Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions

The patterns of polymorphisms in genomes are imprints of the evolutionary forces at play in nature. In particular, polymorphisms have been extensively used to infer the fitness effects of mutations and their dynamics of fixation. However, the role and contribution of molecular biophysics to these ob...

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Main Authors:	Serohijos, Adrian W.R., Shakhnovich, Eugene I.
Format:	Online
Language:	English
Published:	Oxford University Press 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879451/

id	pubmed-3879451
recordtype	oai_dc
spelling	pubmed-38794512014-01-03 Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions Serohijos, Adrian W.R. Shakhnovich, Eugene I. Discoveries The patterns of polymorphisms in genomes are imprints of the evolutionary forces at play in nature. In particular, polymorphisms have been extensively used to infer the fitness effects of mutations and their dynamics of fixation. However, the role and contribution of molecular biophysics to these observations remain unclear. Here, we couple robust findings from protein biophysics, enzymatic flux theory, the selection against the cytotoxic effects of protein misfolding, and explicit population dynamics simulations in the polyclonal regime. First, we recapitulate results on the dynamics of clonal interference and on the shape of the DFE, thus providing them with a molecular and mechanistic foundation. Second, we predict that if evolution is indeed under the dynamic equilibrium of mutation–selection balance, the fraction of stabilizing and destabilizing mutations is almost equal among single-nucleotide polymorphisms segregating at high allele frequencies. This prediction is proven true for polymorphisms in the human coding region. Overall, our results show how selection for protein folding stability predominantly shapes the patterns of polymorphisms in coding regions. Oxford University Press 2014-01 2013-10-11 /pmc/articles/PMC3879451/ /pubmed/24124208 http://dx.doi.org/10.1093/molbev/mst189 Text en © The Author 2013. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Serohijos, Adrian W.R. Shakhnovich, Eugene I.
spellingShingle	Serohijos, Adrian W.R. Shakhnovich, Eugene I. Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions
author_facet	Serohijos, Adrian W.R. Shakhnovich, Eugene I.
author_sort	Serohijos, Adrian W.R.
title	Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions
title_short	Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions
title_full	Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions
title_fullStr	Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions
title_full_unstemmed	Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions
title_sort	contribution of selection for protein folding stability in shaping the patterns of polymorphisms in coding regions
description	The patterns of polymorphisms in genomes are imprints of the evolutionary forces at play in nature. In particular, polymorphisms have been extensively used to infer the fitness effects of mutations and their dynamics of fixation. However, the role and contribution of molecular biophysics to these observations remain unclear. Here, we couple robust findings from protein biophysics, enzymatic flux theory, the selection against the cytotoxic effects of protein misfolding, and explicit population dynamics simulations in the polyclonal regime. First, we recapitulate results on the dynamics of clonal interference and on the shape of the DFE, thus providing them with a molecular and mechanistic foundation. Second, we predict that if evolution is indeed under the dynamic equilibrium of mutation–selection balance, the fraction of stabilizing and destabilizing mutations is almost equal among single-nucleotide polymorphisms segregating at high allele frequencies. This prediction is proven true for polymorphisms in the human coding region. Overall, our results show how selection for protein folding stability predominantly shapes the patterns of polymorphisms in coding regions.
publisher	Oxford University Press
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879451/
_version_	1612043908897832960

Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions

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