@article{49c151d8155d4b8c89415c37741ef503,
title = "Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2",
abstract = "DNA rearrangements resulting in human genome structural variants (SVs) are caused by diverse mutational mechanisms. We used long- and short-read sequencing technologies to investigate end products of de novo chromosome 17p11.2 rearrangements and query the molecular mechanisms underlying both recurrent and non-recurrent events. Evidence for an increased rate of clustered single-nucleotide variant (SNV) mutation in cis with non-recurrent rearrangements was found. Indel and SNV formation are associated with both copy-number gains and losses of 17p11.2, occur up to ∼1 Mb away from the breakpoint junctions, and favor C > G transversion substitutions; results suggest that single-stranded DNA is formed during the genesis of the SV and provide compelling support for a microhomology-mediated break-induced replication (MMBIR) mechanism for SV formation. Our data show an additional mutational burden of MMBIR consisting of hypermutation confined to the locus and manifesting as SNVs and indels predominantly within genes. Newly occurring structural variants within in human genomes spawn extensive, local single-nucleotide changes leading to an enhanced mutational burden within proximal genes.",
keywords = "CNVs, DNA repair, complex rearrangements, genomic characterization, genomic disorders, long-read sequencing, phasing",
author = "Beck, {Christine R.} and Carvalho, {Claudia M.B.} and Akdemir, {Zeynep C.} and Sedlazeck, {Fritz J.} and Xiaofei Song and Qingchang Meng and Jianhong Hu and Harsha Doddapaneni and Zechen Chong and Chen, {Edward S.} and Thornton, {Philip C.} and Pengfei Liu and Bo Yuan and Marjorie Withers and Jhangiani, {Shalini N.} and Divya Kalra and Kimberly Walker and English, {Adam C.} and Yi Han and Ken Chen and Muzny, {Donna M.} and Grzegorz Ira and Shaw, {Chad A.} and Gibbs, {Richard A.} and Hastings, {P. J.} and Lupski, {James R.}",
note = "Funding Information: We thank the patients and family members who participated in this study. This work was supported, in part, by the National Institute of General Medical Sciences (R01GM106373 to P.J.H. and J.R.L., R01GM80600 to G.I., and R00GM120453 to C.R.B.), by the National Institute of Neurological Disorders and Stroke (R01NS058529 and R35NS105078 to J.R.L.), by the National Human Genome Research (U54 HG003273 to R.A.G.), and by a joint National Human Genome Research Institute. /National Heart Blood and Lung Institute (https://www.nhlbi.nih.gov/) grant (UM1HG006542) to the Baylor Hopkins Center for Mendelian Genomics. C.R.B. was previously supported by both a Brain Disorders and Development training grant at BCM (2T32NS043124-11) and an HHMI fellowship from the Damon Runyon Cancer Research Foundation (DRG 2155-13). Funding Information: We thank the patients and family members who participated in this study. This work was supported, in part, by the National Institute of General Medical Sciences ( R01GM106373 to P.J.H. and J.R.L., R01GM80600 to G.I., and R00GM120453 to C.R.B.), by the National Institute of Neurological Disorders and Stroke ( R01NS058529 and R35NS105078 to J.R.L.), by the National Human Genome Research ( U54 HG003273 to R.A.G.), and by a joint National Human Genome Research Institute . / National Heart Blood and Lung Institute ( https://www.nhlbi.nih.gov/ ) grant ( UM1HG006542 ) to the Baylor Hopkins Center for Mendelian Genomics. C.R.B. was previously supported by both a Brain Disorders and Development training grant at BCM ( 2T32NS043124-11 ) and an HHMI fellowship from the Damon Runyon Cancer Research Foundation ( DRG 2155-13 ). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = mar,
day = "7",
doi = "10.1016/j.cell.2019.01.045",
language = "English (US)",
volume = "176",
pages = "1310--1324.e10",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}