Abstract
Structural variants (SVs) can contribute to oncogenesis through a variety of mechanisms. Despite their importance, the identification of SVs in cancer genomes remains challenging. Here, we present a framework that integrates optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole-genome sequencing to systematically detect SVs in a variety of normal or cancer samples and cell lines. We identify the unique strengths of each method and demonstrate that only integrative approaches can comprehensively identify SVs in the genome. By combining Hi-C and optical mapping, we resolve complex SVs and phase multiple SV events to a single haplotype. Furthermore, we observe widespread structural variation events affecting the functions of noncoding sequences, including the deletion of distal regulatory sequences, alteration of DNA replication timing, and the creation of novel three-dimensional chromatin structural domains. Our results indicate that noncoding SVs may be underappreciated mutational drivers in cancer genomes.
Original language | English (US) |
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Pages (from-to) | 1388-1398 |
Number of pages | 11 |
Journal | Nature Genetics |
Volume | 50 |
Issue number | 10 |
DOIs | |
State | Published - Oct 1 2018 |
Funding
This work was supported by NIH grants R35GM124820, R01HG009906, and U01CA200060 (F.Y.), R24DK106766 (R.C.H. and F.Y.), GM083337 (D.M.G.), GM085354 (D.M.G.), DK107965 (D.M.G.), U54HG004592 (J.D. and J.A.S.), HG003143 and DK107980 (J.D.), U41HG007000 (W.S.N.), and DP5OD023071 (J. D.). This work was also supported by European Research Council (No. 615584 to D.T.O.and C.E.), Cancer Research UK (Nos. 20412 and 22398 to D.T.O. and C.E.), Wellcome Trust (No. 84459 to D.T.O. and C.E.), and Wellcome Trust (No. 106985/Z/15/Z to S.H.). J.D. is an investigator of the Howard Hughes Medical Institute. J.R.D. is also supported by the Leona M. and Harry B. Helmsley Charitable Trust grant No. 2017-PG-MED001. F.A. was supported by Institute Leadership Funds from La Jolla Institute for Allergy and Immunology. F.Y. is also supported by the Leukemia Research Foundation and Penn State Clinical and Translational Science Institute. We thank the ENCODE Data Coordination Center for helping with Hi-C and replication time data deposition. We would also like to thank Jan Karlseder and Nausica Arnault for help with the FISH experiments.
ASJC Scopus subject areas
- Genetics