Contributed equally to this work and should be considered as co-first authors.
Inverted Low-Copy Repeats and Genome Instability—A Genome-Wide Analysis
Article first published online: 11 OCT 2012
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 1, pages 210–220, January 2013
How to Cite
Dittwald, P., Gambin, T., Gonzaga-Jauregui, C., Carvalho, C. M.B., Lupski, J. R., Stankiewicz, P. and Gambin, A. (2013), Inverted Low-Copy Repeats and Genome Instability—A Genome-Wide Analysis. Hum. Mutat., 34: 210–220. doi: 10.1002/humu.22217
Communicated by David N. Cooper
Contract grant sponsors: Polish National Science Center (2011/01/B/NZ2/00864 to A.G. and P.D.); EU through the European Social Fund (UDA-POKL.04.01.01–00-072/09–00 to P.D.); the Polish Ministry of Science and Higher Education (R13–0005-04/2008 to P.S.); and the National Institute of Neurological Disorders and Stroke (R01 NS058529 to J.R.L.).
- Issue published online: 20 DEC 2012
- Article first published online: 11 OCT 2012
- Accepted manuscript online: 10 SEP 2012 09:32AM EST
- Manuscript Accepted: 30 AUG 2012
- Manuscript Received: 5 JUN 2012
- Polish National Science Center. Grant Number: 2011/01/B/NZ2/00864
- European Social Fund. Grant Number: UDA-POKL.04.01.01–00-072/09–00
- the Polish Ministry of Science and Higher Education. Grant Number: R13–0005-04/2008
- the National Institute of Neurological Disorders and Stroke. Grant Number: R01 NS058529
- segmental duplications;
- inverted repeats;
- genomic inversions;
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.