[论文解读] Minor alleles of common SNPs quantitatively affect traits/diseases and are under both positive and negative selection

Dejian Yuan, Zuobin Zhu+22 more|arXiv (Cornell University)|Sep 12, 2012

Genetic Associations and Epidemiology参考文献 39被引用 18

一句话总结

本研究表明，常见SNP的次要等位基因（MAs）在模式生物和人类中定量影响复杂性状和疾病，极端MA负荷与极端表型相关。研究结果支持最大遗传多样性（MGD）假说，并揭示MAs同时受到正向和负向选择，表明大多数MAs近乎中性或轻微有害。

ABSTRACT

A new understanding of the genetic equidistance result of Margoliash that originally inspired the neutral theory has disproven the theory’s implicit message of a forever correlation between genetic distance and time. The more complete Maximum Genetic Diversity (MGD) hypothesis is a newly proposed alternative and considers genetic diversity today to be mostly at an optimum equilibrium. To use the MGD to help solve major biomedical problems, we here asked whether extreme values in genetic diversity as represented by the amount of minor alleles (MAs) of common SNPs may represent extreme trait values and common diseases. We analyzed panels of genetic reference populations and identified the MAs in each panel and the MA fractions that each strain carried. We also analyzed 21 published GWAS datasets of human diseases and identified the MA fractions of each case or control. MA amounts in model organisms were nearly linearly linked to quantitative variations in numerous traits including life span, tumor susceptibility, anxiety, depression, learning and memory, sensitivity to alcohol, methamphetamine, cocaine, pain and anti-psychotic drugs, levels in glucose, insulin, resistin, IL17, iron, and dopamine, and two correlated traits poor reproductive fitness and strong immunity. Similarly, in Europeans or European Americans, enrichment of MAs of fast but not slow evolutionary rate was linked to autoimmune and numerous other diseases including type 2 diabetes, Parkinson’s disease, psychiatric disorders, alcohol and cocaine addictions, cancer, and less life span. Therefore, both high and low MA amounts correlated with extreme values in many traits and are hence negatively selected, indicating that most MAs may be nearly neutral or slightly deleterious due to both positive and negative selection. These results add further evidence for the MGD hypothesis and open a new avenue of inquiry into the genetic basis of complex traits/diseases.

研究动机与目标

• 调查常见SNP中次要等位基因（MA）负荷是否与极端性状值及疾病易感性相关。
• 检验MAs同时受到正向和负向选择的假说，挑战中性理论关于遗传漂变恒定的假设。
• 评估MAs在模式生物和人类群体中复杂疾病及数量性状中的作用。
• 为最大遗传多样性（MGD）假说提供实证支持，作为分子进化中性理论的替代方案。

提出的方法

• 分析模式生物的遗传参考面板，量化每株系的次要等位基因（MA）频率，并将其与表型变异相关联。
• 系统分析21个已发表的GWAS数据集，比较人类群体中疾病患者与对照组的MA频率。
• 根据进化速率（快 vs. 慢）对SNP进行分层，评估其与自身免疫病及其他复杂疾病的不同关联。
• 使用线性模型检验MA负荷与寿命、代谢标志物及药物敏感性等数量性状之间的关系。
• 比较欧洲人与欧洲裔美国人的MA情况，评估其与2型糖尿病和帕金森病等疾病在人群特异性的关联。
• 应用MGD假说来解释观察到的遗传多样性及MAs选择模式。

实验结果

研究问题

• RQ1 常见SNP中次要等位基因（MA）负荷的极端水平是否与数量性状和疾病风险的极端值相关？
• RQ2 次要等位基因是否同时受到正向和负向选择，表明其并非严格中性？
• RQ3 SNP的进化速率是否调节其与自身免疫病及其他复杂疾病的相关性？
• RQ4 在模式生物中，高或低MA负荷是否在多种性状中一致关联于表型极端？
• RQ5 人类群体中MA频率与精神疾病、代谢疾病及神经退行性疾病易感性的关系如何？

主要发现

• 在模式生物中，次要等位基因（MA）负荷与寿命、肿瘤易感性、焦虑、抑郁、学习与记忆能力，以及对酒精、甲基苯丙胺、可卡因、疼痛和抗精神病药物的敏感性等表型变异呈近乎线性相关。
• 在欧洲人和欧洲裔美国人中，快速进化SNP中MAs的富集显著与自身免疫病、2型糖尿病、帕金森病、精神障碍及物质使用障碍相关。
• 高MAs和低MAs均与极端性状值相关，表明MAs受到负向选择，提示大多数MAs近乎中性或轻微有害。
• 观察到的MAs在性状和疾病中的模式支持最大遗传多样性（MGD）假说，该假说认为当前遗传多样性处于进化平衡状态。
• 在慢速进化SNP中未发现此类关联，表明进化速率调节了MAs对疾病风险的功能影响。
• 这些结果挑战了中性理论关于分子钟恒定的假设，支持遗传多样性维持的更动态模型。