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

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...

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Autores: Roca-Ayats N, Maceda I, Bruque CD, Martínez-Gil N, Garcia-Giralt N, Cozar M, Mellibovsky L, Van Hul W, Lao O, Grinberg D, Balcells S
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p26317
Acesso em linha:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=26317
Access Level:acceso abierto
Palavra-chave:LRP5
Bone mineral density
Neanderthal
Denisovan
Human evolution
Archaic introgression
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spelling Evolutionary and functional analyses of LRP5 in archaic and extant modern humansRoca-Ayats NMaceda IBruque CDMartínez-Gil NGarcia-Giralt NCozar MMellibovsky LVan Hul WLao OGrinberg DBalcells SLRP5Bone mineral densityNeanderthalDenisovanHuman evolutionArchaic introgressionBackground 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 beta-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.BMC2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=26317Human GenomicsISSN: 14739542ISSNe: 14797364reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p263172026-05-27T12:37:41Z
dc.title.none.fl_str_mv Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
title Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
spellingShingle Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
Roca-Ayats N
LRP5
Bone mineral density
Neanderthal
Denisovan
Human evolution
Archaic introgression
title_short Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
title_full Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
title_fullStr Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
title_full_unstemmed Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
title_sort Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
dc.creator.none.fl_str_mv Roca-Ayats N
Maceda I
Bruque CD
Martínez-Gil N
Garcia-Giralt N
Cozar M
Mellibovsky L
Van Hul W
Lao O
Grinberg D
Balcells S
author Roca-Ayats N
author_facet Roca-Ayats N
Maceda I
Bruque CD
Martínez-Gil N
Garcia-Giralt N
Cozar M
Mellibovsky L
Van Hul W
Lao O
Grinberg D
Balcells S
author_role author
author2 Maceda I
Bruque CD
Martínez-Gil N
Garcia-Giralt N
Cozar M
Mellibovsky L
Van Hul W
Lao O
Grinberg D
Balcells S
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv LRP5
Bone mineral density
Neanderthal
Denisovan
Human evolution
Archaic introgression
topic LRP5
Bone mineral density
Neanderthal
Denisovan
Human evolution
Archaic introgression
description 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 beta-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.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
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status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=26317
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=26317
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv Human Genomics
ISSN: 14739542
ISSNe: 14797364
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
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