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Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions
Author(s) -
Chen JianMin,
Chuzhanova Nadia,
Stenson Peter D.,
Férec Claude,
Cooper David N.
Publication year - 2005
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20230
Subject(s) - biology , genetics , gene duplication , gene , sequence (biology) , mutation , slippage , inversion (geology) , chromosomal inversion , computational biology , chromosome , paleontology , karyotype , structural engineering , structural basin , engineering
Abstract Serial replication slippage in cis (SRS cis ) provides a plausible explanation for many complex genomic rearrangements that underlie human genetic disease. This concept, taken together with the intra‐ and intermolecular strand switch models that account for mutations that arise via quasipalindrome correction, suggest that intrachromosomal SRS in trans (SRS trans ) mediated by short inverted repeats may also give rise to a diverse series of complex genomic rearrangements. If this were to be so, such rearrangements would invariably generate inversions. To test this idea, we collated all informative mutations involving inversions of ≥5 bp but <1 kb by screening the Human Gene Mutation Database (HGMD; www.hgmd.org ) and conducting an extensive literature search. Of the 21 resulting mutations, only two (both of which coincidentally contain untemplated additions) were found to be incompatible with the SRS trans model. Eighteen (one simple inversion, six inversions involving sequence replacement by upstream or downstream sequence, five inversions involving the partial reinsertion of removed sequence, and six inversions that occurred in a more complicated context) of the remaining 19 mutations were found to be consistent with either two steps of intrachromosomal SRS trans or a combination of replication slippage in cis plus intrachromosomal SRS trans . The remaining lesion, a 31‐kb segmental duplication associated with a small inversion in the SLC3A1 gene, is explicable in terms of a modified SRS model that integrates the concept of “break‐induced replication.” This study therefore lends broad support to our postulate that intrachromosomal SRS trans can account for a variety of complex gene rearrangements that involve inversions. Hum Mutat 26(4), 362–373, 2005. © 2005 Wiley‐Liss, Inc.