Mechanisms of insertional mutagenesis in human genes causing genetic disease

Abstract

Examples of the insertion of less than 10 bp of DNA sequence into human gene-coding regions causing genetic disease were collated in order to study the underlying causative mechanisms. The nature of these insertions was found to be consistent with several mechanisms of mutagenesis including: (1) slipped mispairing mediated by direct repeats or runs of identical bases and (2) the templated misincorporation of bases by secondary-structure intermediates whose formation is facilitated by palindromic (inverted repeat) sequences, quasi-palindromic sequences or symmetric elements. Both the size and position of insertions were found to be non-random and highly dependent upon the surrounding DNA sequence. Inferred mechanisms of insertional mutagenesis thus appear to be very similar to those involved in the causation of gene deletions.