title: A single-nucleotide polymorphism of human neuropeptide s gene originated from Europe shows decreased bioactivity.
abstract: 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 6(th) 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 ~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 ~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 6(th) 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.
authors.affiliation: Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Deng
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ximiao
authors.initials: X
authors.lastname: He
authors.affiliation: Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Aaron J W
authors.initials: AJ
authors.lastname: Hsueh
mesh_terms: D000595:Amino Acid Sequence; D005060:Europe; D057809:HEK293 Cells; D016045:Human Genome Project; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D008024:Ligands; C484532:NPSR1 protein, human; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; C506531:neuropeptide S, human