Thesis--M. Phil., University of Hong Kong, 1987.

Thesis (Ph. D.)--Harvard University, 1977. / Includes bibliographical references (leaves 253-266).

Thesis (Ph. D.)--University of Michigan, 1971. / Includes bibliographical references (leaves 106-110).

published_or_final_version / Medicine / Master / Master of Philosophy

Currently, the most widely used in vivo mutation monitoring system in humans is the hypoxanthine-guanine phosphoribosyltransferase (hprt) T-cell clonal assay. This dissertation examines the current state of the hprt monitoring system and the usefulness of hprt mutational spectra in revealing environmental exposures. The nature of spontaneous mutational spectra recovered through the implementation of this system is detailed. An examination of hprt mutation frequencies obtained from a set of monozygotic twins revealed a striking influence of genetic factors. As age increases, the influence of genetic factors controlling mutation frequency appears to be modified by environmental factors. Mutational spectra obtained from Russian individuals living in Moscow were distinct from the spectrum of mutation observed in age-matched Western controls. Analysis of the relationship between mutation frequency and subject age clearly demonstrated the lack of any relationship for subjects after the age of 55. This finding contradicts many previously published reports on the relationship between mutation frequency and age. Finally, the influence of tobacco smoking on mutational frequency is clear, however, no change in the mutational spectrum of smokers was revealed. Changes in mutational spectrum are analyzed in the context of the T-cell biology and reveal that the dynamics of this tissue are likely responsible for the observations made in this dissertation. Although the hprt gene is a highly robust and suitable target for the analysis of mutation, the target has not yet been saturated, and new single base-pair substitutions are still being characterized. The data clearly suggest that the T-cell clonal assay in its current state may not be a suitable mutational monitoring system for human populations. This dissertation concludes that new mutational assays need to be developed for monitoring mutations in human populations. / Graduate

No description available.

Genetic variation contains detailed and quantitative evidence about the history of populations. The historical traces of demographic growth and contraction, as well as the history of human disease, have left traces on the patterns of modern variation and can be studied by sampling present-day populations. However, the data sets that are necessary in order to take full advantage of this living archaeological record have not been available until recently. The quality and quantity of data have increased dramatically during the past decade because of the identification of polymorphisms, including SNPs and microsatellites, that are much more amenable to mathematical modeling and efficient genotyping than earlier marker systems. The research in this thesis has been carried out in response to the need to provide new methods of analysis to match the new types of data. Chapter 1 describes multilocus tests of demographic history and their application to real data. Chapter 2 describes how the pattern of linkage disequilibrium around a disease-predisposing mutation can be used to estimate the date of a mutation that is, the age of the most recent common ancestor of a set of modern samples. Finally, Chapter 3 draws several direct connections between human evolutionary history and medical genetics.

The past fifteen years have seen a revolution in human population genetics. We have gone from anecdotal genetic data from a few individuals at a few genetic loci to an avalanche of genome-wide sequencing data, from many individuals in many different human populations. These new data have opened up many new directions of research in human population genetics. In this work, I explore two such directions. Genomic data have uncovered that recent changes in human population size have had dramatic effects of on the genomes of different human populations. These effects have raised the question of whether historic changes in population size have led to differences in the burden of deleterious mutations, or mutation load, between different human populations. In Chapter 1 of this thesis, I show that despite earlier arguments to the contrary only minor differences in load are expected and indeed observed between Africans and Europeans. Over the past decade, genome-wide association studies (GWAS) have begun to systematically identify the genetic variants underlying heritable variation in quantitative traits. The number, frequencies and effect sizes of these variants reflect the selection, and other evolutionary processes, acting on traits. In Chapter 2, I develop a model for traits under pleiotropic, stabilizing selection, relate the model’s predictions to GWAS findings, and show that GWAS findings for height and BMI indeed follow model predictions. In Chapter 3, I develop a method to infer the distribution of selection coefficients acting on genome-wide significant associations made by GWAS.

Thesis (Ph. D.)--University of Chicago, Committee of Genetics, 2002. / Includes bibliographical references. Also available on the Internet.

No description available.