The Molecular Clock in the Evolution of Protein Structures

The molecular clock hypothesis, which states that substitutions accumulate in protein sequences at a constant rate, plays a fundamental role in molecular evolution but it is violated when selective or mutational processes vary with time. Such violations of the molecular clock have been widely invest...

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Detalhes bibliográficos
Autores: Pascual-García, Alberto, Arenas, Miguel, Bastolla, Ugo
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/374558
Acesso em linha:http://hdl.handle.net/10261/374558
https://api.elsevier.com/content/abstract/scopus_id/85073668537
Access Level:acceso abierto
Palavra-chave:Co-evolution
Molecular clock
Protein structure evolution
Selection
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spelling The Molecular Clock in the Evolution of Protein Structures Pascual-García, Alberto Arenas, Miguel Bastolla, Ugo Co-evolution Molecular clock Protein structure evolution Selection The molecular clock hypothesis, which states that substitutions accumulate in protein sequences at a constant rate, plays a fundamental role in molecular evolution but it is violated when selective or mutational processes vary with time. Such violations of the molecular clock have been widely investigated for protein sequences, but not yet for protein structures. Here, we introduce a novel statistical test (Significant Clock Violations) and perform a large scale assessment of the molecular clock in the evolution of both protein sequences and structures in three large superfamilies. After validating our method with computer simulations, we find that clock violations are generally consistent in sequence and structure evolution, but they tend to be larger and more significant in structure evolution. Moreover, changes of function assessed through Gene Ontology and InterPro terms are associated with large and significant clock violations in structure evolution. We found that almost one third of significant clock violations are significant in structure evolution but not in sequence evolution, highlighting the advantage to use structure information for assessing accelerated evolution and gathering hints of positive selection. Clock violations between closely related pairs are frequently significant in sequence evolution, consistent with the observed time dependence of the substitution rate attributed to segregation of neutral and slightly deleterious polymorphisms, but not in structure evolution, suggesting that these substitutions do not affect protein structure although they may affect stability. These results are consistent with the view that natural selection, both negative and positive, constrains more strongly protein structures than protein sequences. Our code for computing clock violations is freely available at https://github.com/ugobas/Molecular_clock. This work has been funded by the Spanish Ministry of Science [BIO2016-79043-P and BFU2012-40020]; the Spanish Government [RYC-2015-18241] and the Xunta de Galiciaž [ED431F 2018/08] to M.A.; the Simons Foundation [542381 to A.P.G., in part]. Peer reviewed Oxford University Press http://hdl.handle.net/10261/374558 https://api.elsevier.com/content/abstract/scopus_id/85073668537
title The Molecular Clock in the Evolution of Protein Structures
spellingShingle The Molecular Clock in the Evolution of Protein Structures
Pascual-García, Alberto
Co-evolution
Molecular clock
Protein structure evolution
Selection
title_short The Molecular Clock in the Evolution of Protein Structures
title_full The Molecular Clock in the Evolution of Protein Structures
title_fullStr The Molecular Clock in the Evolution of Protein Structures
title_full_unstemmed The Molecular Clock in the Evolution of Protein Structures
title_sort The Molecular Clock in the Evolution of Protein Structures
author Pascual-García, Alberto
author_facet Pascual-García, Alberto
Arenas, Miguel
Bastolla, Ugo
author_role author
author2 Arenas, Miguel
Bastolla, Ugo
author2_role author
author
topic Co-evolution
Molecular clock
Protein structure evolution
Selection
topic_facet Co-evolution
Molecular clock
Protein structure evolution
Selection
description The molecular clock hypothesis, which states that substitutions accumulate in protein sequences at a constant rate, plays a fundamental role in molecular evolution but it is violated when selective or mutational processes vary with time. Such violations of the molecular clock have been widely investigated for protein sequences, but not yet for protein structures. Here, we introduce a novel statistical test (Significant Clock Violations) and perform a large scale assessment of the molecular clock in the evolution of both protein sequences and structures in three large superfamilies. After validating our method with computer simulations, we find that clock violations are generally consistent in sequence and structure evolution, but they tend to be larger and more significant in structure evolution. Moreover, changes of function assessed through Gene Ontology and InterPro terms are associated with large and significant clock violations in structure evolution. We found that almost one third of significant clock violations are significant in structure evolution but not in sequence evolution, highlighting the advantage to use structure information for assessing accelerated evolution and gathering hints of positive selection. Clock violations between closely related pairs are frequently significant in sequence evolution, consistent with the observed time dependence of the substitution rate attributed to segregation of neutral and slightly deleterious polymorphisms, but not in structure evolution, suggesting that these substitutions do not affect protein structure although they may affect stability. These results are consistent with the view that natural selection, both negative and positive, constrains more strongly protein structures than protein sequences. Our code for computing clock violations is freely available at https://github.com/ugobas/Molecular_clock.
publishDate 2019
format article
status_str acceptedVersion
url http://hdl.handle.net/10261/374558
https://api.elsevier.com/content/abstract/scopus_id/85073668537
eu_rights_str_mv openAccess
publisher Oxford University Press
institution Consejo Superior de Investigaciones Científicas (CSIC)
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
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publishDateSort 2019
author_browse Arenas, Miguel
Bastolla, Ugo
Pascual-García, Alberto
publisherStr Oxford University Press
score 6,924472

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