| Summary: | Genetic variation in a population is shaped by dynamic interactions between mutation, recombination, genetic drift and natural selection. In this dissertation, I focus on the role of two of these forces---selection and mutation---in shaping genetic variation in humans, and develop new approaches to study them. I first consider a scenario where genetic diversity is actively maintained by selection over millions of years: trans-species polymorphisms that result from long-lasting balancing selection pressures. I characterize the expected patterns of linked polymorphisms under this scenario and propose a new method to detect trans-species polymorphisms. By applying it to whole-genome variation data of humans and chimpanzees, collaborators and I find six new candidate targets under ancient balancing selection in the human genome. The flip side to genetic variation actively maintained by balancing selection is the transient presence of deleterious variants as a result of mutation-selection-drift balance. I describe a new approach to quantify the burden of recessive deleterious alleles in humans, which is not confounded by socio-economic factors. By this approach, I estimate that each human individual carries on average 0.58 autosomal recessive alleles that, when homozygous, lead to complete sterility or death between birth and reproductive age. Last, I shift my focus to mutation, the ultimate source of genetic variability and the raw material for molecular evolution. I investigate the time and sex dependencies of mutations that arise through replication errors and non-replicative sources. This work helps to understand the extent to which changes in the human generation time could impact the per year mutation rate in humans, and suggests that the mutation rate per cell division may vary across different stages of germ cell development. My modeling also reveals that the accumulation of mutations with a non-replicative source may depend on cell division rate, a finding that helps to interpret tumor sequencing studies. In summary, I develop and apply a set of models to elucidate how mutations arise and are maintained in the population, notably in humans.
|
|---|
