Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2.

TitleMegabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2.
Publication TypeJournal Article
Year of Publication2019
AuthorsBeck, CR, Carvalho, CMB, Akdemir, ZC, Sedlazeck, FJ, Song, X, Meng, Q, Hu, J, Doddapaneni, H, Chong, Z, Chen, ES, Thornton, PC, Liu, P, Yuan, B, Withers, M, Jhangiani, SN, Kalra, D, Walker, K, English, AC, Han, Y, Chen, K, Muzny, DM, Ira, G, Shaw, CA, Gibbs, RA, Hastings, PJ, Lupski, JR
JournalCell
Volume176
Issue6
Pagination1310-1324.e10
Date Published2019 Mar 07
ISSN1097-4172
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.

DOI10.1016/j.cell.2019.01.045
Alternate JournalCell
PubMed ID30827684
PubMed Central IDPMC6438178
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
K99 GM120453 / GM / NIGMS NIH HHS / United States
R01 GM080600 / GM / NIGMS NIH HHS / United States
R01 GM106373 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
R00 GM120453 / GM / NIGMS NIH HHS / United States