cellular antigens of cattle. A, Formulation of the Hypothesis The hypothesis, as i t applies to the oases i n the Ubyssey herd, may be stated as follows. T#e sire. Commodore, possesses*? certain cellular antigen or group of antigens that i s not possessed by the dams of the edematous calves. If the fetus by Commodore i s positive for antigens for which the dam i s negative, and the antigens traverse the placenta to enter the blood stream of the dam, the production of antibodies specific to each antigen i s incited. These antibodies, carried in the serum of the dam, may traverse the placenta to enter the serum of the fetus. The antibodies of the dam cause a hemolysis of the fetal erythrocytes or erythroblasts and i n i t i a t e the chain of developments leading to the manifestation of congenital dropsy. Commodore w i l l pass on to his offspring a sample half of the i n heritance governing the phenotypic expression of the antigens for whioh he  26 i s positive. I t i s not necessary that a l l the dams of edematous oalves be negative for the same antigens. If the blood of Commodore i s not compatible to the blood of each of the dams of edematous calves the theory accepted i n human genetics may be applicable to cattle genetics. B  Testing the Hypothesis The hypothesis was tested by conducting blood hemolysis tests  using the washed cells and the sera of the seven cattle available and four normal rabbits. The bloods of Commodore, Lucy, Ophelia, Primrose, Quaker, Regina, and an edematous oalf out of Primrose were tested. Fresh, normal rabbit serum was used as the source of complement i n a l l hemolytic tests. Detailed procedures for conducting hemolytic tests are presented i n the appendices. Commodore-immune sera were produced by repeatedly injecting i n travenously into normal rabbits suspensions of washed cells from Commodore. Suspensions of the washed blood cells of each cow were also prepared. Hemolytic tests were conduoted using the immune rabbit sera separately and suspensions of the washed cells of eaoh oow. Similar tests were conducted using the so-oalled isoimmune serum of each cow and suspensions of the washed cells of Commodore. These latter tests served to test the belief that the fetus can inherit certain antigens from i t s sire that w i l l incite the production of antibodies i n the dam. A l l isoimmune and immune sera were used i n three dilutions and adequate controls were prepared i n a l l tests. The tests were conducted i n triplicate and repeated twice. None of the so-called isoimmune sera produced a hemolysis of Commodore cells. The Commodore-immune rabbit sera eaoh produced hemolysis i n a l l oases when tested with suspensions of the washed cells of the cows*  \  These results show that Commodore's cells possessed antigens that inoited the production of antibodies i n the rabbit sera. These antibodies were specific for at least one antigen i n each of the cows' c e l l s , showing that Commodore has at least one cellular antigen in common with each cow. Tests using the serum (antibodies) of each of the seven animals and the cells (antigens) of the other six animals showed that the serum of Luoy contained antibodies which would lyse the cells of Ophelia, Quaker, and Regina. None of the other sera contained antibodies to the antigens of the cells of the other animals. C Discussion of Results While the tests employed were not sufficiently extensive to eonfirm that the hypothesis i s inoorreot, i t would seem probable that the isoimmune theory i s not applicable to the incidence of congenital dropsy. It would be expected that the production of antibodies inoited in the dam by the paternal antigens of the fetus would have resulted i n the accumulation of sufficient amounts of the antibodies to cause a hemolysis of the oells of Commodore. Especially i n the oase of Primrose would this be 'expected since her serum was used i n tests shortly after the birth of her edematous oalf when the antibody t i t r e would likely be at a maximum. None of the cow sera produoed hemolysis of Commodore cells, therefore noae of the sera was carrying antibodies for the antigens of Commodore. The serum of Primrose did not cause a hemolysis of the cells of her calf, showing that she had not produced any antibodies specific to the antigens the fetus had inherited from Commodore. I t i s possible, but Highly improbable, that Primrose would carry the same antigens on her cells that the fetus inherited from Commodore. I f the hypothesis was correct, the  serum of Primrose should have caused lysis of both the cells of Commodore and the oells of her calf* The results of tests ueing the Commodore-immune rabbit sera seem consistently i n aberrance to the hypothesis. However, considering the large number of cattle antigens and recognizing that a l l the animals are of similar inheritance, i t i s unlikely that any would have an antigen complement entirely different from that of Commodore. The tests using cells and sera of eaoh animal showed that Lucy carries antibodies for the antigens of three other cows. Luoy must have been sensitized by antigens oommon to each of these cows, but not found i n the other animals. Since her serum would not lyse the oells of Commodore, she could not have been sensitized by the fetus sired by Commodore. A thorough test of the hypothesis would necessitate a complete antigenio analysis of many individual animals. Such an analysis would require the production of isoimmune as well as immune sera. The Wisconsin workers have cited oases of anaphylactic shook during the production of isoimmune sera. The risk involved i s too great when working with valuable breeding stock. Any solution would be very involved beoause of the large number of cellular antigens demonstrable i n cattle.  29 PARI II II  Atresia ani i n a Yorkshire Swine Herd A second hereditary defect has been observed i n a registered  swine herd* While pedigrees of a l l the animals are available, the complex mode of inheritance of the defeot does not make genetic analysis possible without extensive breeding tests* Because of the high prolificacy and lesser value of eaoh individual, breeding tests would be much more easily conducted with swine than with the other classes of livestock. However no suoh breeding tests have been undertaken. An examination of the pedigrees made i t possible to make certain recommendations to the breeder, recommendations that would enable him to r i d his  swine herd of the defeot* A  Review of Literature The defect observed i n these registered Yorkshire swine i s sim-  i l a r to the oondition described by Berge (1941) as ooouring i n the same breed i n Norway* Berge also cites the writings of Kinzelbaoh (1931) and Cartens, et al, (1937) whioh describe the oondition oocuring i n Yorkshire swine i n Germany. The abnormality i s named Atresia ani and i s inoluded i n Lerner's (1944) l i s t of lethal and sub-lethal characters observed i n swine. Rice and Andrews (1951) also l i s t the oondition as a lethal, but do not state the mode of inheritance of the defeot. Berge states that the malformation i s found to be different i n sows and boars. Typical i n boars i s the closed anus. The pigs are usually short-lived beoause of the obstruction of the rectum. In the sows, he continues, the anus i s absent but usually an opening i s found i n the ventral wall of the rectum with a communication to the vagina, resulting i n a type of oloaea. Some of these sows live to maturity and are f e r t i l e .  39i.  B  History of the Occurrence of Atresia ani i n the Local Herd The conditions observed i n the local swine herd seem very sim-  i l a r to those described by Berge. There—ere some cases of Atresia ani previous to 1951, but they were not recorded i n detail nor studied by the breeder. Recently there have been born three l i t t e r s of whioh some piglets were abnormal. In one l i t t e r of eleven males and five females a l l were abnormal. The dam of the l i t t e r was abnormal but had been bred to a normal boar that had sired several normal l i t t e r s . She had previously dropped some abnormal pigs. ' A second l i t t e r of abnormal pigs (eight males and six females) was sired by an imported boar and was out of a sow that had previously given bifcth to two normal l i t t e r s . However, the dam of this sow had shown abnormal formation of anus and vulva. The third l i t t e r of abnormal pigs was also by the imported boar. Of the eighteen pigs, ten were males and eight were females, four of the females being stillborn. The sow had previously given birth to five l i t t e r s of normal pigs. The imported boar had not been mated to either of these sows previously. A l l three of the dams of abnormal pigs are by. the same boar. They are also out of half sisters. Two of the grandams were themselves out of half sisters. There i s no inbreeding i n any of the pedigrees, at least as far back as five generations. C  Pedigree Analyses In his work at the Aas Breeding Station i n Norway, Berge test  -mated boars known carriers of a faotor oaaslng atresia ani.  The two boars  were both apparently normal, but transmitted atresia ani i n different manners. One had 21.2 per cent atresia ani i n l i t t e r s containing abnormal pigs, while the other had 14.3 per oent. The percentages effected i n both sexes  315  were equal. Two f u l l sisters, daughters of boar A, with cloaca reached maturity and were bred to boar A, boar B, and an unrelated boar, C« The results are tabulated i n Table III. SIRE  SOW  I  SOW  Normal Abnormal A  6  i  B  2  0  4  II  Per cent  Normal Abnormal  Atresia ani  15  3  16.0  3  9  1  26.7  0  12  0  0.0  Table III* Incidence of Atresia ani i n Two Inbred Litters and One Outerossed Litter ( Berge, 1941.) The number of offspring was not large enough to justify calculation of the segregation ratio, though i t was dear that a monogenic mode of inheritance was not i n oontrol. Berge has suggested a two-factor hypothesis, but he states i t is impossible to say i f both , one or neither of the factors i s ohiefly dominant. In conclusion he states that when the mode of inheritance i s so i r r egular, the purchasing of breeding stook would be impossible i f the buyer required the animals to be free of genes causing the deleterious character. The pedigrees of wwine with Atresia ani i n the local herd are presented i n Figures 10, 11 and 12. D Genetio Hypotheses 1  Simple Mendelian Recessive Since i n the cases cited a l l pigs i n each l i t t e r were abnormal,  i t i s very unlikely that this defect i s under control of a simple mendelian recessive factor. So many sub-lethal and lethal characters studied i n farm animals are of this type, this may seem the most likely hypothesis to test. TJhe pedigrees examined under the hypothesis show that two animals, C and Q  32  F i g u r e 10. Pedigree I  X (zox 29e) ' f i r s t mating to A  8 males / 6 females\ 2 fern. s-b\ Atresia ani\  B (qual /""  15a)  A ( a r r 264e) two normal > litters previously v  C (qual 19b) A t r e s i a ani  33  F i g u r e 11, Pedigree I I  N  34  F i g u r e 12, Pedigree I I I  Y (hnf 107c) 'had s i r e d no abnormal p i g s previously 10 males 4 females 4 fern, s-b  B (qual  15a)  Atresia ani  £ ( a r r 9b) Atresia ani, abnormal o f f s p r i n g  P  (HHP)  35 i n addition to the pigs i n the three l i t t e r s , are homozygous recessive. The animals, X,I,A,M,B,F,G, and R must therefore also be heterozygous. In pedigrees I and II, sinoe both parents are heterozygous, i t would be expected that only one offspring i n four would be homozygous recessive. I f dominanoe i s assumed, the phenotypes should appear i n the ratio, three normal to one abnormal. In pedigree III, since one parent i s homozygous recessive and one i s heterozygous, i t would be expected that equal numbers of normal and abnormal offspring would be obtained. Sinoe no normal offspring were born i n a l l forty-nine births i t i s reasonable to assume that a more complex mode of inneritande i s i n control. 2  Two-faotor Dominant If the condition Atresia ani i s under the control of a two-faotor  dominant character, as Berge states i s likely, i t i s possible to account for the results i n the above pedigrees. Phenotypic expression i s possible when the genotype i s AABB, AABb, AaBB, or AaBb. These are abnormal phenotypes. Phenotypio expression i s not possible when the genotype i s aabb, aaBb, Aabb, AAbb, or aaBB. These are normal animals. The types of matings possible under the two faotor hypothesis may be outlined as follows. i ) Of normal animals There are ten possible matings of normal phenotypes. In only four of these can any abnormal animals be obtained. In two cases the probability i s 0.50; i n one oase the probability i s 0.25; and i n one case a l l offspring w i l l be abnormal. i i ) Of abnormal animals There are six possible matings of abnormal animals. In four oases a l l offspring w i l l be abnormal. In two oases £he probability of abnormal offspring i s 0.75. It i s not likely that this type of mating would be made except for experimental investigations.  36 i i i ) Of normal to abnormal animals There are twenty- possible matings of this type* In seven oases a l l offspring w i l l be abnormal. In eight oases the probability i s 0.50. In two oases the probability i s 0.75 and i n another two eases the probabilityi s 0.375. In the final oases the probabiltiy of obtaining abnormal offspring i s 0.25. In pedigree I there i s a normal to normal mating. Neither A nor X i s aabb genotypioally.  If animal A or animal X i s Aabb or aaBb then the  other i s neither AAbbnor aaBB. I f either animal i s Aabb and either i s aaBb then the probability of obtaining abnormal offspring i s 0.25. I f either A or X i s Aabb or aaBB and the other i s Homozygous dominant on the other locus, the the probability of obtaining abnormal pigs i s 1.00. The weighted average probability of obtaining an abnormal offspring i s 0.233. In the same pedigree, the mating of B to C i s an abnormal to normal mating. No matter what the genotype of these animals there i s always a chance of abnormal offspring being born. Sinoe A was normal, seven of the twenty possible matings may be omitted. In the remaining types, the probabilities of obtaining abnormal animals range from 0.75 to 0.25. The weighted average probability i s 0.50. In pedigree III the mating of I to Q i s also an abnormal to normal mating, but unlike the mating of B to C, there have been no normal offspring produced. Therefore the mating may have been any of the twentytypes i n this group. The weighted average probability of obtaining abnormal offspring i n this type of mating i s 0.75. B  Recommendations to the Breeder The following recommendations, made after an examination of the  pedigrees and the literature on the defeot, were offered to the breeder to enable him to take the steps neoessary to r i d his herd of the defect.  n i)  Stop servioe of boar X immediately. Butcher him now or de-  lay final judgement until the sows already bred to him have farrowed. i i ) Butoher a l l sows which have born defective offspring and the progeny of these sows. i i i ) Refrain as much as possible from using females closely related to the above sows. For example, descendants or any close relations of the boar B. iv) Any boars i n servioe now or to be i n servioe i n the future should themselves be free of the defect and be chosen from families known to be free of the defect. It i s highly probable that the boar X i s a carrier of the faotors oausing Atresia ani since the sows A and M have previously had no abnormal pigs by other boars. If the boar Y i s used on normal sows from famiUfe&?>3 free of the defect, the probability of attaining abnormal offspring i s rather low. However, none of his offspring should be considered as breeding stock. In the selection program there should be considerable discrimination against descendants and relatives of the boars B and F because they are closely related to the dams of abnormal l i t t e r s . These are severe recommendations, but rather drastic steps must be taken to control this type of defect in breeding stock. It w i l l be necessary to maintain close observation and culling practioe must be very severe for several generations before the herd i s r i d of this defect.  CONCLUSION Iinebreeding, whioh i s often referred to as applied inbreeding, enables the breeder to maintain a high degree of relationship to ancestors highly meritorious for the hereditary traits on whioh he bases his seleotion practioes. His selections are made easier and more accurate i f he i s able to evaluate his stock on the merit of the anoestory as well as on the merit of each individual in the herd* Continued Iinebreeding w i l l increase the inbreeding in his animals to significant levels* By making more gene l o c i that wese formerly heterozygous homozygous, he increases the prepotency of each individual* In payment for the inorease i n prepotency he must risk the greater l i k e l i hood of homozygous recessives occuring. Not a l l , but most homozygous redessives are less desirable than either the heterozygote of homozygous dominant. The breeder who i s following a line breeding program should expect, sooner or later, to be confronted with a hereditary defect. Defeots suoh as the absence of one or a l l dew claws i n cattle are of no praotical significance since the performance of the animal i s not effected. But the breeder should be gravely concerned with severe defeots classed as lethals or sub-lethals which interfere with reproductive efficiency and individual performance. Considerable income may accrue to the progressive breeder from the sale of breeding stock. If his breeding stook, because of i t s homozygosity, i s prepotent, i t w i l l be much i n demand. If the breeding to produoe prepotency also allows the expression of genes (formerly carried in the heterozygous state) which control deleterious characters, the sale value and demand for his stock immediately  suffers.  To r i d his herd of the defect he may have to sacrifice animals proven to be of high breeding worth for the characteristics of  economic importance. The development of suoh individuals would likely require several generations of careful selection and breading. If the facts concerning the occurrence of the defect are not publicized, and the broader i s judicious i n his choice of animals f i t for sale as breeding stock, the reputation of his herd may be maintained while the defect i s eradicated. If he continues to s e l l animals whioh could possibly be carriers of the defect, sooner or later, the genes w i l l segregate as homozygous recessives and the defeot w i l l be uncovered. Meanwhile the deleterious genes may have been spread to several herds.. The ineidenoe of even a lethal character may be so low that i t i s of no practical condern to any breeder. The maximum probability of the ooourrenoe of the defect calculated from the genetic theory of the mode of i n heritance i s seldom reached i n small families. The establishment of the true mode of inheritance and the segregations that may be expeoted should be available to the breeder to enable him to deal with the problem i n a method least deleterious to the breed and at the same time economically possible for him to follow. Defects under control of single genio pairs may be eliminated more easily than those having more complea genetic controls. With the l a s 8 prolifio and less fecund classes of livestock the elimination of even a single-factor reoessive i s d i f f i c u l t . A large fraction of the animals i n a linbred herd oome under suspicion when a defect occurs. Breeding tests to prove the genotypes of the suspected heterozygotes are not praotioal. The breeder can only apply a somewhat passive selection pressure against the individuals under suspioion since the economic characteristics must receive selection priority i f his enterprise i s to remain profitable. The expense of replacing the suspected with other animals of equal worth can be prohibitive i n the less prolifio class* es of livestodk. The salvage value of animals culled from the herds or flocks of these animals i s too low to defray.the expense of replacement.  40 With swine, however, i t i s possible to take rather drastic steps to r i d a herd of a hereditary defect. The salvage value of mature stook i s in line with the purchase price of immature replacements of equal worth. The rapid maturity, high prolificacy and greater fecundity enable the breeding er to quickly replace his herd. In order that he replace his herd with anA  imals free of the same or another defect, he should have available the mode of inheritance and the segregation ratios pertaining to the hereditary defeots of swine. Breeding tests and backerosses are possible with swine and should be carried on by qualified geneticists who would thus i n crease the knowledge of the heredity of swine as well as aiding the practical breeder i n his work.  REFERENCES CITED  7  f  Berge, S., (1941), Journal of Heredity, vol 32, pp 271-374. Cartens, Wenzer and Durr, (1937), Zuohtungsk, vol 12, p 205. Crew, Oliver and Boyd, (1947), Genetics i n Relation to Clinical Medicine, Edinburgh. Davidson, I,, (1945), Journal the American Medical Association, vol 127, num 11, pp 633-638. Eaton, 0. N., (1937), Journal of Heredity, vol228, pp 320-326. Ferguson, L. C , (1941), Journal of Immunology, vol 40, pp 213-242. Ferguson, Stormont and Irwin, (1942), Journal of Immunology, vol 44, pp 147-164. Hadley, F. B. and B. L. Warwick, (1927), Journal the Amerioan Veterinary Medical Association, vol 70, pp 492-504. Hutt, F. B., (1934), Cornell Veterinarian, vol?24, pp 1-25, Imperial Bureau of Animal Genetics,, (1931), Quarterly Bulletin. vol 2, num 3, pp 49-50. Irwin, M. R.,(1947), 'Immunogenetics', Advances i n Genetics, vol 1, pp 133-153. International Congress of Genetios, (1939), Proceedings of the Seventh Congress, Edinburgh, paper 144, p 169. Kinzelbaeh, (1931), Vererb, vol 60, p 84. Korkman, (1944), Biologioal Abstraots, vol 22, abstract 10625. Land8teiner, K,,(193l), Science, vol 73, p 403. Largson, E. L., (1935), Lantbr. Veck Handl, pp 310-331.  Lerner, I. M., (1944). Journal of Heredity, vol 35, 219-224. Levine, P., (1947), oited i n Advanoes i n Genetics vol 1, pI133. Levine, P., (1948), cited i n Advanoes i n Genetios vol 1, p 133. Levine, Burnham, Katzin, and Vogel, (1941), American Journal of Obstetrios and Gynaecology, vol 42, pp 925-937. Levine, Katzin, and Burnham, (1941), Journal the American Medioal Association, vol 116, p 825. Owen, Stormont, and Irwin, (1944), Journal of Animal Soienoe, vol 3, pp 315-321. Potter, £• L. and Wilservi, J. K., (1945), Journal the American Medical Assooiation, vol 127, num 8, pp 458-459. Ranstrom, S., (1947), Journal the American Medioal Association, vol 134, num 13, p 1136. Bioe, V. A. and Andrews, F. N«?, (1951), Breeding and Improvement of Farm Animals, McGraw-Hill Book Company Incorporated, New York, pp 342-343. Stormont and Cumley,(1943), Journal of Heredity, vol 34, $|W35-41. Weiner, A. S.,(1946), Journal the American Medioal Assooiation, vol 133, num 13, p 1097. Wright, Sewall, (1931), Genetios, vol 16, pp 97-159.  i APPENDICES A  Calculation of the Coefficient of Inbreeding The coefficient of inbreeding i s a measure of the amount of de-  crease i n heterozygosis to be expected from a certain amount of oonsanquinous mating. I t indicates the amount of heterozygosity of the whole group of genes i n an individual animal. The coefficient i s exactly one-half of the relationship between the two parents of an individual unless the parents themselves are inbred. The formula i s as follows: F  x  _  i [(i) S  n  (1+F )] a  where Fx i s the inbreeding coefficient of animal X; n i s the number of generations i n a line by which sire and dam are related; Fa i s the inbreeding coefficient of the common ancestor A out of whom that line of descent divides; and S i s the summation of separately evaluated results. The faotor 1 plus Fa corrects for the greater likeness whioh can be expected between the gametes of an inbred individual. B  Calculation of Probability Coefficients In the calculation of the probability of obtaining a homozygous  recessive from the mating of two unknown genotypes i t i s assumed that the likelihood of the genotype of the parent being heterozygous i s  raised to  a power equal to the number of generations the parent i s removed from the ancestor oommon to both parents that i s assumed or known to have been heterozygous.  If both parents are known heterozygotes, the probability of the  offspring being homozygous i s $£50; of being homozygous reoessive i s 0.25. If a common grandparent i s known to be heterozygous, the probability of the genotype of the descendants one generation removed being homozygous reaessive i s one-half raised to the fourth power; or one-sixteenth.  ii C  Test for Goodness of F i t Biometricians measure the goodness of f i t by adding together  the proportional deviations of eaoh class, obtaining a constant known as ohi-squared, and this determining the probability that a deviation as great or greater w i l l occur by chance. Chi-square i s obtained by squaring the deviation of each olass from the theoretical expectation of that class, dividing this by the theoretical expectation for that olass, and adding together the results from a l l olasses. From prepared tables i t i s possible to obtain for a given value of ohi-square and a given number of classes the value F, which measures the probability that a deviationas great or greater w i l l occur by chance, i n other words, the percentage of cases i n which suoh a deviation may be expected by chance. D  Procedures for Serological Studies  Preparation of Immune Serum Source of Antigen Collection 6t Blood Sample Materials* cotton-batten, alcohol, hypodermic needle fitted to rubber tube, 200 ml sterile flask with stopper, 76 ml isotonio citrate solution ( 2$ sodium citrate — 0.5$ sodium chloride), 50 ml tube fitted with stopper and containing glass beads. Method: the blodd i s dra~a from the jugular vein using the hypodermic needle and rubber tube. Approximately 75 ml of blood i s oolleoted in the 200 ml flask containing the 75 ml of isotonic citrate solution. The flask i s stoppered and refrigerated. Approximately 25 ml of blood i s drawn into the 50 ml flask. The flask i s quiokly stoppered and shaken for five minutes to defibrinate the blood sample. Defibrinated blood i s used i n the preparation of cell suspensions. I t must be heated to 56° c hour to destroy the complement.  f o r  one half  iii Preparation of Erythrocyte Suspension Materials* One l i t r e Gelatine Looke's Solution, 50 ml physiological saline solution ( 0.85 % ), sterile 15 ml pipete, 4 •» 20 ml steri l e graduated centrifuge tubes, sterile graduate, 50 ml sterile flask with stopper, 60 ml citrated blood sample. Method: pipete 5 ml of oitrated blood sample into eaoh of the four centrifuge tubes. Cetrifuge to ten minutes. Decant or withdraw with a pipette the citrate-serum mixture. Add 5 ml of gelatine Lookes solution to eaoh tube, shake thouroughly, recentrifuge for ten minutes. Repeat washing four! times. Transfer a l l cells to one tube, pack oells by oentxifuging, record volume of packed cells. Transfer cells to sterile 50 ml flask using equal volume of sterile physiological saline solution. Place 3.5 ml of the 50$ suspension i n eaoh of nine vaooine bottles fitted with rubber stoppers. Inoculation of RabVf ts Inoculations Materials: three mature normal healthy rabbits, razor, cotton-batten, alcohol, sterile 5 ml hypodermic syringe, erythrocyte suspension, 3 sterile hypodermic needles ( Ho. 22 )• Methods: the hair over the marginal vein i s dry shaved. The area i s sterilized with alcohol. The syringe i s f i l l e d aeseptioally and one ml i s injected into the vein. Each rabbit i s injeoted intravenously three times weekly for three weeks with one(l) ml of the 50 % suspension. Drawing the Immunized Blood The rabbit i s held i n a bleeding stock on i t s back with the head oaught i n a well-rounded notch and the four feet held by thongs tightened to draw the limbs to f u l l extension. Blood i s drawn by oardiao puncture technique. The blood i s expelled into sterile tubes with ootton stoppers and allowed to clot. The immune serum i s withdrawn using a sterile pipette.  iv Complement serum may be obtained using the same teohnique and normal healthy rabbits. The blood should be refrigerated as soon as d o t t e d and the serum must be used shortly after the blood i s drawn. Test Suspensions of Washed Cells Blood samples are drawn into defibrinating flasks as described above, 25 ml of blood i s a large enough sample to supply cells for the 2.5$ suspensions used i n the tests. At the same time, 40 ml of blood i s drawn into sterile tubes fitted with cotton stoppers i n whioh i t i s allowed to clot before being refrigerated. Note: To insure s t r i c t aeseptio oonditons each tube i s fitted with a hypodermic needle attached by a plastic tubing. The assembled equipment i s autoolaved at 15 pounds for thirty minutes and i s not dissembled until the serum i s to be withdrawn by a sterile pipette. The preparation of the 2.5$ suspensions of washed cells i s parallel to that of the 50$ suspensions.  Hemolytic Tests Immune Sera Dilutions Materials: undiluted rabbit sera i n 25ml flasks, 9 —  20 ml  test tubes, physiological saline, 5-— 10 ml pipettes. • Method: plaoe five ml of serum A i n tube I, and i n tube II. Add 10 ml of saline solution to tube II. Remove 5 ml of solution from tube II and plaoe i t i n tube III. Add 10 ml of saline solution to tube III. Test Tubes Eaoh tube should contain: - 1 drop of 2.5 $ suspension of washed cells - 2 drops of undiluted or diluted serum from one Immunized rabbit - 1 drop of complement serum Control tubes and replicate tests should be prepared under the same conditions.  


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