Evolutionary and functional analyses of LRP5 in archaic and extant modern humans.
LRP5
Archaic introgression
Bone mineral density
Denisovan
Human evolution
Neanderthal
Journal
Human genomics
ISSN: 1479-7364
Titre abrégé: Hum Genomics
Pays: England
ID NLM: 101202210
Informations de publication
Date de publication:
27 May 2024
27 May 2024
Historique:
received:
02
02
2024
accepted:
07
05
2024
medline:
28
5
2024
pubmed:
28
5
2024
entrez:
27
5
2024
Statut:
epublish
Résumé
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. 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. In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.
Sections du résumé
BACKGROUND
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
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
CONCLUSIONS
In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.
Identifiants
pubmed: 38802968
doi: 10.1186/s40246-024-00616-6
pii: 10.1186/s40246-024-00616-6
doi:
Substances chimiques
Low Density Lipoprotein Receptor-Related Protein-5
0
LRP5 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
53Subventions
Organisme : Ministerio de Ciencia e Innovación
ID : SAF 2016-75948R and PID2019-107188RB-C21
Organisme : Generalitat de Catalunya
ID : GRC 2017 SGR 937
Organisme : Catalan Government
ID : 2017SGR:00738
Organisme : Ministerio de Economía y Competitividad
ID : PGC2018-098574-B-I00
Informations de copyright
© 2024. The Author(s).
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