Global Signatures of Selection in Humans

Abstract

This thesis studies the properties and prevalence of natural selection operating on our species on a global or genome-wide scale. It is still not known how negative selection against deleterious mutations operates genome-wide, whether balancing selection is responsible for maintaining higher genetic diversity in some parts of the genome, and how prevalent adaptation on complex or polygenic traits is in humans. We now have access to population genetic data from healthy populations worldwide, methods to evaluate the functional effects and age of genetic mutations, and Genome-wide Association (GWA) studies to estimate the genetic basis of a complex trait. Using these resources, as well as developing novel statistical methodologies, we show that 1) negative selection in humans involves synergistic epistasis, or deleterious mutations in the human genome interact globally in a manner to reinforce each other’s effects, 2) genes with monoallelic expression contribute disproportionately to genetic diversity in humans, which is maintained through the evolutionary forces of balancing selection and a higher mutation and recombination rate 3) the signal for polygenic adaptation at height-associated genetic variants in humans is confounded by ascertainment biases in the GWAS used to estimate height across populations. We conclude that (1) helps explain how humans tolerate a high incoming rate of deleterious mutations, and why sexual reproduction may have an evolutionary advantage, (2) establishes a link between genetic and epigenetic mechanisms of maintaining and exhibiting high genetic diversity in humans, and (3) demonstrates the presence of confounders that restrict interpretation of signals of polygenic adaptation in humans found using currently existing GWA studies.