title: Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms.
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.
authors.affiliation: Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Alexej
authors.initials: A
authors.lastname: Abyzov
authors.affiliation: 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.
authors.forename: Shantao
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Computer Science, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Daniel Rhee
authors.initials: DR
authors.lastname: Kim
authors.affiliation: Bina Technologies, Roche Sequencing, Redwood City, California 94065, USA.
authors.forename: Marghoob
authors.initials: M
authors.lastname: Mohiyuddin
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg 69117, Germany.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.affiliation: Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Nicholas F
authors.identifier: 0000000269718016
authors.initials: NF
authors.lastname: Parrish
authors.affiliation: 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.
authors.forename: Xinmeng Jasmine
authors.initials: XJ
authors.lastname: Mu
authors.affiliation: 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.
authors.forename: Wyatt
authors.initials: W
authors.lastname: Clark
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hurles
authors.affiliation: 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.
authors.forename: Jan O
authors.identifier: 0000000227983794
authors.initials: JO
authors.lastname: Korbel
authors.affiliation: Bina Technologies, Roche Sequencing, Redwood City, California 94065, USA.
authors.forename: Hugo Y K
authors.initials: HY
authors.lastname: Lam
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Gerstein
mesh_terms: D002843:Chromatin; D056905:Chromosome Breakpoints; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication; D017353:Gene Deletion; D015894:Genome, Human / Q000235:genetics*; D059765:Homologous Recombination; D006801:Humans; D009154:Mutation; D009711:Nucleotides; D017384:Sequence Deletion
chemical_list: D002843:Chromatin; D009711:Nucleotides; D004247:DNA