Conserved noncoding sequences are selectively constrained and not mutation cold spots
Conserved noncoding sequences are selectively constrained and not mutation cold spots
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DOI：
10.1038/ng1710
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发表时间：
2006-02-01
期刊：
影响因子：
30.8
通讯作者：
Hirschhorn, JN
中科院分区：
文献类型：
--
作者：
Drake, JA;Bird, C;Hirschhorn, JN
非编码遗传变异可能会影响人类的生物学和疾病，但是识别功能性非编码变体很困难。在远距离相关的哺乳动物（1-4）中，大约3％的非编码序列是保守的，这表明这些进化保守的非编码区（CNC）被选择性约束并包含功能变化。但是，CNC还可以仅代表局部突变率较低的区域。在这里，我们解决了这个问题，并表明通过分析HAPMAP基因型数据，在人类中有选择地限制CNC。具体而言，CNC中SNP的新（派生）等位基因比未经保护区域的新等位基因（P = 3 x 10（-18））稀有，表明进化压力已抑制了CNC衍生的等位基因频率。基因附近的内含子CNC和CNC显示出更大的等位基因频率移动，其幅度与错义变体相当。因此，保守的非编码变体更可能具有功能性。等位基因频率分布突出了应进行有效调查以进行功能重要变化的选择性约束的基因组区域。
Noncoding genetic variants are likely to influence human biology and disease, but recognizing functional noncoding variants is difficult. Approximately 3% of noncoding sequence is conserved among distantly related mammals(1-4), suggesting that these evolutionarily conserved noncoding regions (CNCs) are selectively constrained and contain functional variation. However, CNCs could also merely represent regions with lower local mutation rates. Here we address this issue and show that CNCs are selectively constrained in humans by analyzing HapMap genotype data. Specifically, new ( derived) alleles of SNPs within CNCs are rarer than new alleles in nonconserved regions (P = 3 x 10(-18)), indicating that evolutionary pressure has suppressed CNC-derived allele frequencies. Intronic CNCs and CNCs near genes show greater allele frequency shifts, with magnitudes comparable to those for missense variants. Thus, conserved noncoding variants are more likely to be functional. Allele frequency distributions highlight selectively constrained genomic regions that should be intensively surveyed for functionally important variation.