Laboratoire Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université de Toulouse, CNRS, UPS, Toulouse, France.
Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen K, Denmark.
Peptides. 2019 Dec;122:170154. doi: 10.1016/j.peptides.2019.170154. Epub 2019 Sep 24.
Given the importance of G-protein coupled receptors in the regulation of many physiological functions, deciphering the relationships between genotype and phenotype in past and present hominin GPCRs is of main interest to understand the evolutionary process that contributed to the present-day variability in human traits and health. Here, we carefully examined the publicly available genomic and protein sequence databases of the archaic hominins (Neanderthal and Denisova) to draw up the catalog of coding variations in GPCRs for peptide ligands, in comparison with living humans. We then searched in the literature the functional changes, phenotypes and risk of disease possibly associated with the detected variants. Our survey suggests that Neanderthal and Denisovan hominins were likely prone to lower risk of obesity, to enhanced platelet aggregation in response to thrombin, to better response to infection, to less anxiety and aggressiveness and to favorable sociability. While some archaic variants were likely advantageous in the past, they might be responsible for maladaptive disorders today in the context of modern life and/or specific regional distribution. For example, an archaic haplotype in the neuromedin receptor 2 is susceptible to confer risk of diabetic nephropathy in type 1 diabetes in present-day Europeans. Paying attention to the pharmacological properties of some of the archaic variants described in this study may be helpful to understand the variability of therapeutic efficacy between individuals or ethnic groups.
鉴于 G 蛋白偶联受体在调节许多生理功能方面的重要性，解析过去和现在原始人类 GPCR 中的基因型和表型之间的关系对于理解有助于导致人类特征和健康的当今多样性的进化过程至关重要。在这里，我们仔细检查了已公布的古人类（尼安德特人和丹尼索瓦人）的基因组和蛋白质序列数据库，以制定与人类相比肽配体 GPCR 编码变异的目录。然后，我们在文献中搜索了可能与检测到的变异相关的功能变化、表型和疾病风险。我们的调查表明，尼安德特人和丹尼索瓦原始人类可能肥胖风险较低，对凝血酶的血小板聚集反应增强，对感染的反应更好，焦虑和攻击性较低，社交能力更强。虽然一些古老的变异可能在过去是有利的，但它们今天可能会导致现代生活和/或特定地区分布背景下的适应性障碍。例如，在当今欧洲人中，神经肽受体 2 的一种古老单倍型易患 1 型糖尿病的糖尿病肾病。关注本研究中描述的一些古老变异的药理学特性可能有助于理解个体或种族之间治疗效果的可变性。
