Inferring causality and functional significance of human coding DNA variants.
Inferring causality and functional significance of human coding DNA variants.
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DOI：
10.1093/hmg/dds385
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发表时间：
2012-10
影响因子：
3.5
通讯作者：
S. Sunyaev
中科院分区：
文献类型：
--
作者：
S. Sunyaev
测序技术使人类遗传变异的完整表征成为可能。统计遗传学研究确定了许多与直接医学感兴趣的表型相关或相关的基因座。剩下的主要挑战是表征与人类性状的遗传基础有因果关系的功能显著的等位基因。在这里，我回顾了三个来源的证据，人类DNA变异的蛋白质编码基因的功能意义。这些包括（i）统计遗传学考虑因素，如与表型共分离，未受影响的对照中的等位基因频率和复发;（ii）体外功能测定和模式生物实验;和（iii）预测氨基酸取代的功能效应的计算方法。尽管最近的研究取得了许多成功，但人类等位基因变体的功能表征仍然存在问题。
Sequencing technology enables the complete characterization of human genetic variation. Statistical genetics studies identify numerous loci linked to or associated with phenotypes of direct medical interest. The major remaining challenge is to characterize functionally significant alleles that are causally implicated in the genetic basis of human traits. Here, I review three sources of evidence for the functional significance of human DNA variants in protein-coding genes. These include (i) statistical genetics considerations such as co-segregation with the phenotype, allele frequency in unaffected controls and recurrence; (ii) in vitro functional assays and model organism experiments; and (iii) computational methods for predicting the functional effect of amino acid substitutions. In spite of many successes of recent studies, functional characterization of human allelic variants remains problematic.