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Nat Commun. 2015 Jun 1;6:7256. doi: 10.1038/ncomms8256.

Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms.

Author information

1
Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota 55905, USA.
2
1] Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Avenue, New Haven, Connecticut 06520, USA [2] Department of Computer Science, Yale University, New Haven, Connecticut 06520, USA.
3
Department of Computer Science, Yale University, New Haven, Connecticut 06520, USA.
4
Bina Technologies, Roche Sequencing, Redwood City, California 94065, USA.
5
European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg 69117, Germany.
6
Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
7
1] Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Avenue, New Haven, Connecticut 06520, USA [2] Department of Molecular Biophysics and Biochemistry, School of Medicine, Yale University, New Haven, Connecticut 06520, USA.
8
The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
9
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
10
1] European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg 69117, Germany [2] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
11
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA.
12
1] Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Avenue, New Haven, Connecticut 06520, USA [2] Department of Molecular Biophysics and Biochemistry, School of Medicine, Yale University, New Haven, Connecticut 06520, USA [3] Department of Computer Science, Yale University, New Haven, Connecticut 06520, USA.

Abstract

Investigating genomic structural variants at basepair resolution is crucial for understanding their formation mechanisms. We identify and analyse 8,943 deletion breakpoints in 1,092 samples from the 1000 Genomes Project. We find breakpoints have more nearby SNPs and indels than the genomic average, likely a consequence of relaxed selection. By investigating the correlation of breakpoints with DNA methylation, Hi-C interactions, and histone marks and the substitution patterns of nucleotides near them, we find that breakpoints with the signature of non-allelic homologous recombination (NAHR) are associated with open chromatin. We hypothesize that some NAHR deletions occur without DNA replication and cell division, in embryonic and germline cells. In contrast, breakpoints associated with non-homologous (NH) mechanisms often have sequence microinsertions, templated from later replicating genomic sites, spaced at two characteristic distances from the breakpoint. These microinsertions are consistent with template-switching events and suggest a particular spatiotemporal configuration for DNA during the events.

PMID:
26028266
PMCID:
PMC4451611
DOI:
10.1038/ncomms8256
[Indexed for MEDLINE]
Free PMC Article

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