Mackeh Rafah, Marr Alexandra K, Dargham Soha R, Syed Najeeb, Fakhro Khalid A, Kino Tomoshige
Department of Human Genetics, Division of Translational Medicine, Sidra Medical and Research Center, Doha 26999, Qatar.
Biostatistics, Epidemiology and Biomathematics Research Core, Weill Cornell Medicine in Qatar, Doha 24811, Qatar.
J Endocr Soc. 2017 Dec 4;2(1):77-90. doi: 10.1210/js.2017-00406. eCollection 2018 Jan 1.
Nuclear hormone receptors (NRs) mediate biologic actions of lipophilic molecules to gene transcription and are phylogenetically and functionally categorized into seven subfamilies and three groups, respectively. Single-nucleotide variations (SNVs) or polymorphisms are genetic changes influencing individual response to environmental factors and susceptibility to various disorders, and are part of the genetic diversification and basis for evolution. We sorted out SNVs of the human genes from 60,706 individuals, calculated three parameters (percentage of all variants, percentage of loss-of-function variants, and ratio of nonsynonymous/synonymous variants in their full protein-coding or major domain-coding sequences), and compared them with several valuables. Comparison of these parameters between and control groups identified that form a highly conserved gene family. The three parameters for the full coding sequence are positively correlated with each other, whereas four genes are distinct from the others with much higher tolerance to protein sequence-changing variants. DNA-binding domain and -terminal domain are respectively those bearing the least and the most variation. NR subfamilies based on their phylogenetic proximity or functionality as well as diversity of tissue distribution and numbers of partner molecules are all not correlated with the variation parameters, whereas their gene age demonstrates an association. Our results suggest that the natural selection driving the family evolution still operates in humans. Gene age and probably the potential to adapt to various new ligands, but not current functional diversity, are major determinants for SNVs of the human genes.
核激素受体（NRs）介导亲脂性分子对基因转录的生物学作用，在系统发育和功能上分别分为七个亚家族和三个组。单核苷酸变异（SNVs）或多态性是影响个体对环境因素反应和对各种疾病易感性的基因变化，是遗传多样性的一部分和进化的基础。我们从60706个个体中筛选出人类基因的SNVs，计算了三个参数（所有变异的百分比、功能丧失变异的百分比以及其完整蛋白质编码或主要结构域编码序列中非同义/同义变异的比率），并将它们与几个有价值的指标进行比较。病例组和对照组之间这些参数的比较确定了……构成一个高度保守的基因家族。完整编码序列的三个参数彼此呈正相关，而四个……基因与其他基因不同，对蛋白质序列变化变异的耐受性要高得多。DNA结合结构域和……末端结构域分别是变异最少和最多的结构域。基于系统发育亲缘关系或功能以及组织分布多样性和伴侣分子数量的NR亚家族均与变异参数无关，而它们的基因年龄显示出一种关联。我们的结果表明，驱动……家族进化的自然选择在人类中仍然起作用。基因年龄以及可能适应各种新配体的潜力，而非当前的功能多样性，是人类……基因SNVs的主要决定因素。
