Evolutionary and functional analyses of LRP5 in archaic and extant modern humans

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• dc.contributor.author Roca Ayats, Neus
• dc.contributor.author Maceda Porto, Iago, 1986-
• dc.contributor.author Bruque, Carlos David
• dc.contributor.author Martínez-Gil, Núria
• dc.contributor.author Garcia Giralt, Natàlia
• dc.contributor.author Cozar, Mónica
• dc.contributor.author Mellibovsky, Leonardo
• dc.contributor.author Van Hul, Wim
• dc.contributor.author Lao Grueso, Oscar, 1976-
• dc.contributor.author Grinberg, Daniel
• dc.contributor.author Balcells, Susana
• dc.date.accessioned 2025-06-02T06:23:19Z
• dc.date.available 2025-06-02T06:23:19Z
• dc.date.issued 2024
• dc.description.abstract Background: The human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced. Results: We have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first β-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation. Conclusions: In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.
• dc.description.sponsorship NRA, NMG, MC, DG and SB acknowledge the financial support from Spanish Ministry of Science and Innovation (SAF 2016-75948R and PID2019-107188RB-C21) and Catalan Government (2017SGR:00738). NRA was a recipient of a FPU predoctoral fellowship from the Spanish Minsterio de Educación Cultura y Deporte. NMG was a recipient of a FI predoctoral fellowship from AGAUR (Catalan Agency for Management of University and Research Grants). OL and IM acknowledge the support from Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa, CERCA Program/Generalitat de Catalunya, Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement, Co-financing with funds from the European Regional Development Fund by the Spanish Ministry of Science and Innovation corresponding to the Programa Operativo FEDER Plurirregional de España (POPE) 2014–2020 and by the Secretaria d’Universitats i Recerca, Departament d’Empresa i Coneixement of the Generalitat de Catalunya corresponding to the Programa Operatiu FEDER de Catalunya 2014–2020. OL gratefully acknowledges the financial support from Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness) PGC2018-098574-B-I00, Generalitat de Catalunya (Government of Catalonia)—GRC 2017 SGR 937 and CSIC (Proyecto Intramural 2022). IM gratefully acknowledges the financial support from the Government of Catalonia | Agència de Gestió d’Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants)—GRC 2014 SGR 615.
• dc.format.mimetype application/pdf
• dc.identifier.citation Roca-Ayats N, Maceda I, Bruque CD, Martínez-Gil N, Garcia-Giralt N, Cozar M, et al. Evolutionary and functional analyses of LRP5 in archaic and extant modern humans. Hum Genomics. 2024 May 27;18(1):53. DOI: 10.1186/s40246-024-00616-6
• dc.identifier.doi http://dx.doi.org/10.1186/s40246-024-00616-6
• dc.identifier.issn 1473-9542
• dc.identifier.uri http://hdl.handle.net/10230/70586
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Hum Genomics. 2024 May 27;18(1):53
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75948-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-107188RB-C21
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-098574-B-I00
• dc.rights © The Author(s) 2024. 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword LRP5
• dc.subject.keyword Archaic introgression
• dc.subject.keyword Bone mineral density
• dc.subject.keyword Denisovan
• dc.subject.keyword Human evolution
• dc.subject.keyword Neanderthal
• dc.title Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion