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Genes 2018, 9(12), 582; https://doi.org/10.3390/genes9120582

Selective Pressures on Human Cancer Genes along the Evolution of Mammals

1,2
and
1,2,3,*
1
Department of Biochemistry, Genetics and Immunology, University of Vigo, 36310 Vigo, Spain
2
Biomedical Research Center (CINBIO), University of Vigo, 36310 Vigo, Spain
3
Galicia Sur Health Research Institute, 36310 Vigo, Spain
*
Author to whom correspondence should be addressed.
Received: 30 October 2018 / Revised: 21 November 2018 / Accepted: 21 November 2018 / Published: 28 November 2018
(This article belongs to the Special Issue Evolutionary Medicine)
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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. View Full-Text
Keywords: positive selection; somatic evolution; germline evolution; dN/dS positive selection; somatic evolution; germline evolution; dN/dS
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Vicens, A.; Posada, D. Selective Pressures on Human Cancer Genes along the Evolution of Mammals. Genes 2018, 9, 582.

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