title: Inverted low-copy repeats and genome instability--a genome-wide analysis.
abstract: Inverse paralogous low-copy repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.
authors.affiliation: Institute of Informatics, University of Warsaw, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Dittwald
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: Anna
authors.initials: A
authors.lastname: Gambin
mesh_terms: D007446:Chromosome Inversion; D002874:Chromosome Mapping; D017353:Gene Deletion; D018628:Gene Dosage; D020440:Gene Duplication; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D008957:Models, Genetic; D011995:Recombination, Genetic; D056916:Segmental Duplications, Genomic / Q000235:genetics*