NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 117456, Singapore.
Division of Medical Sciences, National Cancer Centre, Singapore, 169610, Singapore.
Hum Genomics. 2018 Sep 15;12(1):43. doi: 10.1186/s40246-018-0175-1.
Genetic polymorphisms can contribute to phenotypic differences amongst individuals, including disease risk and drug response. Characterization of genetic polymorphisms that modulate gene expression and/or protein function may facilitate the identification of the causal variants. Here, we present the architecture of genetic polymorphisms in the human genome focusing on those predicted to be potentially functional/under natural selection and the pathways that they reside.
In the human genome, polymorphisms that directly affect protein sequences and potentially affect function are the most constrained variants with the lowest single-nucleotide variant (SNV) density, least population differentiation and most significant enrichment of rare alleles. SNVs which potentially alter various regulatory sites, e.g. splicing regulatory elements, are also generally under negative selection. Interestingly, genes that regulate the expression of transcription/splicing factors and histones are conserved as a higher proportion of these genes is non-polymorphic, contain ultra-conserved elements (UCEs) and/or has no non-synonymous SNVs (nsSNVs)/coding INDELs. On the other hand, major histocompatibility complex (MHC) genes are the most polymorphic with SNVs potentially affecting the binding of transcription/splicing factors and microRNAs (miRNA) exhibiting recent positive selection (RPS). The drug transporter genes carry the most number of potentially deleterious nsSNVs and exhibit signatures of RPS and/or population differentiation. These observations suggest that genes that interact with the environment are highly polymorphic and targeted by RPS.
In conclusion, selective constraints are observed in coding regions, master regulator genes, and potentially functional SNVs. In contrast, genes that modulate response to the environment are highly polymorphic and under positive selection.
遗传多态性可导致个体表型差异，包括疾病风险和药物反应。对调节基因表达和/或蛋白功能的遗传多态性的特征分析，可能有助于鉴定因果变异。在此，我们介绍人类基因组中遗传多态性的结构，重点介绍那些预测具有潜在功能/受自然选择的多态性以及它们所在的途径。
在人类基因组中，直接影响蛋白序列并可能影响功能的多态性是受约束程度最高的变体，其单核苷酸变异（SNV）密度最低、群体分化最小，稀有等位基因富集度最高。可能改变各种调控位点（如剪接调控元件）的 SNV 通常也受到负选择。有趣的是，调节转录/剪接因子和组蛋白表达的基因作为一个更高比例的非多态性基因被保守下来，包含超保守元件（UCE）和/或没有非同义 SNV（nsSNV）/编码插入缺失（INDEL）。另一方面，主要组织相容性复合体（MHC）基因是多态性最高的，SNV 可能影响转录/剪接因子和 microRNA（miRNA）的结合，表现出近期的正选择（RPS）。药物转运基因携带最多数量的潜在有害 nsSNV，并表现出 RPS 和/或群体分化的特征。这些观察结果表明，与环境相互作用的基因高度多态性，并受到 RPS 的靶向作用。
总之，选择约束存在于编码区、主调控基因和潜在的功能性 SNV 中。相比之下，调节环境响应的基因是高度多态性的，并受到正选择的影响。
