Copy number variations and constitutional chromothripsis (Review)

Brás,Aldina; Rodrigues,António Sebastião; Rueff,José

doi:10.3892/br.2020.1318

Copy number variations and constitutional chromothripsis (Review)

Authors:
- Aldina Brás
- António Sebastião Rodrigues
- José Rueff
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Affiliations: Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School, Faculty of Medical Sciences, NOVA University of Lisbon, Lisbon 1169‑056, Portugal
Published online on: June 26, 2020 https://doi.org/10.3892/br.2020.1318
Article Number: 11
Copyright : © Brás et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

Both copy number variations (CNVs) and chromothripsis are phenomena that involve complex genomic rearrangements. Chromothripsis results in CNVs and other structural changes. CNVs are frequently observed in the human genome. Studies on CNVs have been increasing exponentially; the Database of Genomic Variants shows an increase in the number of data published on structural variations added to the database in the last 15 years. CNVs may be a result of replicative and non‑replicative mechanisms, and are hypothesized to serve important roles in human health and disease. Chromothripsis is a phenomena of chromosomal rearrangement following chromosomal breaks at multiple locations and involves impaired DNA repair. In 2011, Stephens et al coined the term chromothripsis for this type of fragmenting event. Several proposed mechanisms have been suggested to underlie chromothripsis, such as p53 inactivation, micronuclei formation, abortive apoptosis and telomere fusions in telomere crisis. Chromothripsis gives rise to normal or abnormal phenotypes. In this review, constitutional chromothripsis, which may coexist with multiple de novo CNVs are described and discussed. This reviews aims to summarize recent advances in our understanding of CNVs and chromothripsis, and describe the effects of these phenomena on human health and birth defects.

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1	Snijders AM, Nowak N, Segraves R, Blackwood S, Brown N, Conroy J, Hamilton G, Hindle AK, Huey B, Kimura K, et al: Assembly of microarrays for genome-wide measurement of DNA copy number. Nat Genet. 29:263–264. 2001.PubMed/NCBI View Article : Google Scholar
2	Database of Genomic Variants: A curated catalogue of human genomic structural variation. dgv.tcag.ca/. Accessed September 24, 2019.
3	Chen L, Zhou W, Zhang L and Zhang F: Genome architecture and its roles in human copy number variation. Genomics Inform. 12:136–144. 2014.PubMed/NCBI View Article : Google Scholar
4	Zarrei M, MacDonald JR, Merico D and Scherer SW: A copy number variation map of the human genome. Nat Rev Genet. 16:172–183. 2015.PubMed/NCBI View Article : Google Scholar
5	Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, Aerts J, Andrews TD, Barnes C, Campbell P, et al: Origins and functional impact of copy number variation in the human genome. Nature. 464:704–712. 2010.PubMed/NCBI View Article : Google Scholar
6	Harel T and Lupski JR: Genomic disorders 20 years on-mechanisms for clinical manifestations. Clin Genet. 93:439–449. 2018.PubMed/NCBI View Article : Google Scholar
7	Marcozzi A, Pellestor F and Kloosterman WP: The genomic characteristics and origin of chromothripsis. Methods Mol Biol. 1769:3–19. 2018.PubMed/NCBI View Article : Google Scholar
8	Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, Meyerson M and Pellman D: Chromothripsis from DNA damage in micronuclei. Nature. 522:179–184. 2015.PubMed/NCBI View Article : Google Scholar
9	Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD, Raine K, Jones D, Hinton J, Marshall J, Stebbings LA, et al: Mutational processes molding the genomes of 21 breast cancers. Cell. 149:979–993. 2012.PubMed/NCBI View Article : Google Scholar
10	Luijten MNH, Lee JXT and Crasta KC: Mutational game changer: Chromothripsis and its emerging relevance to cancer. Mutat Res. 777:29–51. 2018.PubMed/NCBI View Article : Google Scholar
11	Bickhart DM (ed): Copy Number Variants. Methods and Protocols. Humana Press, New York, NY, pp10-206, 2018.
12	Dhokarh D and Abyzov A: Elevated variant density around SV breakpoints in germline lineage lends support to error-prone replication hypothesis. Genome Res. 26:874–881. 2016.PubMed/NCBI View Article : Google Scholar
13	Emanuel BS and Shaikh TH: Segmental duplications: An ‘expanding’ role in genomic instability and disease. Nat Rev Genet. 2:791–800. 2001.PubMed/NCBI View Article : Google Scholar
14	Carvalho CM and Lupski JR: Mechanisms underlying structural variant formation in genomic disorders. Nat Rev Genet. 17:224–238. 2016.PubMed/NCBI View Article : Google Scholar
15	Hastings PJ, Lupski JR, Rosenberg SM and Ira G: Mechanisms of change in gene copy number. Nat Rev Genet. 10:551–564. 2009.PubMed/NCBI View Article : Google Scholar
16	Gu S, Yuan B, Campbell IM, Beck CR, Carvalho CM, Nagamani SC, Erez A, Patel A, Bacino CA, Shaw CA, et al: Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3. Hum Mol Genet. 24:4061–4077. 2015.PubMed/NCBI View Article : Google Scholar
17	Koren A, Polak P, Nemesh J, Michaelson JJ, Sebat J, Sunyaev SR and McCarroll SA: Differential relationship of DNA replication timing to different forms of human mutation and variation. Am J Hum Genet. 91:1033–1040. 2012.PubMed/NCBI View Article : Google Scholar
18	Hattori A, Okamura K, Terada Y, Tanaka R, Katoh-Fukui Y, Matsubara Y, Matsubara K, Kagami M, Horikawa R and Fukami M: Transient multifocal genomic crisis creating chromothriptic and non-chromothriptic rearrangements in prezygotic testicular germ cells. BMC Med Genomics. 12(77)2019.PubMed/NCBI View Article : Google Scholar
19	Liu P, Yuan B, Carvalho CMB, Wuster A, Walter K, Zhang L, Gambin T, Chong Z, Campbell IM, Coban Akdemir Z, et al: An organismal CNV mutator phenotype restricted to early human development. Cell. 168:830–842.e7. 2017.PubMed/NCBI View Article : Google Scholar
20	Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F and South ST: Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee. American college of medical genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 13:680–685. 2011.PubMed/NCBI View Article : Google Scholar
21	Zepeda-Mendoza CJ and Morton CC: The iceberg under water: Unexplored complexity of chromoanagenesis in congenital disorders. Am J Hum Genet. 104:565–577. 2019.PubMed/NCBI View Article : Google Scholar
22	Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, et al: Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 144:27–40. 2011.PubMed/NCBI View Article : Google Scholar
23	Chromothripsis DB: A curated database of chromothripsis. http://cgma.scu.edu.cn/ChromothripsisDB. Accessed September 2, 2019.
24	Cai H: ChromothripsisDB: A curated database for the documentation, visualization, and mining of chromothripsis data. Methods Mol Biol. 1769:279–289. 2018.PubMed/NCBI View Article : Google Scholar
25	Morishita M, Muramatsu T, Suto Y, Hirai M, Konishi T, Hayashi S, Shigemizu D, Tsunoda T, Moriyama K and Inazawa J: Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system. Oncotarget. 7:10182–10192. 2016.PubMed/NCBI View Article : Google Scholar
26	Mladenov E, Saha J and Iliakis G: Processing-challenges generated by clusters of dna double-strand breaks underpin increased effectiveness of High-LET radiation and chromothripsis. Adv Exp Med Biol. 1044:149–168. 2018.PubMed/NCBI View Article : Google Scholar
27	Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, Nezi L, Protopopov A, Chowdhury D and Pellman D: DNA breaks and chromosome pulverization from errors in mitosis. Nature. 482:53–58. 2012.PubMed/NCBI View Article : Google Scholar
28	Leibowitz ML, Zhang CZ and Pellman D: Chromothripsis: A new mechanism for rapid karyotype evolution. Annu Rev Genet. 49:183–211. 2015.PubMed/NCBI View Article : Google Scholar
29	Maciejowski J, Li Y, Bosco N, Campbell PJ and de Lange T: Chromothripsis and kataegis induced by telomere crisis. Cell. 163:1641–1654. 2015.PubMed/NCBI View Article : Google Scholar
30	Tubio JM and Estivill X: Cancer: When catastrophe strikes a cell. Nature. 470:476–477. 2011.PubMed/NCBI View Article : Google Scholar
31	Mardin BR, Drainas AP, Waszak SM, Weischenfeldt J, Isokane M, Stütz AM, Raeder B, Efthymiopoulos T, Buccitelli C, Segura-Wang M, et al: A cell-based model system links chromothripsis with hyperploidy. Mol Syst Biol. 11(828)2015.PubMed/NCBI View Article : Google Scholar
32	Ivkov R and Bunz F: Pathways to chromothripsis. Cell Cycle. 14:2886–2890. 2015.PubMed/NCBI View Article : Google Scholar
33	Kloosterman WP, Guryev V, van Roosmalen M, Duran KJ, de Bruijn E, Bakker SC, Letteboer T, van Nesselrooij B, Hochstenbach R, Poot M and Cuppen E: Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Hum Mol Genet. 20:1916–1924. 2011.PubMed/NCBI View Article : Google Scholar
34	Kloosterman WP, Tavakoli-Yaraki M, van Roosmalen MJ, van Binsbergen E, Renkens I, Duran K, Ballarati L, Vergult S, Giardino D, Hansson K, et al: Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. Cell Rep. 1:648–655. 2012.PubMed/NCBI View Article : Google Scholar
35	Nazaryan-Petersen L, Bertelsen B, Bak M, Jønson L, Tommerup N, Hancks DC and Tümer Z: Germline chromothripsis driven by L1-mediated retrotransposition and Alu/Alu homologous recombination. Hum Mutat. 37:385–395. 2016.PubMed/NCBI View Article : Google Scholar
36	Masset H, Hestand MS, Van Esch H, Kleinfinger P, Plaisancié J, Afenjar A, Molignier R, Schluth-Bolard C, Sanlaville D and Vermeesch JR: A distinct class of chromoanagenesis events characterized by focal copy number gains. Hum Mutat. 37:661–668. 2016.PubMed/NCBI View Article : Google Scholar
37	Fukami M, Shima H, Suzuki E, Ogata T, Matsubara K and Kamimaki T: Catastrophic cellular events leading to complex chromosomal rearrangements in the germline. Clin Genet. 91:653–660. 2017.PubMed/NCBI View Article : Google Scholar
38	Kloosterman WP and Cuppen E: Chromothripsis in congenital disorders and cancer: Similarities and differences. Curr Opin Cell Biol. 25:341–348. 2013.PubMed/NCBI View Article : Google Scholar
39	Pellestor F and Gatinois V: Potential role of chromothripsis in the genesis of complex chromosomal rearrangements in human gametes and preimplantation embryo. Methods Mol Biol. 1769:35–41. 2018.PubMed/NCBI View Article : Google Scholar
40	Poot M and Haaf T: Mechanisms of origin, phenotypic effects and diagnostic implications of complex chromosome rearrangements. Mol Syndromol. 6:110–134. 2015.PubMed/NCBI View Article : Google Scholar
41	Macera MJ, Sobrino A, Levy B, Jobanputra V, Aggarwal V, Mills A, Esteves C, Hanscom C, Pereira S, Pillalamarri V, et al: Prenatal diagnosis of chromothripsis, with nine breaks characterized by karyotyping, FISH, microarray and whole-genome sequencing. Prenat Diagn. 35:299–301. 2015.PubMed/NCBI View Article : Google Scholar
42	Gamba BF, Richieri-Costa A, Costa S, Rosenberg C and Ribeiro-Bicudo LA: Chromothripsis with at least 12 breaks at 1p36.33-p35.3 in a boy with multiple congenital anomalies. Mol Genet Genomics. 290:2213–2216. 2015.PubMed/NCBI View Article : Google Scholar
43	van Heesch S, Simonis M, van Roosmalen MJ, Pillalamarri V, Brand H, Kuijk EW, de Luca KL, Lansu N, Braat AK, Menelaou A, et al: Genomic and functional overlap between somatic and germline chromosomal rearrangements. Cell Rep. 9:2001–2010. 2014.PubMed/NCBI View Article : Google Scholar
44	de Pagter MS, van Roosmalen MJ, Baas AF, Renkens I, Duran KJ, van Binsbergen E, Tavakoli-Yaraki M, Hochstenbach R, van der Veken LT, Cuppen E and Kloosterman WP: Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring. Am J Hum Genet. 96:651–656. 2015.PubMed/NCBI View Article : Google Scholar
45	Bertelsen B, Nazaryan-Petersen L, Sun W, Mehrjouy MM, Xie G, Chen W, Hjermind LE, Taschner PE and Tümer Z: A germline chromothripsis event stably segregating in 11 individuals through three generations. Genet Med. 18:494–500. 2016.PubMed/NCBI View Article : Google Scholar
46	Chiang C, Jacobsen JC, Ernst C, Hanscom C, Heilbut A, Blumenthal I, Mills RE, Kirby A, Lindgren AM, Rudiger SR, et al: Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nat Genet. 44:390–397, S1. 2012.PubMed/NCBI View Article : Google Scholar
47	Nazaryan-Petersen L, Eisfeldt J, Pettersson M, Lundin J, Nilsson D, Wincent J, Lieden A, Lovmar L, Ottosson J, Gacic J, et al: Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization. PLoS Genet. 14(e1007780)2018.PubMed/NCBI View Article : Google Scholar
48	Pettersson M, Eisfeldt J, Syk Lundberg E, Lundin J and Lindstrand A: Flanking complex copy number variants in the same family formed through unequal crossing-over during meiosis. Mutat Res. 812:1–4. 2018.PubMed/NCBI View Article : Google Scholar
49	Slamova Z, Nazaryan-Petersen L, Mehrjouy MM, Drabova J, Hancarova M, Marikova T, Novotna D, Vlckova M, Vlckova Z, Bak M, et al: Very short DNA segments can be detected and handled by the repair machinery during germline chromothriptic chromosome reassembly. Hum Mutat. 39:709–716. 2018.PubMed/NCBI View Article : Google Scholar
50	Liu P, Erez A, Nagamani SC, Dhar SU, Kołodziejska KE, Dharmadhikari AV, Cooper ML, Wiszniewska J, Zhang F, Withers MA, et al: Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell. 146:889–903. 2011.PubMed/NCBI View Article : Google Scholar
51	Pellestor F (ed): Chromothripsis. Methods and Protocols. Humana Press, Montpellier, Hérault, pp11-367, 2018.