Comparative analysis of mammal genomes unveils key genomic variability for human life span

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• dc.contributor.author Farré, Xavier
• dc.contributor.author Molina, Ruben
• dc.contributor.author Barteri, Fabio
• dc.contributor.author Timmers, Paul R.H.J.
• dc.contributor.author Joshi, Peter K.
• dc.contributor.author Oliva Miguel, Baldomero
• dc.contributor.author Acosta, Sandra
• dc.contributor.author Esteve Altava, Borja
• dc.contributor.author Navarro i Cuartiellas, Arcadi, 1969-
• dc.contributor.author Muntané, Gerard
• dc.date.accessioned 2021-12-01T07:35:48Z
• dc.date.available 2021-12-01T07:35:48Z
• dc.date.issued 2021
• dc.description.abstract The enormous mammal's lifespan variation is the result of each species' adaptations to their own biological trade-offs and ecological conditions. Comparative genomics have demonstrated that genomic factors underlying both, species lifespans and longevity of individuals, are in part shared across the tree of life. Here, we compared protein-coding regions across the mammalian phylogeny to detect individual amino acid (AA) changes shared by the most long-lived mammals and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 AA in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (P = 0.003). These genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 AA showed a significant association with maximum lifespan in a phylogenetic test. Interestingly, most of the detected AA positions do not vary in extant human populations (81.2%) or have allele frequencies below 1% (99.78%). Consequently, almost none of these putatively important variants could have been detected by genome-wide association studies. Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected, successfully demonstrating for the first time that comparative genomics can be used to enhance interpretation of human genome-wide association studies. Finally, we show that the human longevity-associated proteins are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.
• dc.description.sponsorship This work was supported by AEI-PGC2018-101927-BI00 (FEDER/UE), the Spanish National Institute of Bioinformatics of the Instituto de Salud Carlos III (PT17/0009/0020), FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo), “Unidad de Excelencia María de Maeztu,” funded by the AEI (CEX2018-000792-M) and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880).
• dc.format.mimetype application/pdf
• dc.identifier.citation Farré X, Molina R, Barteri F, Timmers PRHJ, Joshi PK, Oliva B, Acosta S, Esteve-Altava B, Navarro A, Muntané G. Comparative analysis of mammal genomes unveils key genomic variability for human life span. Mol Biol Evol. 2021;38(11):4948-61. DOI: 10.1093/molbev/msab219
• dc.identifier.doi http://dx.doi.org/10.1093/molbev/msab219
• dc.identifier.issn 0737-4038
• dc.identifier.uri http://hdl.handle.net/10230/49116
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.ispartof Mol Biol Evol. 2021;38(11):4948-61
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-101927-BI00
• dc.rights © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), 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
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword GWAS
• dc.subject.keyword Aging
• dc.subject.keyword Comparative genomics
• dc.subject.keyword Convergent evolution
• dc.subject.keyword Genetics
• dc.subject.keyword Maximum lifespan
• dc.title Comparative analysis of mammal genomes unveils key genomic variability for human life span
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion