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.