七种复杂疾病中观察到的正选择的极端进化差异。
Extreme evolutionary disparities seen in positive selection across seven complex diseases.
机构信息
Lucile Packard Children's Hospital, Stanford, California, United States of America.
出版信息
PLoS One. 2010 Aug 17;5(8):e12236. doi: 10.1371/journal.pone.0012236.
Positive selection is known to occur when the environment that an organism inhabits is suddenly altered, as is the case across recent human history. Genome-wide association studies (GWASs) have successfully illuminated disease-associated variation. However, whether human evolution is heading towards or away from disease susceptibility in general remains an open question. The genetic-basis of common complex disease may partially be caused by positive selection events, which simultaneously increased fitness and susceptibility to disease. We analyze seven diseases studied by the Wellcome Trust Case Control Consortium to compare evidence for selection at every locus associated with disease. We take a large set of the most strongly associated SNPs in each GWA study in order to capture more hidden associations at the cost of introducing false positives into our analysis. We then search for signs of positive selection in this inclusive set of SNPs. There are striking differences between the seven studied diseases. We find alleles increasing susceptibility to Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), and Crohn's Disease (CD) underwent recent positive selection. There is more selection in alleles increasing, rather than decreasing, susceptibility to T1D. In the 80 SNPs most associated with T1D (p-value <7.01 x 10(-5)) showing strong signs of positive selection, 58 alleles associated with disease susceptibility show signs of positive selection, while only 22 associated with disease protection show signs of positive selection. Alleles increasing susceptibility to RA are under selection as well. In contrast, selection in SNPs associated with CD favors protective alleles. These results inform the current understanding of disease etiology, shed light on potential benefits associated with the genetic-basis of disease, and aid in the efforts to identify causal genetic factors underlying complex disease.
正选择已知发生在生物体栖息的环境突然改变时,就像人类历史上最近发生的情况一样。全基因组关联研究(GWAS)已经成功地阐明了与疾病相关的变异。然而,人类进化是否总体上正在朝着对疾病的易感性发展,还是一个悬而未决的问题。常见复杂疾病的遗传基础可能部分是由正选择事件引起的,这些事件同时增加了适应性和对疾病的易感性。我们分析了 Wellcome Trust Case Control Consortium 研究的七种疾病,以比较与疾病相关的每个基因座的选择证据。我们在每个 GWAS 研究中采用了大量最强相关的 SNP,以便在分析中引入更多隐藏的关联,同时也引入了假阳性。然后,我们在这个综合 SNP 集中寻找正选择的迹象。七种研究疾病之间存在显著差异。我们发现增加 1 型糖尿病(T1D)、类风湿性关节炎(RA)和克罗恩病(CD)易感性的等位基因经历了最近的正选择。增加而不是减少 T1D 易感性的等位基因受到更多的选择。在与 T1D (p 值 <7.01 x 10(-5)) 最强相关的 80 个 SNP 中,有 58 个与疾病易感性相关的等位基因显示出强烈的正选择迹象,而只有 22 个与疾病保护相关的等位基因显示出正选择迹象。增加 RA 易感性的等位基因也受到选择。相比之下,与 CD 相关的 SNP 中的选择有利于保护性等位基因。这些结果为当前对疾病病因的理解提供了信息,揭示了与疾病遗传基础相关的潜在益处,并有助于识别复杂疾病潜在因果遗传因素的努力。