Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation
2017 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 38, no 2, 180-192 p.Article in journal (Refereed) Published
Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15% of the interchromosomal translocation events.
Place, publisher, year, edition, pages
John Wiley & Sons, 2017. Vol. 38, no 2, 180-192 p.
balanced chromosomal aberration, microhomology, nonhomologous end joining, reciprocal translocation, replication-based repair mechanisms, whole-genome sequencing
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
IdentifiersURN: urn:nbn:se:kth:diva-201964DOI: 10.1002/humu.23146ISI: 000393687800007ScopusID: 2-s2.0-85006421176OAI: oai:DiVA.org:kth-201964DiVA: diva2:1078392
Funding text: Contract grant sponsors: Swedish Research Council [2012-1526, 2013-2603]; The Swedish Society for Medical Research; the Marianne and Marcus Wallenberg Foundation [2014.0084]; Stockholm County Council; the Harald and Greta Jeanssons Foundation; the Ulf Lundahl memory fund through the Swedish Brain Foundation; the Nilsson Ehle donations and the Erik Rönnberg Foundation; US National Institutes of Health [HG006542] to the Baylor Hopkins Center for Mendelian Genomics. We are grateful to the patients and their families for their cooperation and enthusiasm during this study. We also gratefully acknowledge the use of computer infrastructure resources at UPPMAX, projects b2011162 and b2014152.
QC 201703032017-03-032017-03-032017-03-20Bibliographically approved