Extreme evolutionary disparities seen in positive selection across seven complex diseases.
Extreme evolutionary disparities seen in positive selection across seven complex diseases.
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DOI：
10.1371/journal.pone.0012236
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发表时间：
2010-08-17
期刊：
影响因子：
3.7
通讯作者：
Butte AJ
中科院分区：
文献类型：
--
作者：
Corona E;Dudley JT;Butte AJ
众所周知，当有机体栖息的环境突然改变时，就会发生正选择，就像人类近代史上的情况一样。全基因组关联研究（GWAS）已成功阐明了与疾病相关的变异。然而，人类进化总体上是朝着还是远离疾病易感性的方向发展仍然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，该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 病例控制联盟研究的七种疾病，以比较与疾病相关的每个位点的选择证据。我们在每项 GWA 研究中都选取了大量相关性最强的 SNP，以便捕获更多隐藏的关联，但代价是在我们的分析中引入了误报。然后，我们在这组包容性 SNP 中寻找正向选择的迹象。所研究的七种疾病之间存在显着差异。我们发现最近正选择的等位基因增加了对 1 型糖尿病 (T1D)、类风湿关节炎 (RA) 和克罗恩病 (CD) 的易感性。等位基因的选择更多，会增加而不是降低 T1D 的易感性。在与 T1D 最相关的 80 个 SNP（p 值 <7.01×10−5）中，显示出强烈的正选择迹象，其中 58 个与疾病易感性相关的等位基因显示出正选择的迹象，而只有 22 个与疾病保护相关的等位基因显示出正选择的迹象。增加 RA 易感性的等位基因也在选择中。相反，与 CD 相关的 SNP 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学的理解提供了信息，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背后的因果遗传因素。
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 <7.01×10−5) 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.
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