Genome instability is associated with mitotic errors and cancer. This phenomenon can lead to deleterious rearrangements, but also genetic novelty, and many questions regarding its genesis, fate and evolutionary role remain unanswered. Here, we describe extreme chromosomal restructuring during genome elimination, a process resulting from hybridization of Arabidopsis plants expressing different centromere histones H3. Shattered chromosomes are formed from the genome of the haploid inducer, consistent with genomic catastrophes affecting a single, laggard chromosome compartmentalized within a micronucleus. Analysis of breakpoint junctions implicates breaks followed by repair through non-homologous end joining (NHEJ) or stalled fork repair. Furthermore, mutation of required NHEJ factor DNA Ligase 4 results in enhanced haploid recovery. Lastly, heritability and stability of a rearranged chromosome suggest a potential for enduring genomic novelty. These findings provide a tractable, natural system towards investigating the causes and mechanisms of complex genomic rearrangements similar to those associated with several human disorders.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Molecular and Cellular Biology University of California Davis Davis United States

Department of Plant Biology University of California Davis Davis United States

Genome Center University of California Davis Davis United States

Gordon and Betty Moore Foundation Howard Hughes Medical Institute University of California Davis Davis United States

School of Biology Indian Institute of Science Education and Research Thiruvananthapuram India

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Cai H, Kumar N, Bagheri HC, von Mering C, Robinson MD, Baudis M. Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens. BMC Genomics. 2014;15:82. doi: 10.1186/1471-2164-15-82. PubMed DOI PMC

Comai L, Madlung A, Josefsson C, Tyagi A. Do the different parental ‘heteromes’ cause genomic shock in newly formed allopolyploids? Philosophical Transactions of the Royal Society of London Series B, Biological Sciences. 2003;358:1149–1155. doi: 10.1098/rstb.2003.1305. PubMed DOI PMC

Costas C, de la Paz Sanchez M, Stroud H, Yu Y, Oliveros JC, Feng S, Benguria A, López-Vidriero I, Zhang X, Solano R, Jacobsen SE, Gutierrez C. Genome-wide mapping of Arabidopsis thaliana origins of DNA replication and their associated epigenetic marks. Nature Structural & Molecular Biology. 2011;18:395–400. doi: 10.1038/nsmb.1988. PubMed DOI PMC

Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, Nezi L, Protopopov A, Chowdhury D, Pellman D. DNA breaks and chromosome pulverization from errors in mitosis. Nature. 2012;482:53–58. doi: 10.1038/nature10802. PubMed DOI PMC

Gernand D, Rutten T, Varshney A, Rubtsova M, Prodanovic S, Brüss C, Kumlehn J, Matzk F, Houben A. Uniparental chromosome elimination at mitosis and interphase in wheat and pearl millet crosses involves micronucleus formation, progressive heterochromatinization, and DNA fragmentation. The Plant Cell. 2005;17:2431–2438. doi: 10.1105/tpc.105.034249. PubMed DOI PMC

Gordon DJ, Resio B, Pellman D. Causes and consequences of aneuploidy in cancer. Nature Reviews Genetics. 2012;13:189–203. doi: 10.1038/nrg3123. PubMed DOI

Hastings PJ, Ira G, Lupski JR. A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genetics. 2009;5:e1000327. doi: 10.1371/journal.pgen.1000327. PubMed DOI PMC

Hatch EM, Fischer AH, Deerinck TJ, Hetzer MW. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell. 2013;154:47–60. doi: 10.1016/j.cell.2013.06.007. PubMed DOI PMC

Henry IM, Dilkes BP, Comai L. Genetic basis for dosage sensitivity in Arabidopsis thaliana. PLoS Genetics. 2007;3:e70. doi: 10.1371/journal.pgen.0030070. PubMed DOI PMC

Henry IM, Dilkes BP, Miller ES, Burkart-Waco D, Comai L. Phenotypic consequences of aneuploidy in Arabidopsis thaliana. Genetics. 2010;186:1231–1245. doi: 10.1534/genetics.110.121079. PubMed DOI PMC

Henry IM, Dilkes BP, Tyagi AP, Lin HY, Comai L. Dosage and parent-of-origin effects shaping aneuploid swarms in A. thaliana. Heredity. 2009;103:458–468. doi: 10.1038/hdy.2009.81. PubMed DOI

Huettel B, Kreil DP, Matzke M, Matzke AJ. Effects of aneuploidy on genome structure, expression, and interphase organization in Arabidopsis thaliana. PLoS Genetics. 2008;4:e1000226. doi: 10.1371/journal.pgen.1000226. PubMed DOI PMC

Janssen A, van der Burg M, Szuhai K, Kops GJ, Medema RH. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science. 2011;333:1895–1898. doi: 10.1126/science.1210214. PubMed DOI

Jones MJ, Jallepalli PV. Chromothripsis: chromosomes in crisis. Developmental Cell. 2012;23:908–917. doi: 10.1016/j.devcel.2012.10.010. PubMed DOI PMC

Kloosterman WP, Cuppen E. Chromothripsis in congenital disorders and cancer: similarities and differences. Current Opinion in Cell Biology. 2013;25:341–348. doi: 10.1016/j.ceb.2013.02.008. PubMed DOI

Koornneef M, Vanderveen JH. Trisomics in Arabidopsis thaliana and the location of linkage groups. Genetica. 1983;61:41–46. doi: 10.1007/Bf00563230. DOI

Korbel JO, Campbell PJ. Criteria for inference of chromothripsis in cancer genomes. Cell. 2013;152:1226–1236. doi: 10.1016/j.cell.2013.02.023. PubMed DOI

Lamesch P, Berardini TZ, Li D, Swarbreck D, Wilks C, Sasidharan R, Muller R, Dreher K, Alexander DL, Garcia-Hernandez M, Karthikeyan AS, Lee CH, Nelson WD, Ploetz L, Singh S, Wensel A, Huala E. The Arabidopsis Information Resource (TAIR): improved gene annotation and new tools. Nucleic Acids Research. 2012;40:D1202–D1210. doi: 10.1093/nar/gkr1090. PubMed DOI PMC

Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–1760. doi: 10.1093/bioinformatics/btp324. PubMed DOI PMC

Liu P, Erez A, Nagamani SC, Dhar SU, Kołodziejska KE, Dharmadhikari AV, Cooper ML, Wiszniewska J, Zhang F, Withers MA, Bacino CA, Campos-Acevedo LD, Delgado MR, Freedenberg D, Garnica A, Grebe TA, Hernández-Almaguer D, Immken L, Lalani SR, McLean SD, Northrup H, Scaglia F, Strathearn L, Trapane P, Kang SH, Patel A, Cheung SW, Hastings PJ, Stankiewicz P, Lupski JR, Bi W. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell. 2011;146:889–903. doi: 10.1016/j.cell.2011.07.042. PubMed DOI PMC

Lysak MA, Mandáková T. Analysis of plant meiotic chromosomes by chromosome painting. Methods in Molecular Biology. 2013;990:13–24. doi: 10.1007/978-1-62703-333-6_2. PubMed DOI

Maheshwari S, Tan EH, West A, Franklin FC, Comai L, Chan SW. Naturally occurring differences in CENH3 affect chromosome segregation in zygotic mitosis of hybrids. PLoS Genetics. 2015;11:e1004970. doi: 10.1371/journal.pgen.1004970. PubMed DOI PMC

McClintock B. The significance of responses of the genome to challenge. Science. 1984;226:792–801. doi: 10.1126/science.15739260. PubMed DOI

Morrison CD, Liu P, Woloszynska-Read A, Zhang J, Luo W, Qin M, Bshara W, Conroy JM, Sabatini L, Vedell P, Xiong D, Liu S, Wang J, Shen H, Li Y, Omilian AR, Hill A, Head K, Guru K, Kunnev D, Leach R, Eng KH, Darlak C, Hoeflich C, Veeranki S, Glenn S, You M, Pruitt SC, Johnson CS, Trump DL. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer. Proceedings of the National Academy of Sciences of USA. 2014;111:E672–E681. doi: 10.1073/pnas.1313580111. PubMed DOI PMC

Ravi M, Chan SW. Haploid plants produced by centromere-mediated genome elimination. Nature. 2010;464:615–618. doi: 10.1038/nature08842. PubMed DOI

Ravi M, Marimuthu MP, Tan EH, Maheshwari S, Henry IM, Marin-Rodriguez B, Urtecho G, Tan J, Thornhill K, Zhu F, Panoli A, Sundaresan V, Britt AB, Comai L, Chan SW. A haploid genetics toolbox for Arabidopsis thaliana. Nature Communications. 2014;5:5334. doi: 10.1038/ncomms6334. PubMed DOI

Ravi M, Kwong PN, Menorca RM, Valencia JT, Ramahi JS, Stewart JL, Tran RK, Sundaresan V, Comai L, Chan SW. The rapidly evolving centromere-specific histone has stringent functional requirements in Arabidopsis thaliana. Genetics. 2010;186:461–471. doi: 10.1534/genetics.110.120337. PubMed DOI PMC

Ruby JG, Bellare P, Derisi JL. PRICE: software for the targeted assembly of components of (Meta) genomic sequence data. G3. 2013;3:865–880. doi: 10.1534/g3.113.005967. PubMed DOI PMC

Sanei M, Pickering R, Kumke K, Nasuda S, Houben A. Loss of centromeric histone H3 (CENH3) from centromeres precedes uniparental chromosome elimination in interspecific barley hybrids. Proceedings of the National Academy of Sciences of USA. 2011;108:E498–E505. doi: 10.1073/pnas.1103190108. PubMed DOI PMC

Sequeira-Mendes J, Aragüez I, Peiró R, Mendez-Giraldez R, Zhang X, Jacobsen SE, Bastolla U, Gutierrez C. The functional topography of the Arabidopsis genome is organized in a reduced number of linear motifs of chromatin states. The Plant Cell. 2014;26:2351–2366. doi: 10.1105/tpc.114.124578. PubMed DOI PMC

Steinitz-Sears LM. Chromosome studies in Arabidopsis thaliana. Genetics. 1963;48:483–490. PubMed PMC

Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27–40. doi: 10.1016/j.cell.2010.11.055. PubMed DOI PMC

Subrahmanyam NC, Kasha KJ. Selective chromosomal elimination during haploid formation in barley following interspecific hybridization. Chromosoma. 1973;42:111–125. doi: 10.1007/Bf00320934. DOI

Tan EH, Comai L, Henry IM. Chromosome dosage analysis in plants using whole genome sequencing. Bio-protocol. 2016;6:e1854. doi: 10.21769/BioProtoc.1854. DOI

Verdaasdonk JS, Bloom K. Centromeres: unique chromatin structures that drive chromosome segregation. Nature Reviews Molecular Cell Biology. 2011;12:320–332. doi: 10.1038/nrm3107. PubMed DOI PMC

Wang Z, Yin H, Lv L, Feng Y, Chen S, Liang J, Huang Y, Jiang X, Jiang H, Bukhari I, Wu L, Cooke HJ, Shi Q. Unrepaired DNA damage facilitates elimination of uniparental chromosomes in interspecific hybrid cells. Cell Cycle. 2014;13:1345–1356. doi: 10.4161/cc.28296. PubMed DOI PMC

Zhang W, Zhang T, Wu Y, Jiang J. Genome-wide identification of regulatory DNA elements and protein-binding footprints using signatures of open chromatin in Arabidopsis. The Plant Cell. 2012;24:2719–2731. doi: 10.1105/tpc.112.098061. PubMed DOI PMC

Zhang CZ, Leibowitz ML, Pellman D. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes & Development. 2013;27:2513–2530. doi: 10.1101/gad.229559.113. PubMed DOI PMC

Gradual chromosomal lagging drive programmed genome elimination in hemiclonal fishes from the genus Hypseleotris

Origin and Evolution of Diploid and Allopolyploid Camelina Genomes Were Accompanied by Chromosome Shattering