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Inverted Low‐Copy Repeats and Genome Instability—A Genome‐Wide Analysis
Author(s) -
Dittwald Piotr,
Gambin Tomasz,
GonzagaJauregui Claudia,
Carvalho Claudia M.B.,
Lupski James R.,
Stankiewicz Paweł,
Gambin Anna
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22217
Subject(s) - library science , human genome , genome , biology , genetics , computer science , gene
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.

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