Impact of genomic structural variation in Drosophila melanogaster based on population-scale sequencing.
Zichner, T., Garfield, D.A., Rausch, T., Stutz, A.M., Cannavo, E., Braun, M., Furlong, E.E. & Korbel, J.O.
Genome Res. 2013 Mar;23(3):568-79. doi: 10.1101/gr.142646.112. Epub 2012 Dec 6.
Genomic structural variation (SV) is a major determinant for phenotypic variation. Although it has been extensively studied in humans, the nucleotide resolution structure of SVs within the widely used model organism Drosophila remains unknown. We report a highly accurate, densely validated map of unbalanced SVs comprising 8962 deletions and 916 tandem duplications in 39 lines derived from short-read DNA sequencing in a natural population (the "Drosophila melanogaster Genetic Reference Panel," DGRP). Most SVs (>90%) were inferred at nucleotide resolution, and a large fraction was genotyped across all samples. Comprehensive analyses of SV formation mechanisms using the short-read data revealed an abundance of SVs formed by mobile element and nonhomologous end-joining-mediated rearrangements, and clustering of variants into SV hotspots. We further observed a strong depletion of SVs overlapping genes, which, along with population genetics analyses, suggests that these SVs are often deleterious. We inferred several gene fusion events also highlighting the potential role of SVs in the generation of novel protein products. Expression quantitative trait locus (eQTL) mapping revealed the functional impact of our high-resolution SV map, with quantifiable effects at >100 genic loci. Our map represents a resource for population-level studies of SVs in an important model organism.
Criteria for inference of chromothripsis in cancer genomes.
Korbel, J.O. & Campbell, P.J.
Cell. 2013 Mar 14;152(6):1226-36. doi: 10.1016/j.cell.2013.02.023.
Chromothripsis scars the genome when localized chromosome shattering and repair occurs in a one-off catastrophe. Outcomes of this process are detectable as massive DNA rearrangements affecting one or a few chromosomes. Although recent findings suggest a crucial role of chromothripsis in cancer development, the reproducible inference of this process remains challenging, requiring that cataclysmic one-off rearrangements be distinguished from localized lesions that occur progressively. We describe conceptual criteria for the inference of chromothripsis, based on ruling out the alternative hypothesis that stepwise rearrangements occurred. Robust means of inference may facilitate in-depth studies on the impact of, and the mechanisms underlying, chromothripsis.
Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations.
Rausch, T., Jones, D.T., Zapatka, M., Stutz, A.M., Zichner, T., Weischenfeldt, J., Jager, N., Remke, M., Shih, D., Northcott, P.A., Pfaff, E., Tica, J., Wang, Q., Massimi, L., Witt, H., Bender, S., Pleier, S., Cin, H., Hawkins, C., Beck, C., von Deimling, A., Hans, V., Brors, B., Eils, R., Scheurlen, W., Blake, J., Benes, V., Kulozik, A.E., Witt, O., Martin, D., Zhang, C., Porat, R., Merino, D.M., Wasserman, J., Jabado, N., Fontebasso, A., Bullinger, L., Rucker, F.G., Dohner, K., Dohner, H., Koster, J., Molenaar, J.J., Versteeg, R., Kool, M., Tabori, U., Malkin, D., Korshunov, A., Taylor, M.D., Lichter, P., Pfister, S.M. & Korbel, J.O.
Cell. 2012 Jan 20;148(1-2):59-71.
Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific
Mapping copy number variation by population-scale genome sequencing.
Mills, R.E., Walter, K., Stewart, C., Handsaker, R.E., Chen, K., Alkan, C., Abyzov, A., Yoon, S.C., Ye, K., Cheetham, R.K., Chinwalla, A., Conrad, D.F., Fu, Y., Grubert, F., Hajirasouliha, I., Hormozdiari, F., Iakoucheva, L.M., Iqbal, Z., Kang, S., Kidd, J.M., Konkel, M.K., Korn, J., Khurana, E., Kural, D., Lam, H.Y., Leng, J., Li, R., Li, Y., Lin, C.Y., Luo, R., Mu, X.J., Nemesh, J., Peckham, H.E., Rausch, T., Scally, A., Shi, X., Stromberg, M.P., Stutz, A.M., Urban, A.E., Walker, J.A., Wu, J., Zhang, Y., Zhang, Z.D., Batzer, M.A., Ding, L., Marth, G.T., McVean, G., Sebat, J., Snyder, M., Wang, J., Ye, K., Eichler, E.E., Gerstein, M.B., Hurles, M.E., Lee, C., McCarroll, S.A., Korbel, J.O.; 1000 Genomes Project.
Nature. 2011 Feb 3;470(7332):59-65.
Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differe