Evolutionary and functional analyses of LRP5 in Neanderthals, Denisovans and anatomically modern humans

Background The human lineage has suffered a skeleton gracilization 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 be also genetically determined. Results We have analyzed the LRP5 gene from an evolutionary and functional point of view, taking advantage of the published genomes of archaic Homo populations. Mutations in LRP5 are involved in high bone mineral density conditions. Our results suggest that this gene has a complex evolutionary history both between archaic and anatomically modern humans and within the anatomically modern human populations. In particular, we identified the presence of different selective pressures in archaics and anatomically modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000G. Furthermore, we observed limited evidence of archaic introgression in this gene at haplotypes of East Asian ancestry, compatible with a general clearing of the archaic introgression due to functional differences in archaics compared to anatomically modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing high 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 anatomically modern humans and archaic Homo populations.