title: Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions.
abstract: Serial replication slippage in cis (SRScis) 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 (SRStrans) 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 >or=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 SRStrans 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 SRStrans or a combination of replication slippage in cis plus intrachromosomal SRStrans. 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 SRStrans can account for a variety of complex gene rearrangements that involve inversions.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U613, Etablissement Français du Sang-Bretagne, Université de Bretagne Occidentale, Centre Hospitalier Universitaire, Brest, France. Jian-Min.Chen@univ-brest.fr
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Nadia
authors.initials: N
authors.lastname: Chuzhanova
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stenson
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D001483:Base Sequence; D007446:Chromosome Inversion / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D030541:Databases, Genetic; D020440:Gene Duplication; D015321:Gene Rearrangement; D030342:Genetic Diseases, Inborn / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D050396:TRPP Cation Channels; D014157:Transcription Factors / Q000235:genetics
chemical_list: D026923:Amino Acid Transport Systems, Basic; D026921:Amino Acid Transport Systems, Neutral; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D050396:TRPP Cation Channels; D014157:Transcription Factors; C018322:IDS protein, human; C489892:IGHMBP2 protein, human; C489857:SLC3A1 protein, human