Ph.D. - Biomedical Sciences (Genetics - Cell, Molecular and Neuro Sciences)

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    Applications of distribution theory in quantitative genetics
    ( 1976) Yamashita, Toyoko S.
    The present study was designed to develop procedures for estimating genetic parameters in a quantitative trait and detecting association between a quantitative trait and a genetic marker using a random sample of individuals from the population. An exact distribution of phenotypic values of a quantitative trait was used by which parameters such as number of loci involved, gene frequency at each locus, additive and dominant genotypic value, and the variance of environmental effects were estimated. When association between the quantitative trait and a genetic marker occurred, an additional parameter for the degree of linkage disequilibrium was introduced in the exact distribution. For testing the validity and usefulness of the procedures, individual phenotypic values were simulated by the computer with given parameters. The number of loci involved in the quantitative trait was 2, 5, and la, and gene frequency at each locus was chosen at random. Three heritability values were investigated; namely, 0.2, 0.5, and 0.8. The genotypic values were then calculated by setting degree of the dominance either to zero (no dominance) or one (complete dominance). The environmental effects were assumed to be normally distributed; however, the phenotypic distribution of the quantitative trait under investigation was not specified. Five replicate runs were made for most tests to allow variations in gene frequencies, each sample size being set to 5000. Smaller samples of 100 and 500 individuals were also tested. Based on the log likelihood function values, good estimations by the maximum likelihood method were obtained when heritability of the quantitative trait was moderately high (h^2 ≥.5). When the heritability value was low, the phenotypic distribution of the quantitative trait was mainly determined by environmental effects and, therefore, was expected to be normal by assumption. In this case, the method might not give consistent estimates of genetic parameters. As the number of loci increased, the phenotypic distribution would approach normal by the Central Limit Theorem; however, the procedure was still effective for traits with high heritability. Several cases for the association between one of the loci involved in the quantitative trait and a genetic marker were considered, including (1) complete independence (no linkage), (2) partial linkage, and (3) complete linkage or identical locus. The approach employed was mainly based on the distributions of phenotypic values. Data were subgrouped by the genotypes of the marker locus resulting in several phenotypic distributions, one for each genotype of the genetic marker. When association occurred between a quantitative trait locus and a genetic marker locus, the subclass distributions would be expected to be different from one another. The subsequent estimates of parameters including the degree of linkage disequilibrium were then derived from the exact distributions by the maximum likelihood method. The results were generally good. The present study using simulated data has clearly demonstrated that by employing the distribution of phenotypic values of the quantitative trait, it is possible to establish a genetic basis for the character from a random sample of individual data. When information on other genetic markers is available, the association between the quantitative trait and a genetic marker as measured by linkage disequilibrium may be estimated. However, further research would be needed to apply the procedures to real (non-simulated) data and to consider other parameters such as genotype-environmental interactions and epistatic effects in the phenotypic distribution.
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    Demonstration on zymograms and genetic studies of some enzymes from human saliva
    ( 1975) Tan, Soon Guan
    Saliva samples were collected, processed, concentrated and then subjected to polyacrylamide flat slab gel electrophoresis followed by staining to detect enzyme activities. Six different enzyme activities were detected out of the fifty enzyme staining procedures attempted. Repeatable and constant variants were observed in three of these, saliva acid phosphatases, esterases and glucose-6-phosphate dehydrogenase (hexose-6-phosphate dehydrogenase). Genetic studies were done on these three. Seven phenotypes were found for saliva acid phosphatases. Family and population studies suggested that these phenotypes are the products of two loci, Sap-A with three alleles, A, A' and O, and Sap-B with 1 three alleles, B, B^1 , and O. These loci were found to be polymorphic in Americans of Japanese and Caucasian ancestries living in the State of Hawaii. Saliva esterases show a complex picture on zymograms and had been divided into four major regions. Variants were observed in region 1, the fastest anodal migrating region. Three phenotypes had been observed in region 1. Family and population studies suggested that these phenotypes are the products of an autosomal locus with two alleles, Set-IF and Set-IS. This locus is polymorphic in Americans of Japanese and Caucasian ancestries. Region I esterases are carboxylesterases. Saliva glucose-6-phosphate dehydrogenase (hexose-6-phosphate dehydrogenase) showed three phenotypes on acrylamide gel zymograms. Family and population studies suggested that these phenotypes are the products of an autosomal locus with two alleles, Sgd 1 and Sgd 2. All the above three saliva enzymes in which variants were observed thus allowing genetic studies to be done proved to be different from the analogous enzymes with similar functions in the red blood cell. They constitute previously undescribed polymorphisms in the human species. The three other enzymes whose presence in the saliva had been detected on zymograms were an oxidase, lactate dehydrogenase and superoxide dimutase. No variants were observed for these enzymes which would enable genetic studies to be done. Association and linkage studies were attempted between the three newly described polymorphic saliva enzymes among themselves and between them and the ABH secretor status, Lewis A substance in saliva, ABO blood group, C5, adenosine deaminase, esterase D, PGM I , haptoglobin, Gc protein, MN blood group, P blood group, Duffy blood group, Kell blood group and Kidd blood group loci using data from random Caucasian individuals. Significant associations were only found between Sap-A and haptoglobin locus and between Set-l and MN blood group locus. These significant associations are most probably due to chance. Linkage studies were not very fruitful because of the small numbers of informative families available due to the small family size in most of the sampled families. None of the accumulative lod scores yielded conclusive results.
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    The genetics of pigeon populations on Oahu
    ([Honolulu], 1972) Go, Rodney Chun-Pung
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    A genetic and epidemiological study of cleft lip and cleft palate in Hawaii
    ([Honolulu], 1970) Ching, Gerald Hong Sung
    The purpose of this study was (1) to obtain unbiased estimates of cleft incidences in the major racial groups in Hawaii, (2) to evaluate the extent and nature of racial differences in incidence, (3) to determine how the segregation of cleft defects varies among racial groups, and (4) to estimate the heritability of cleft defects using a multifactorial model of quasicontinuity. Cleft cases were ascertained through birth and death certificates and records of the Crippled Children Branch (Hawaii Health Department) and major Honolulu hospitals. The reference population which provided the basis for the analysis of incidence was composed of live births in Hawaii from 1948 to 1966, as compiled by Drs. Morton, Chung, and Mi. Live birth certificates provided demographic data on all individuals in the reference population. Variables included race and age of each parent, sex of child, birth order, year of birth, and occupation and military status of father. Families of probands were interviewed for additional data on types and numbers of affected and normal relatives and parental consanguinity. The ascertainment of CL(P) was estimated to be 97% complete, and that of CP to be 93% complete. The danger of relying exclusively on birth certificates for the ascertainment of cases was made clear by our findings that only 80.7% of CLP, 66.7% of CL, and 47.7% of CP probands born in 1948-1966 had their defects noted on their birth certificates. A number of factors were found to be related to the ascertainment probabilities of CP and CL(P). In the case of CP, ascertainment appeared more likely when the individual had three or more additional malformations and less likely when his father was actively engaged in military service. The case of CL(P) was more complicated. The probability of ascertainment of CL(P) apparently increased when the defect extended to the palate and when any additional malformation was present; it seemed to decrease with year of birth, age of father, death in infancy, and father in the military. Significantly, however, no racial biases in ascertainment were detected after adjustment for the effects of non-racial factors. After correcting for ascertainment biases, the estimated overall incidence of CP in Hawaii was .78 per thousand live births. In the pure Caucasian group, the estimated incidence was .50; in the pure Japanese group, it was .74. Incidences in excess of one per thousand were found in groups with Hawaiian ancestry. Regression analysis showed a definite association between Hawaiian parentage and high incidence of CP. This strong Hawaiian effect could not be attributed to maternal racial factors or to interracial hybridization. Orientals as a whole did not appear to have a significantly higher incidence of CP than Caucasians. For CL(P), the corrected incidence was estimated at 1.05 per thousand in Caucasians, 1.92 in Japanese, and 1.28 in the general population. Unlike in the case of CP, Hawaiian ancestry was not associated with high incidence of CL(P). Instead, the Oriental groups, particularly the Japanese and Filipinos (1.56), presented the highest risks. No maternal or hybridity racial effects were detected for any of the Oriental groups. The effects of non-racial factors (father's age, mother's age, birth order, year of birth, father's occupational and military status) on incidence were tested by separate regression analyses in the Japanese and in the Caucasian racial . groups. No consistent relationship between incidence and any non-racial variable was detected for either cleft type. However, CP incidence did appear to increase with lower occupational status in the Caucasian group, although not in the Japanese group. Estimates of mean segregation frequencies for CP were 2.2% in families of Hawaiian ancestry and 1.3% in all other families. Although the difference was not statistically significant, the higher risk in Hawaiian families would be expected under the multifactorial hypothesis which equates risk approximately to the square root of the population incidence. Heritability of CP was estimated to be 69%, which possibly indicates that additive genetic factors are very important in the etiology of CP. Mean segregation frequencies for CL(P) were 6.1% in pure Japanese, 6.4% in pure Filipinos, and 4.2% in all other groups. The higher risks in Japanese and Filipinos may reflect their higher incidences of CL(P). Overall heritability of CL(P) was estimated at 86%, with no significant differences among Japanese, Filipinos, and all other groups combined. The weight of evidence now seems to favor a multifactorial hypothesis of CL(P) inheritance, and the present estimates of heritability would suggest a large additive hereditary component.