A Single-Nucleotide Polymorphism of Human Neuropeptide S Gene Originated from Europe Shows Decreased Bioactivity

作者：Deng Cheng^*; He Ximiao; Hsueh Aaron J W

来源：PLos One, 2013, 8(12): e83009.

DOI：10.1371/journal.pone.0083009

Using accumulating SNP (Single-Nucleotide Polymorphism) data, we performed a genome-wide search for polypeptide hormone ligands showing changes in the mature regions to elucidate genotype/phenotype diversity among various human populations. Neuropeptide S (NPS), a brain peptide hormone highly conserved in vertebrates, has diverse physiological effects on anxiety, fear, hyperactivity, food intake, and sleeping time through its cognate receptor-NPSR. Here, we report a SNP rs4751440 (L-6-NPS) causing non-synonymous substitution on the 6th position (V to L) of the NPS mature peptide region. L-6-NPS has a higher allele frequency in Europeans than other populations and probably originated from European ancestors similar to 25,000 yrs ago based on haplotype analysis and Approximate Bayesian Computation. Functional analyses indicate that L-6-NPS exhibits a significant lower bioactivity than the wild type NPS, with similar to 20-fold higher EC50 values in the stimulation of NPSR. Additional evolutionary and mutagenesis studies further demonstrate the importance of the valine residue in the 6th position for NPS functions. Given the known physiological roles of NPS receptor in inflammatory bowel diseases, asthma pathogenesis, macrophage immune responses, and brain functions, our study provides the basis to elucidate NPS evolution and signaling diversity among human populations.

• 出版日期2013-12-27