Chuzhanova Nadia A, Anassis Emmanuel J, Ball Edward V, Krawczak Michael, Cooper David N
Department of Computer Science, Cardiff University, Cardiff, UK.
Hum Mutat. 2003 Jan;21(1):28-44. doi: 10.1002/humu.10146.
A relatively rare type of mutation causing human genetic disease is the indel, a complex lesion that appears to represent a combination of micro-deletion and micro-insertion. In the absence of meta-analytical studies of indels, the mutational mechanisms underlying indel formation remain unclear. Data from the Human Gene Mutation Database (HGMD) were therefore used to compare and contrast 211 different indels underlying genetic disease in an attempt to deduce the processes responsible for their genesis. Each indel was treated as if it were the result of a two-step insertion/deletion process and was assessed in the context of 10 base-pairs DNA sequence flanking the lesion on either side. Several indel hotspots were noted and a GTAAGT motif was found to be significantly over-represented in the vicinity of the indels studied. Previously postulated mechanisms underlying micro-deletions and micro-insertions were initially explored in terms of local DNA sequence regularity as measured by its complexity. The change in complexity consequent to a mutation was found to be indicative of the type of repeat sequence involved in mediating the event, thereby providing clues as to the underlying mutational mechanism. Complexity analysis was then employed to examine the possible intermediates through which each indel could have occurred and to propose likely mechanisms and pathways for indel generation on an individual basis. Manual analysis served to confirm that the majority of indels (>90%) are explicable in terms of a two-step process involving established mutational mechanisms. Indels equivalent to double base-pair substitutions (22% of the total) were found to be mechanistically indistinguishable from the remainder and may therefore be regarded as a special type of indel. The observed correspondence between changes in local DNA sequence complexity and the involvement of specific mutational mechanisms in the insertion/deletion process, and the ability of generated models to account for both the number and identity of the bases deleted and/or inserted, makes this approach invaluable not only for the analysis of indel formation, but also for the study of other types of complex lesion.
一种相对罕见的导致人类遗传疾病的突变类型是插入缺失（indel），这是一种复杂的病变，似乎代表了微缺失和微插入的组合。由于缺乏对插入缺失的荟萃分析研究，插入缺失形成的突变机制仍不清楚。因此，利用来自人类基因突变数据库（HGMD）的数据，对导致遗传疾病的211种不同插入缺失进行比较和对比，试图推断出其产生的过程。每个插入缺失都被视为两步插入/缺失过程的结果，并在病变两侧侧翼的10个碱基对DNA序列背景下进行评估。发现了几个插入缺失热点，并且发现在所研究的插入缺失附近，GTAAGT基序显著富集。最初根据局部DNA序列的复杂性（通过其复杂度来衡量）来探索先前假定的微缺失和微插入的潜在机制。发现突变导致的复杂度变化表明了介导该事件的重复序列类型，从而为潜在的突变机制提供了线索。然后采用复杂度分析来检查每个插入缺失可能发生的中间过程，并针对个体提出插入缺失产生的可能机制和途径。人工分析证实，大多数插入缺失（>90%）可以用涉及既定突变机制的两步过程来解释。发现相当于双碱基对替换的插入缺失（占总数的22%）在机制上与其余部分无法区分，因此可被视为一种特殊类型的插入缺失。在局部DNA序列复杂度变化与插入/缺失过程中特定突变机制的参与之间观察到的对应关系，以及所生成模型解释缺失和/或插入碱基的数量和身份的能力，使得这种方法不仅对分析插入缺失的形成非常宝贵，而且对研究其他类型的复杂病变也很有价值。
