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

Neus Roca-Ayats, Iago Maceda, Carlos David Bruque, Núria Martínez-Gil, Natàlia Garcia-Giralt, Mónica Cozar, Leonardo Mellibovsky, Wim Van Hul, Oscar Lao, Daniel Grinberg, Susanna Balcells

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 diferences in the mechanical load that our ancestors exercised.
However, there is growing evidence that gracilization could also be genetically infuenced.
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 identifed the presence of diferent 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 fngerprint of archaic introgression due to functional diferences 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 fve archaic missense mutations afecting the frst 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
diferences between extant modern humans and archaic Homo populations.
Keywords LRP5, Bone mineral density, Neanderthal, Denisovan, Human evolution, Archaic introgression

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