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

## TL;DR

This study explores how genetic changes in the LRP5 gene may have contributed to differences in bone structure between modern humans and ancient human populations like Neanderthals.

## Contribution

The study reveals novel evidence of genetic selection and functional differences in the LRP5 gene between archaic and modern human populations.

## Key findings

- LRP5 shows evidence of different selective pressures in archaic and modern humans.
- Positive selection in African and Southeast Asian populations was detected.
- Archaic LRP5 mutations enhance Wnt pathway activation, potentially increasing bone mineral density.

## Abstract

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.

The online version contains supplementary material available at 10.1186/s40246-024-00616-6.