Common sequence variants affect molecular function more than rare variants?

Abstract Any two unrelated individuals differ by about 10,000 single amino acid variants (SAVs). Do these impact molecular function? Experimental answers cannot answer comprehensively, while state-of-the-art prediction methods can. We predicted the functional impacts of SAVs within human and for var...

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Autores principales:	Yannick Mahlich, Jonas Reeb, Maximilian Hecht, Maria Schelling, Tjaart Andries Petrus De Beer, Yana Bromberg, Burkhard Rost
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/66cc665838b94fa7aa47fd0e62cc4786
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spelling	oai:doaj.org-article:66cc665838b94fa7aa47fd0e62cc47862021-12-02T16:06:24ZCommon sequence variants affect molecular function more than rare variants?10.1038/s41598-017-01054-22045-2322https://doaj.org/article/66cc665838b94fa7aa47fd0e62cc47862017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01054-2https://doaj.org/toc/2045-2322Abstract Any two unrelated individuals differ by about 10,000 single amino acid variants (SAVs). Do these impact molecular function? Experimental answers cannot answer comprehensively, while state-of-the-art prediction methods can. We predicted the functional impacts of SAVs within human and for variants between human and other species. Several surprising results stood out. Firstly, four methods (CADD, PolyPhen-2, SIFT, and SNAP2) agreed within 10 percentage points on the percentage of rare SAVs predicted with effect. However, they differed substantially for the common SAVs: SNAP2 predicted, on average, more effect for common than for rare SAVs. Given the large ExAC data sets sampling 60,706 individuals, the differences were extremely significant (p-value < 2.2e-16). We provided evidence that SNAP2 might be closer to reality for common SAVs than the other methods, due to its different focus in development. Secondly, we predicted significantly higher fractions of SAVs with effect between healthy individuals than between species; the difference increased for more distantly related species. The same trends were maintained for subsets of only housekeeping proteins and when moving from exomes of 1,000 to 60,000 individuals. SAVs frozen at speciation might maintain protein function, while many variants within a species might bring about crucial changes, for better or worse.Yannick MahlichJonas ReebMaximilian HechtMaria SchellingTjaart Andries Petrus De BeerYana BrombergBurkhard RostNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yannick Mahlich Jonas Reeb Maximilian Hecht Maria Schelling Tjaart Andries Petrus De Beer Yana Bromberg Burkhard Rost Common sequence variants affect molecular function more than rare variants?
description	Abstract Any two unrelated individuals differ by about 10,000 single amino acid variants (SAVs). Do these impact molecular function? Experimental answers cannot answer comprehensively, while state-of-the-art prediction methods can. We predicted the functional impacts of SAVs within human and for variants between human and other species. Several surprising results stood out. Firstly, four methods (CADD, PolyPhen-2, SIFT, and SNAP2) agreed within 10 percentage points on the percentage of rare SAVs predicted with effect. However, they differed substantially for the common SAVs: SNAP2 predicted, on average, more effect for common than for rare SAVs. Given the large ExAC data sets sampling 60,706 individuals, the differences were extremely significant (p-value < 2.2e-16). We provided evidence that SNAP2 might be closer to reality for common SAVs than the other methods, due to its different focus in development. Secondly, we predicted significantly higher fractions of SAVs with effect between healthy individuals than between species; the difference increased for more distantly related species. The same trends were maintained for subsets of only housekeeping proteins and when moving from exomes of 1,000 to 60,000 individuals. SAVs frozen at speciation might maintain protein function, while many variants within a species might bring about crucial changes, for better or worse.
format	article
author	Yannick Mahlich Jonas Reeb Maximilian Hecht Maria Schelling Tjaart Andries Petrus De Beer Yana Bromberg Burkhard Rost
author_facet	Yannick Mahlich Jonas Reeb Maximilian Hecht Maria Schelling Tjaart Andries Petrus De Beer Yana Bromberg Burkhard Rost
author_sort	Yannick Mahlich
title	Common sequence variants affect molecular function more than rare variants?
title_short	Common sequence variants affect molecular function more than rare variants?
title_full	Common sequence variants affect molecular function more than rare variants?
title_fullStr	Common sequence variants affect molecular function more than rare variants?
title_full_unstemmed	Common sequence variants affect molecular function more than rare variants?
title_sort	common sequence variants affect molecular function more than rare variants?
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/66cc665838b94fa7aa47fd0e62cc4786
work_keys_str_mv	AT yannickmahlich commonsequencevariantsaffectmolecularfunctionmorethanrarevariants AT jonasreeb commonsequencevariantsaffectmolecularfunctionmorethanrarevariants AT maximilianhecht commonsequencevariantsaffectmolecularfunctionmorethanrarevariants AT mariaschelling commonsequencevariantsaffectmolecularfunctionmorethanrarevariants AT tjaartandriespetrusdebeer commonsequencevariantsaffectmolecularfunctionmorethanrarevariants AT yanabromberg commonsequencevariantsaffectmolecularfunctionmorethanrarevariants AT burkhardrost commonsequencevariantsaffectmolecularfunctionmorethanrarevariants
_version_	1718385029246091264

Common sequence variants affect molecular function more than rare variants?

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