Selective Pressures on Human Cancer Genes along the Evolution of Mammals

Abstract

Cancer is a disease driven by both somatic mutations that increase survival and proliferation of cell lineages and the evolution of genes associated with cancer risk in populations. Several genes associated with cancer in humans, hereafter cancer genes, show evidence of germline positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for signatures of germline positive selection in 430 cancer genes available in COSMIC. We identified 40 cancer genes with a robust signal of positive selection in mammals. We found evidence for fewer selective constraints—higher number of non-synonymous substitutions per non-synonymous site to the number of synonymous substitutions per synonymous site (dN/dS)—and higher incidence of positive selection—more positively selected sites—in cancer genes bearing germline and recessive mutations that predispose to cancer. This finding suggests a potential association between relaxed selection, positive selection, and risk of hereditary cancer. On the other hand, we did not find significant differences in terms of tissue or gene type. Human cancer genes under germline positive selection in mammals are significantly enriched in the processes of DNA repair, with high presence of Fanconi anaemia/Breast Cancer A (FA/BRCA) pathway components and T cell proliferation genes. We also show that the inferred positively selected sites in the two genes with the strongest signal of positive selection, i.e., BRCA2 and PTPRC, are in regions of functional relevance, which could be relevant to cancer susceptibility.

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

“…Our data provide comprehensive insights into several adaptive evolutionary features of cancer genes since divergence from the CHLCA. As previously reported, we find strong positive selection in genes within the non-homologous end joining (NHEJ) pathway [45][46][47][48][49] . Moreover, we have identified variants in cancer genes with unappreciated significance for a putative role in the human evolution such as ALB, ZNF268, HERC4, EMG1, GNRHR or DNM1L.…”

Evidence that DNA repair genes, a family of tumor suppressor genes, are associated with evolution rate and size of genomes

“…DNA repair genes are considered as tumor suppressor genes. There is evidence that tumor suppressor genes are related to environmental adaptation in humans [70, 71] and selective pressures along the evolution of mammals [72]. We can imagine that certain evolutionary procedures may be DNA repair-dependent, this showing the way for future analyses and experiments.…”

The Evolution of Human Cancer Gene Duplications across Mammals

“…This suggests that pathways associated with hereditary cancers, which are caused by germline mutations, may face different constraints than those associated with sporadic cancers. Vicens and Posada (2018) analyzed ratios of the proportion of nonsynonymous substitutions per site to the proportion of synonymous substitutions per site in human cancer genes across mammals and found evidence for relaxed selective constraint in cancer genes with germline mutations relative to those with somatic mutations. Thus, there may be stronger purifying selection acting on pathways associated with highly deleterious sporadic cancers, which would reduce the fixation rate of copy number variants related to those pathways.…”