Abstract
Integrated analysis of structural variants (SVs) and copy number alterations (CNAs) in aneuploid cancer genomes is key to understanding the tumor genome complexity. A recently developed new algorithm Weaver can estimate, for the first time, allele-specific copy number of SVs and their interconnectivity in aneuploid cancer genomes. However, one major limitation is that not all SVs identified by Weaver are phased. In this paper, we develop a general convex programming framework that predicts the interconnectivity of unphased SVs with possibly noisy allele-specific copy number estimations as input. We demonstrated through applications to both simulated data and the HeLa whole-genome sequencing data that our method is robust to the noise in the input copy numbers and can predict SV phasings with high specificity. We found that our method can make consistent predictions with Weaver even if a large proportion of the input variants are unphased. We also applied our method to TCGA ovarian cancer whole-genome sequencing samples to phase unphased SVs obtained by Weaver. Our work provides an important new algorithmic framework for recovering more complete allele-specific cancer genome graphs.
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Adey, A., Burton, J.N., Kitzman, J.O., Hiatt, J.B., Lewis, A.P., Martin, B.K., Qiu, R., Lee, C., Shendure, J.: The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature 500(7461), 207–211 (2013)
Beroukhim, R., Mermel, C.H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J.S., Dobson, J., Urashima, M., et al.: The landscape of somatic copy-number alteration across human cancers. Nature 463(7283), 899–905 (2010)
Carter, S.L., Cibulskis, K., Helman, E., McKenna, A., Shen, H., Zack, T., Laird, P.W., Onofrio, R.C., Winckler, W., Weir, B.A., et al.: Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol. 30(5), 413–421 (2012)
Diamond, S., Boyd, S.: CVXPY: a python-embedded modeling language for convex optimization. J. Mach. Learn. Res. 17(83), 1–5 (2016)
Dzamba, M., Ramani, A.K., Buczkowicz, P., Jiang, Y., Yu, M., Hawkins, C., Brudno, M.: Identification of complex genomic rearrangements in cancers using CouGaR. Genome Res. 27(1), 107–117 (2017)
Eid, J., Fehr, A., Gray, J., Luong, K., Lyle, J., Otto, G., Peluso, P., Rank, D., Baybayan, P., Bettman, B., et al.: Real-time DNA sequencing from single polymerase molecules. Science 323(5910), 133–138 (2009)
Gordon, D.J., Resio, B., Pellman, D.: Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13(3), 189–203 (2012)
Greenman, C.D., Pleasance, E.D., Newman, S., Yang, F., Fu, B., Nik-Zainal, S., Jones, D., Lau, K.W., Carter, N., Edwards, P.A., et al.: Estimation of rearrangement phylogeny for cancer genomes. Genome Res. 22(2), 346–361 (2012)
Gupta, A., Place, M., Goldstein, S., Sarkar, D., Zhou, S., Potamousis, K., Kim, J., Flanagan, C., Li, Y., Newton, M.A., et al.: Single-molecule analysis reveals widespread structural variation in multiple myeloma. Proc. Nat. Acad. Sci. 112(25), 7689–7694 (2015)
Gurobi Optimization Inc.: Gurobi optimizer reference manual (2015)
Karp, R.M.: Reducibility among combinatorial problems. In: Miller, R.E., Thatcher, J.W., Bohlinger, J.D. (eds.) Complexity of Computer Computations, pp. 85–103. Springer, New York (1972)
Kimura, M.: The number of heterozygous nucleotide sites maintained in a finite population due to steady flux of mutations. Genetics 61(4), 893 (1969)
Li, Y., Zhou, S., Schwartz, D.C., Ma, J.: Allele-specific quantification of structural variations in cancer genomes. Cell Syst. 3(1), 21–34 (2016)
Ma, J., Ratan, A., Raney, B.J., Suh, B.B., Miller, W., Haussler, D.: The infinite sites model of genome evolution. Proc. Nat. Acad. Sci. 105(38), 14254–14261 (2008)
Medvedev, P., Fiume, M., Dzamba, M., Smith, T., Brudno, M.: Detecting copy number variation with mated short reads. Genome Res. 20(11), 1613–1622 (2010)
Medvedev, P., Stanciu, M., Brudno, M.: Computational methods for discovering structural variation with next-generation sequencing. Nat. Methods 6, S13–S20 (2009)
Oesper, L., Ritz, A., Aerni, S.J., Drebin, R., Raphael, B.J.: Reconstructing cancer genomes from paired-end sequencing data. BMC Bioinform. 13(6), S10 (2012)
Van Loo, P., Nordgard, S.H., Lingjærde, O.C., Russnes, H.G., Rye, I.H., Sun, W., Weigman, V.J., Marynen, P., Zetterberg, A., Naume, B., et al.: Allele-specific copy number analysis of tumors. Proc. Nat. Acad. Sci. 107(39), 16910–16915 (2010)
Wang, J., Mullighan, C.G., Easton, J., Roberts, S., Heatley, S.L., Ma, J., Rusch, M.C., Chen, K., Harris, C.C., Ding, L., et al.: Crest maps somatic structural variation in cancer genomes with base-pair resolution. Nat. Methods 8(8), 652–654 (2011)
Zack, T.I., Schumacher, S.E., Carter, S.L., Cherniack, A.D., Saksena, G., Tabak, B., Lawrence, M.S., Zhang, C.Z., Wala, J., Mermel, C.H., et al.: Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45(10), 1134–1140 (2013)
Zerbino, D.R., Ballinger, T., Paten, B., Hickey, G., Haussler, D.: Representing and decomposing genomic structural variants as balanced integer flows on sequence graphs. BMC Bioinform. 17(1), 400 (2016)
Zheng, G.X., Lau, B.T., Schnall-Levin, M., Jarosz, M., Bell, J.M., Hindson, C.M., Kyriazopoulou-Panagiotopoulou, S., Masquelier, D.A., Merrill, L., Terry, J.M., et al.: Haplotyping germline and cancer genomes with high-throughput linked-read sequencing. Nat. Biotechnol. 34(3), 303–311 (2016)
Acknowledgments
The authors would like to thank anonymous reviewers for suggestions that improved the paper. The authors would also like to thank the TCGA Research Network for making the data publicly available. This work is supported in part by National Institutes of Health Grants CA182360, HG007352, and DK107965 (to J.M.), and National Science Foundation Grants 1054309 and 1262575 (to J.M.).
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Rajaraman, A., Ma, J. (2017). Towards Recovering Allele-Specific Cancer Genome Graphs. In: Sahinalp, S. (eds) Research in Computational Molecular Biology. RECOMB 2017. Lecture Notes in Computer Science(), vol 10229. Springer, Cham. https://doi.org/10.1007/978-3-319-56970-3_14
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DOI: https://doi.org/10.1007/978-3-319-56970-3_14
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