Mutational load and loss of function variant diversity in great apes

Trabajo presentado en la XIII Jornada de Biologia Evolutiva, celebrada en Barcelona el 2 de julio de 2013.
Humans have been recently shown to harbor an unexpectedly high number of polymorphic stop gain or loss codon mutations, frameshift indels and large deletions. Loss of function (LoF) variants are predicted to disrupt gene function, and these results suggest an important level of pathway robustness and gene redundancy in the human genome. We have analyzed the mutational load and performed a systematic research based on human gene annotations of the LoF variants in the Great Ape Genome Diversity Project dataset, including 73 whole-genome sequences from chimpanzee, bonobo, gorilla and orangutan populations. The site frequency spectrum (SFS) shows differences across the primate species, since it is shaped by the particular demographic history of each population. One common pattern of SFS, also seen in humans, is that missense variants are enriched relative to synonymous variants at the lower frequencies, because of the action of purifying selection. However the relative amount of nonsynonymous compared to synonymous variants shows differences across the different populations, related to the different efficiency of natural selection to remove detrimental mutations in each population as a consequence of more efficient purifying selection at larger population sizes. After applying stringent filters on mapping, sequence quality and gene annotation, we observed that the total number of polymorphic LoF variants per individual varies from similar estimates to the one hundred reported in humans up to two or three fold across primate species. Homozygous variants potentially producing a complete lack of function also follow this tendency. Because of their functional impact LoF variants accumulate at low frequencies, and the proportion of LoF to synonymous variants per individual correlates negatively with the Ne, concordant with the same findings on the overall mutational load. This high and seemingly excessive individual mutational load is found to proportionally increase with diversity and effective population size, suggesting that a fraction of LoF variants may not have an important functional effect. Enrichment analysis of genes with polymorphic LoF variants did not detect an accumulation of mutations in particular pathways and functional categories, and we found little sharing both at the gene, pathway or functional levels across ape species.