Institute of Pharmacology & Toxicology, Friedrich-Schiller-University, Jena, Germany; Institute of Physiology I, Westfälische-Wilhelms-University, Münster, Germany.
Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany.
Peptides. 2021 Apr;138:170506. doi: 10.1016/j.peptides.2021.170506. Epub 2021 Feb 5.
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.
神经肽 S（NPS）系统在恐惧和恐惧记忆处理中起着重要作用，但也与过敏和炎症性疾病有关。NPS 和其受体 NPSR1 的基因存在于所有四足动物中。与非人类灵长类动物相比，人类这两个基因中存在几个非同义单核苷酸多态性（SNP），这些 SNP 共同导致功能减弱，表明在人类环境中存在适应机制。为了研究这些功能减弱突变的历史和地理起源，并探索遗传选择的迹象，我们分析了 NPS 系统中四个原型 SNP 的古代基因组和全球基因型频率。尼安德特人和丹尼索瓦人的基因组仅包含 NPSR1 的祖先等位基因，而所有衍生等位基因都出现在现代人类的古代基因组中，这表明它们是在现代人类中出现的。三个 NPSR1 低功能 SNP 的全球基因型频率显示出明显的区域同质性，但朝着衍生等位基因频率增加的梯度发展，支持了非洲以外起源的情景。三个 NPSR1 基因座周围高频率多态性的密度增加表明存在弱选择或可能的平衡选择。然而，在欧亚大陆尼安德特人基因组中检测到 NPS 前体的一个低功能突变，并且具有遗传特征表明它是通过与尼安德特人杂交而被引入人类基因库的，特别是在南欧。我们讨论了包括行为和基于免疫的自然选择在内的潜在进化情景。
