title: Genome-wide analyses of LINE-LINE-mediated nonallelic homologous recombination.
abstract: Nonallelic homologous recombination (NAHR), occurring between low-copy repeats (LCRs) >10 kb in size and sharing >97% DNA sequence identity, is responsible for the majority of recurrent genomic rearrangements in the human genome. Recent studies have shown that transposable elements (TEs) can also mediate recurrent deletions and translocations, indicating the features of substrates that mediate NAHR may be significantly less stringent than previously believed. Using >4 kb length and >95% sequence identity criteria, we analyzed of the genome-wide distribution of long interspersed element (LINE) retrotransposon and their potential to mediate NAHR. We identified 17 005 directly oriented LINE pairs located <10 Mbp from each other as potential NAHR substrates, placing 82.8% of the human genome at risk of LINE-LINE-mediated instability. Cross-referencing these regions with CNVs in the Baylor College of Medicine clinical chromosomal microarray database of 36 285 patients, we identified 516 CNVs potentially mediated by LINEs. Using long-range PCR of five different genomic regions in a total of 44 patients, we confirmed that the CNV breakpoints in each patient map within the LINE elements. To additionally assess the scale of LINE-LINE/NAHR phenomenon in the human genome, we tested DNA samples from six healthy individuals on a custom aCGH microarray targeting LINE elements predicted to mediate CNVs and identified 25 LINE-LINE rearrangements. Our data indicate that LINE-LINE-mediated NAHR is widespread and under-recognized, and is an important mechanism of structural rearrangement contributing to human genomic variability.
authors.affiliation: Faculty of Mathematics, Informatics, and Mechanics, University of Warsaw, 2 Banacha street, 02-097 Warsaw, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Startek
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hixson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA pawels@bcm.edu.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: Faculty of Mathematics, Informatics, and Mechanics, University of Warsaw, 2 Banacha street, 02-097 Warsaw, Poland Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego street, 02-106 Warsaw, Poland aniag@mimuw.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Gambin
mesh_terms: D000465:Algorithms; D056905:Chromosome Breakpoints; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D059765:Homologous Recombination; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D016133:Polymerase Chain Reaction