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Meta-analysis of indels causing human genetic disease: mechanisms of mutagenesis and the role of local DNA sequence complexity

Chuzhanova, N. A., Anassis, E. J., Ball, Edward Vincent, Krawczak, M. and Cooper, David Neil 2003. Meta-analysis of indels causing human genetic disease: mechanisms of mutagenesis and the role of local DNA sequence complexity. Human Mutation 21 (1) , pp. 28-44. 10.1002/humu.10146

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RZ Other systems of medicine
Additional Information: Publication Types Comparative Study Meta-Analysis Full Text Sources John Wiley & Sons, Inc. ProQuest Other Literature Sources COS Scholar Universe Labome Researcher Resource - ExactAntigen/Labome Medical Genetic Disorders - MedlinePlus Health Information
Publisher: Wiley-Blackwell
ISSN: 1059-7794
Last Modified: 04 Jun 2017 06:30
URI: http://orca.cf.ac.uk/id/eprint/61028

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