Neandertal introgression and accumulation of hypomorphic mutations in the neuropeptide S (NPS) system promote attenuated functionality

The neuropeptide S (NPS) system plays an important role in fear and fear memory processing but has also been associated with allergic and inflammatory diseases. Genes for NPS and its receptor NPSR1 are found in all tetrapods. Compared to non-human primates, several non-synonymous single-nucleotide polymorphisms (SNPs) occur in both human genes that collectively result in functional attenuation, suggesting adaptive mechanisms in a human context. To investigate historic and geographic origins of these hypomorphic mutations and explore genetic signs of selection, we analyzed ancient genomes and worldwide genotype frequencies of four prototypic SNPs in the NPS system. Neandertal and Denisovan genomes contain exclusively ancestral alleles for NPSR1 while all derived alleles occur in ancient genomes of anatomically modern humans, indicating that they arose in modern Homo sapiens. Worldwide genotype frequencies for three hypomorphic NPSR1 SNPs show significant regional homogeneity but follow a gradient towards increasing derived allele frequencies that supports an out-of Africa scenario. Increased density of high-frequency polymorphisms around the three NPSR1 loci suggests weak or possibly balancing selection. A hypomorphic mutation in the NPS precursor, however, was detected at high frequency in Eurasian Neandertal genomes and shows genetic signatures indicating that it was introgressed into the human gene pool, particularly in Southern Europe, by interbreeding with Neandertals. We discuss potential evolutionary scenarios including behavior and immune-based natural selection.

Automated summary

The study of the NPS peptide system reveals functional attenuation mutations in human genes, potentially for adaptation to environmental conditions. Ancestral alleles of NPSR1 are found in Neandertal and Denisovan genomes, while derived alleles are present in ancient anatomically modern human genomes, suggesting they arose in modern Homo sapiens. World genotype frequencies for NPSR1 SNPs show regional homogeneity but also support an out-of-Africa scenario, with potential weak or balancing selection indicated by high-frequency polymorphisms. The presence of a hypomorphic mutation in NPS precursor in Eurasian Neandertal genomes suggests introgression into the human gene pool through interbreeding, particularly in Southern Europe.