Cis-regulatory mutations in human disease
Cis-regulatory mutations in human disease
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DOI：
10.1093/bfgp/elp021
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发表时间：
2009-07-01
期刊：
影响因子：
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通讯作者：
Epstein, Douglas J.
中科院分区：
文献类型：
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作者：
Epstein, Douglas J.
顺式作用调控序列是基因表达的适当时空控制所必需的。基因表达的变异具有高度遗传性，是人类疾病易感性的重要决定因素。全部或部分归因于非编码调节序列突变的人类遗传疾病的多样性正在增加。将遗传变异与人类疾病相关联的全基因组方法的改进以及预测具有顺式调节潜力的DNA是这些最新进展的两个主要原因。这篇综述将突出选择的例子，从文献中成功地整合了遗传和基因组的方法，揭示顺式调控突变改变基因表达的分子基础，并有助于人类疾病。致病变异的精细作图导致了新的顺式作用调控元件的发现，在某些情况下，这些元件位于距离靶基因1.5 Mb的地方。在其他情况下，围绕感兴趣的基因的监管景观的先验知识有助于选择用于突变筛选的增强子。这些研究的成功应该为后续大量的全基因组关联研究提供一个框架，这些研究已经确定了基因组非编码区的常见变异，这些变异与人类疾病风险增加有关，包括糖尿病，自闭症，克罗恩病，结肠直肠癌和哮喘，仅举几例。
Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few.