Long-term balancing selection in the genomes of humans and other great apes

Balancing selection maintains advantageous genetic diversity in populations through a variety of mechanisms including overdominance, negative frequency-dependent selection, temporal or spatial variation in selective pressures, and pleiotropy. If environmental pressures are constant through time, balancing selection can affect the evolution of selected loci for millions of years, and its targets might be shared by different species. This thesis is comprised of two different approaches aimed at detecting shared signatures of balancing selection in the genomes of humans and other great apes. In the first part of the thesis, we focus on extreme loci where the action of balancing selection has maintained several coding trans-species polymorphisms in humans, chimpanzees and bonobos. These trSNPs segregate since the common ancestor of the Homo-Pan clade and have survived for ~14 million years of independent evolution. These loci show the characteristic signatures of long-term balancing selection, as they define haplotypes with high genetic diversity that show cluster of sequences by allele rather than by species, and segregate at intermediate allele frequencies. Apart from several trSNPs in the MHC region, we were able to uncover a non-synonymous trSNP in the autoimmune gene LAD1. In the second part of the thesis we explore shared signatures of balancing selection outside trSNPs. We first implement a genome scan designed to detect signatures of balancing selection using NCD2 in the genomes of nine great ape species, including chimpanzee, bonobo, gorilla and orangutan. We show that targets of balancing selection are shared between species that have diverged millions of years ago, and that this observation cannot be explained by shared ancestry. We further demonstrate that targets of balancing selection primarily affect the evolution of genic regions of the genome, although we see evidence for their involvement in the regulation of gene expression. Overall, we provide comprehensive evidence that similar environmental pressures maintain advantageous diversity through the action of balancing selection in humans and other great apes, notwithstanding the deep divergence times between many of these species