(564d) Genomic Approaches to Evolution and Adaptation of Modern Human Populations

Our understanding about the forces that have shaped human genome evolution has accelerated during the last years based on the study of the human diversity utilizing large genomic datasets. The availability of data from 11 diverse populations has allowed us to examine the role of genetic variation in population migration, organ differentiation, and the process of evolution itself, and we present here an illustration of each. In terms of migration, previous studies have focused on mitochondrial DNA (mtDNA) polymorphisms and have shown astonishing correlations between individuals' geographic origin and mitochondrial haplogroup, revealing the migration and settlement history of human species. Based on a world sampling of 629 unrelated individuals, we have now studied the polymorphisms of the 80 genes encoding nuclear subunits of the mitochondrial respiratory (OXPHOS) complexes. We have shown that (i) populations can be distinguished based only on amino-acid replacements in nuclear encoded OXPHOS subunits, and (ii) amino-acid replacement frequencies are significantly correlated with their pathogenicity probability. These results, which are congruent with the major mtDNA haplogroups, suggest that OXPHOS complexes are different across the populations in both nuclear and in mitochondrial encoded subunits.

In terms of organ differentiation, studies about gene expression have suggested that some tissue-specific genes evolved rapidly on the human lineage. Thus, it appears that constraint on genes have varied during human evolution depending on the tissue in which they are expressed. To gain insight into the evolution of tissue determined negative selection forces, we compared the nonsynonymous SNP diversity of genes expressed in different tissues. For each SNP, we determined its frequency in 11 human populations and in each case predicted whether or not the change it produces is deleterious. We have shown that, with one exception, for all organs under study SNPs predicted to be deleterious are present at a significantly lower frequency than SNPs predicted to be tolerated. However, testis specific genes contain a notably higher proportion of deleterious SNPs compared to those of other organs, suggesting that negative (maintaining) selection on human testis specific genes has recently decreased.

In terms of evolution, the question of whether it is ongoing in modern human populations is one of continuing interest. To address it, we studied the selective strengths acting presently on the genome and show that, with one exception, the genetic diversity for all the major pathways is still constrained by negative selection in all 11 human populations studied. The exception was a relaxation of negative selection acting on olfactory receptors. Since a decreased number of functioning olfactory receptors in human compared with other primates had already been shown, this suggests that the role of olfactory receptors for survival and reproductive success has decreased during human evolution. By showing that negative selection is still relaxed, the present results imply that no plateau of minimal function has yet been reached in modern humans and therefore that olfactory capability might still be decreasing. This is a first clue to present human evolution.