Derived SNP alleles are used more frequently than ancestral alleles as risk-associated variants in common human diseases.
Derived SNP alleles are used more frequently than ancestral alleles as risk-associated variants in common human diseases.
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DOI：
10.1142/s0219720012410089
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发表时间：
2012-04
影响因子：
1
通讯作者：
Gorlov IP
中科院分区：
文献类型：
--
作者：
Gorlova OY;Ying J;Amos CI;Spitz MR;Peng B;Gorlov IP
人类常见疾病的遗传结构的进化方面仍然是个谜。迄今为止发表的200多项全基因组关联研究的结果汇编在一个目录中（http：//www.genome.gov/26525384/）。我们使用编目数据来确定衍生（突变）等位基因是否比祖先等位基因更频繁地与人类疾病的高风险相关。我们将所有等位基因变体以10%的增量分为10类人群频率（0%-100%）。然后，我们分析了等位基因频率，多态性位点的进化状态（祖先与衍生）和疾病风险状态（风险与保护）之间的关系。在相同的人群频率下，衍生等位基因比祖先等位基因更可能与风险相关，因为是罕见的等位基因。对这种关联的普遍解释是，负选择阻止了风险变体的固定。然而，将疾病分层为早发或晚发表明，对风险相关等位基因的弱选择不太可能是形成常见疾病遗传结构的主要因素。我们的研究结果清楚地表明，等位基因在人群中存在的时间更重要。存在时间较长的等位基因往往与相邻等位基因（包括致病等位基因）表现出较弱的连锁不平衡，并且不太可能标记SNP-疾病关联。
Evolutionary aspects of the genetic architecture of common human diseases remain enigmatic. The results of more than 200 genome-wide association studies published to date were compiled in a catalog (http://www.genome.gov/26525384/). We used cataloged data to determine whether derived (mutant) alleles are associated with higher risk of human disease more frequently than ancestral alleles. We placed all allelic variants into ten categories of population frequency (0%–100%) in 10% increments. We then analyzed the relationship between allelic frequency, evolutionary status of the polymorphic site (ancestral versus derived), and disease risk status (risk versus protection). Given the same population frequency, derived alleles are more likely to be risk associated than ancestral alleles, as are rarer alleles. The common interpretation of this association is that negative selection prevents fixation of the risk variants. However, disease stratification as early or late onset suggests that weak selection against risk-associated alleles is unlikely a major factor shaping genetic architecture of common diseases. Our results clearly suggest that the duration of existence of an allele in a population is more important. Alleles existing longer tend to show weaker linkage disequilibrium with neighboring alleles, including the causal alleles, and are less likely to tag a SNP-disease association.