Inverted Low‐Copy Repeats and Genome Instability—A Genome‐Wide Analysis. Issue 1 (11th October 2012)

• Record Type: Journal Article
• Authors: Dittwald, Piotr; Gambin, Tomasz; Gonzaga‐Jauregui, Claudia; Carvalho, Claudia M.B.; Lupski, James R.; Stankiewicz, Paweł; Gambin, Anna
• Is Part Of: Human mutation. Volume 34:Issue 1(2013:Jan.)
• Page Start: 210
• Page End: 220
• Publication Date: 2012-10-11
• Subjects: Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22217
• Languages: English
• ISSNs: 1059-7794

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>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.</p> </abstract>