Selection for Decreased BRCA2 Functional Activity inHomo sapiensAfter Divergence from the Chimpanzee-Human Last Common Ancestor

Abstract

Humans have an increased incidence of epithelial neoplasia compared to non-human primates. We performed a comparative analysis of 21 non-human primate genomes and 54 ancient human genomes to identify variations in known cancer genes that may explain this difference. We identified 299 human-specific fixed non-silent single nucleotide polymorphisms. Bioinformatics analyses for functional consequences identified a number of variants predicted to have altered protein function, one of which was located at the most evolutionarily conserved domain of human BRCA2. This variant, in which a polar threonine residue replaces a hydrophobic methionine residue to codon 2662 within the DSS1 binding domain, decreases the interactions of BRCA2 with other proteins, specifically the binding of BRCA2 and RAD51, as well as the repairing ability of cells for DNA double-strand breaks. We conclude that a 20% reduction in BRCA2 DNA repair ability was positively selected for in the course of human evolution.One Sentence SummaryReduction of BRCA2 functional activity has been selected for during human evolution since the chimpanzee-human last common ancestor.