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Kumar S , Patel R
Neutral theory, disease mutations, and personal exomes
Mol Biol Evol. 2018 Jun 1;35(6) :1297-1303
PMID: 29688514    PMCID: PMC5967454    URL: https://www.ncbi.nlm.nih.gov/pubmed/29688514
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Genetic differences between species and within populations are two sides of the same coin under the neutral theory of molecular evolution. This theory posits that a vast majority of evolutionary substitutions, which appear as differences between species, are (nearly) neutral, i.e., these substitutions are permitted without a significantly adverse impact on a species' survival. We refer to them as evolutionarily permissible variation. Evolutionary permissibility of any possible variant can be inferred from multispecies sequence alignments by applying sophisticated statistical methods to the evolutionary tree of species. Here, we explore the evolutionary permissibility of amino acid variants associated with genetic diseases and those observed in personal exomes. Consistent with the predictions of the neutral theory, disease associated amino acid variants are rarely evolutionarily permissible, much more biochemically radical, and found predominantly at more conserved positions than their non-disease counterparts. Only 10% of amino acid mutations are evolutionarily permissible, but these variants rise to become two-thirds of all substitutions in the human lineage (a 6-fold enrichment). In contrast, only a minority of the variants in a personal exome are evolutionarily permissible, a seemingly counterintuitive pattern that results from a combination of mutational and evolutionary processes that are, in fact, broadly consistent with the neutral theory. Evolutionarily forbidden variants outnumber detrimental variants in individual exomes and may play an under-appreciated role in protecting against disease. We discuss these observations and conclude that the long-term evolutionary history of species can illuminate functional biomedical properties of variation present in personal exomes.
1537-1719 Kumar, Sudhir Patel, Ravi Journal Article United States Mol Biol Evol. 2018 Apr 23. pii: 4983860. doi: 10.1093/molbev/msy085.