Inverted Low‐Copy Repeats and Genome Instability—A Genome‐Wide Analysis

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 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 ‐ LCR s larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP ‐ LCR s, DTIP ‐ LCR s) 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 ‐ LCR s 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 LCR s as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.