On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease.
On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease.
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DOI：
10.1002/humu.21557
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发表时间：
2011-10
期刊：
影响因子：
3.9
通讯作者：
Chen, Jian-Min
中科院分区：
文献类型：
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作者：
Cooper, David N.;Bacolla, Albino;Ferec, Claude;Vasquez, Karen M.;Kehrer-Sawatzki, Hildegard;Chen, Jian-Min
关键词：
不同类型的人类基因突变可能在大小上有所不同，从结构变异（SVs）到单碱基对替换，但它们都有一个共同点，即它们的性质、大小和位置通常由局部DNA序列环境的特定特征或基因组结构的高阶特征决定。人类基因组现在被认为包含“普遍的结构缺陷”，因为某些DNA序列由于其碱基组成、序列重复和/或表观遗传修饰而天生容易发生突变。在这里，我们探索了导致遗传性疾病的不同类型突变的性质、位置和频率在很大程度上是如何被局部DNA序列环境塑造的，并且通常以非常可预测的方式。给定基因或基因组区域的易变性也可能间接受到各种非规范（非b）二级结构的影响，这些二级结构的形成由潜在的DNA序列促进。由于这些非b DNA结构可以干扰随后的DNA复制和修复，并可能以普遍的方式增加突变频率（即在微妙突变和SVs的背景下），因此它们有可能作为人类遗传性疾病突变机制研究的统一概念。
Different types of human gene mutation may vary in size, from structural variants (SVs) to single base-pair substitutions, but what they all have in common is that their nature, size and location are often determined either by specific characteristics of the local DNA sequence environment or by higher-order features of the genomic architecture. The human genome is now recognized to contain ‘pervasive architectural flaws’ in that certain DNA sequences are inherently mutation-prone by virtue of their base composition, sequence repetitivity and/or epigenetic modification. Here we explore how the nature, location and frequency of different types of mutation causing inherited disease are shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment. The mutability of a given gene or genomic region may also be influenced indirectly by a variety of non-canonical (non-B) secondary structures whose formation is facilitated by the underlying DNA sequence. Since these non-B DNA structures can interfere with subsequent DNA replication and repair, and may serve to increase mutation frequencies in generalized fashion (i.e. both in the context of subtle mutations and SVs), they have the potential to serve as a unifying concept in studies of mutational mechanisms underlying human inherited disease.
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影响因子：
3.5
作者：
Antonacci F;Kidd JM;Marques-Bonet T;Ventura M;Siswara P;Jiang Z;Eichler EE
通讯作者：
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通讯作者：
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影响因子：
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