Human genetic adaptation related to cellular zinc homeostasis

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• dc.contributor.author Roca-Umbert Würth, Ana
• dc.contributor.author García Calleja, Jorge
• dc.contributor.author Vogel González, Marina, 1993-
• dc.contributor.author Fierro Villegas, José Alejandro
• dc.contributor.author Ill-Raga, Gerard, 1982-
• dc.contributor.author Herrera-Fernández, Víctor
• dc.contributor.author Bosnjak, Anja
• dc.contributor.author Muntané, Gerard
• dc.contributor.author Gutiérrez García, Esteban
• dc.contributor.author Campelo, Felix
• dc.contributor.author Vicente García, Rubén, 1978-
• dc.contributor.author Bosch Fusté, Elena
• dc.date.accessioned 2023-12-05T07:10:39Z
• dc.date.available 2023-12-05T07:10:39Z
• dc.date.issued 2023
• dc.description.abstract SLC30A9 encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show is found in homozygosis in the Denisovan genome and displays accompanying signatures suggestive of archaic introgression. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. Notably, the ZnT9 50Val variant was found associated with differences in zinc handling by the mitochondria and endoplasmic reticulum, with an impact on mitochondrial metabolism. Given the essential role of the mitochondria in skeletal muscle and since the derived allele at rs1047626 is known to be associated with greater susceptibility to several neuropsychiatric traits, we propose that adaptation to cold may have driven this selection event, while also impacting predisposition to neuropsychiatric disorders in modern humans.
• dc.description.sponsorship This work was supported by Ministerio de Ciencia e Innovación (MCIN) and Agencia Estatal de Investigación (AEI; DOI:10.13039/501100011033) with project grants RYC-2017-22227, PID2019-106232RB-I00 (to FC), PID2019-110933GB-I00 (to EB), PID2019-106755RB-I00 (to RV), and Unidad de Excelencia María de Maeztu CEX2018-000792-M (to EB and RV) and Severo Ochoa CEX2019-000910-S (to FC); and by Direcció General de Recerca, Generalitat de Catalunya with project grant 2017SGR00702 (to EB). FC was supported by Fundació Cellex, Fundació Mir-Puig, and Generalitat de Catalunya (CERCA, AGAUR). JGC was supported with an FPI-MCIN/AEI PhD contract (PRE2020-095762). GM was supported by funding from Instituto de Salud Carlos III (ISCIII) through project PI21/00612 and co-funded by the European Union. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• dc.format.mimetype application/pdf
• dc.identifier.citation Roca-Umbert A, Garcia-Calleja J, Vogel-González M, Fierro-Villegas A, Ill-Raga G, Herrera-Fernández V, Bosnjak A, Muntané G, Gutiérrez E, Campelo F, Vicente R, Bosch E. Human genetic adaptation related to cellular zinc homeostasis. PLoS Genet. 2023 Sep 25;19(9):e1010950. DOI: 10.1371/journal.pgen.1010950
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1010950
• dc.identifier.issn 1553-7390
• dc.identifier.uri http://hdl.handle.net/10230/58440
• dc.language.iso eng
• dc.publisher Public Library of Science (PLoS)
• dc.relation.ispartof PLoS Genet. 2023 Sep 25;19(9):e1010950
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-106232RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-110933GB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-106755RB-I00
• dc.rights © 2023 Roca-Umbert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Haplotypes
• dc.subject.keyword Mitochondria
• dc.subject.keyword Genomics
• dc.subject.keyword Introgression
• dc.subject.keyword Transfection
• dc.subject.keyword Single nucleotide polymorphisms
• dc.subject.keyword Human genomics
• dc.subject.keyword Homeostasis
• dc.title Human genetic adaptation related to cellular zinc homeostasis
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion