Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
Por:
Roca N, Maceda I, Bruque CD, Martinez-Gil N, Garcia-Giralt N, Cozar M, Mellibovsky L, Van Hul W, Lao O, Grinberg-Vaisman DR and Balcells S
Publicada:
27 may 2024
Ahead of Print:
27 may 2024
Resumen:
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.
Filiaciones:
Roca N:
Departament de Genètica, Microbiologia i Estadística and IBUB, Universitat de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) ISCIII, Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain
Maceda I:
CNAG, Centre Nacional d'Analisi Genòmic, C/ Baldiri I Reixach 4, 08028, Barcelona, Spain
Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain
Bruque CD:
Unidad de Conocimiento Traslacional Hospitalaria Patagónica, Hospital de Alta Complejidad El Calafate - S.A.M.I.C., Santa Cruz, Argentina
Martinez-Gil N:
Departament de Genètica, Microbiologia i Estadística and IBUB, Universitat de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) ISCIII, Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain
Garcia-Giralt N:
Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, Departament de Genètica, Microbiologia i Estadística, UB, Barcelona, Spain
Cozar M:
Departament de Genètica, Microbiologia i Estadística and IBUB, Universitat de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) ISCIII, Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain
Mellibovsky L:
Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, Barcelona, Spain
Van Hul W:
Center of Medical Genetics, University of Antwerp, 2650, Antwerp, Belgium
Lao O:
Institute of Evolutionary Biology, CSIC-Universitat Pompeu Fabra, 08003, Barcelona, Spain
Grinberg-Vaisman DR:
Departament de Genètica, Microbiologia i Estadística and IBUB, Universitat de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) ISCIII, Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain
Balcells S:
Departament de Genètica, Microbiologia i Estadística and IBUB, Universitat de Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) ISCIII, Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain
Green Submitted, Green Published, gold
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