Adaptive selection drives TRPP3 loss-of-function in an Ethiopian population

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• dc.contributor.author Walsh Capdevila, Sandra, 1991-
• dc.contributor.author Izquierdo Serra, Mercè
• dc.contributor.author Acosta, Sandra
• dc.contributor.author Edo, Albert
• dc.contributor.author Lloret, María
• dc.contributor.author Moret, Roser
• dc.contributor.author Bosch Fusté, Elena
• dc.contributor.author Oliva Miguel, Baldomero
• dc.contributor.author Bertranpetit, Jaume, 1952-
• dc.contributor.author Fernández-Fernández, José Manuel, 1967-
• dc.date.accessioned 2021-01-14T07:13:01Z
• dc.date.available 2021-01-14T07:13:01Z
• dc.date.issued 2020
• dc.description.abstract TRPP3 (also called PKD2L1) is a nonselective, cation-permeable channel activated by multiple stimuli, including extracellular pH changes. TRPP3 had been considered a candidate for sour sensor in humans, due to its high expression in a subset of tongue receptor cells detecting sour, along with its membership to the TRP channel family known to function as sensory receptors. Here, we describe the functional consequences of two non-synonymous genetic variants (R278Q and R378W) found to be under strong positive selection in an Ethiopian population, the Gumuz. Electrophysiological studies and 3D modelling reveal TRPP3 loss-of-functions produced by both substitutions. R278Q impairs TRPP3 activation after alkalinisation by mislocation of H+ binding residues at the extracellular polycystin mucolipin domain. R378W dramatically reduces channel activity by altering conformation of the voltage sensor domain and hampering channel transition from closed to open state. Sour sensitivity tests in R278Q/R378W carriers argue against both any involvement of TRPP3 in sour detection and the role of such physiological process in the reported evolutionary positive selection past event.
• dc.description.sponsorship This work was funded by the Spanish Ministry of Science and Innovation, the State Research Agency (AEI, Agencia Estatal de Investigación) and FEDER Funds (Fondo Europeo de Desarrollo Regional): Grants BFU2016-77961-P to J.B. and E.B., RTI2018-094809-B-I00 to J.M.F.F., PID2019-110933GB-I00/AEI/10.13039/501100011033 to E.B. and J.B., and CEX2018-000792-M through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”. With the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 702). S.W. has had a F.P.I. grant (BES-2014-068994) and M.I.-S. a “Juan de la Cierva-Incorporación” Fellowship funded by the Spanish Ministry of Science and Innovation.
• dc.format.mimetype application/pdf
• dc.identifier.citation Walsh S, Izquierdo-Serra M, Acosta S, Edo A, Lloret M, Moret R, Bosch E, Oliva B, Bertranpetit J, Fernández-Fernández JM. Adaptive selection drives TRPP3 loss-of-function in an Ethiopian population. Sci Rep. 2020; 10(1):20999. DOI: 10.1038/s41598-020-78081-z
• dc.identifier.doi http://dx.doi.org/10.1038/s41598-020-78081-z
• dc.identifier.issn 2045-2322
• dc.identifier.uri http://hdl.handle.net/10230/46166
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Sci Rep. 2020; 10(1):20999
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-P
• dc.rights © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Biophysics
• dc.subject.keyword Evolution
• dc.subject.keyword Genetics
• dc.subject.keyword Molecular biology
• dc.subject.keyword Physiology
• dc.subject.keyword Structural biology
• dc.title Adaptive selection drives TRPP3 loss-of-function in an Ethiopian population
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion