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

摘要: A relatively rare type of mutation causing human genetic disease is the indel, a complex lesion that appears to represent combination micro-deletion and micro-insertion. In absence meta-analytical studies indels, mutational mechanisms underlying indel formation remain unclear. Data from Human Gene Mutation Database (HGMD) were therefore used compare contrast 211 different indels in an attempt deduce processes responsible for their genesis. Each was treated as if it result two-step insertion/deletion process assessed context 10 base-pairs DNA sequence flanking on either side. Several hotspots noted GTAAGT motif found be significantly over-represented vicinity studied. Previously postulated micro-deletions micro-insertions initially explored terms local regularity measured by its complexity. The change complexity consequent indicative repeat involved mediating event, thereby providing clues mechanism. Complexity analysis then employed examine possible intermediates through which each could have occurred propose likely pathways generation individual basis. Manual served confirm majority (>90%) are explicable involving established mechanisms. Indels equivalent double base-pair substitutions (22% total) mechanistically indistinguishable remainder may regarded special indel. observed correspondence between changes involvement specific process, ability generated models account both number identity bases deleted and/or inserted, makes this approach invaluable not only formation, but also study other types lesion.