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.

Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineagespecific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans.