Inverted low‐copy repeats and genome instability—a genome‐wide analysis
Human mutation, 2013•Wiley Online Library
Inverse paralogous low‐copy repeats (IP‐LCR s) 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‐LCR s> 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‐LCR s. Remarkably, our results show that 12.0% of the human genome is …
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‐LCR s> 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‐LCR s. Remarkably, our results show that 12.0% of the human genome is …
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.
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