От цитогенетики к протеогеномике: новые горизонты в исследовании анеуплоидий

Анеуплоидией принято считать потерю или приобретение копии целой хромосомы или ее района. Уже на ранних стадиях развития она, как правило, приводит к фатальным последствиям, включая гибель организма и пороки/аномалии развития. Длительное время предполагалось, что именно нарушение баланса генов приводит к выраженным эффектам как на клеточном, так и на организменном уровне, негативно сказываясь на формировании организма. Было показано, что возникший вследствие анеуплоидии дисбаланс генов индуцирует протеотоксический и метаболический стресс в клетке, ее замедленную пролиферацию, нестабильность ее генома, оксидативный стресс и пр. Однако для некоторых организмов была описана толерантность к анеуплоидиям, которая даже могла способствовать возникновению у них адаптивных преимуществ (например, резистентность к антибиотикам у патогенных штаммов грибов). Вероятно, значимым фактором является сложность тканевой и органной организации особей конкретного вида. К анеуплоидии преимущественно более толерантны полиплоидные организмы и виды, относительно недавно прошедшие полногеномную дупликацию. Особое внимание в обзоре уделено рассмотрению анеуплоидий половых хромосом человека. Помимо первичных эффектов или цис-эффектов (изменение количества транскриптов генов, находящихся на анеуплоидной хромосоме), анеуплоидия может вызывать вторичные или транс-эффекты (изменение уровня экспрессии генов, расположенных на других хромосомах). Результаты исследований последних лет заставили по-новому взглянуть на влияние анеуплоидии на структурно-функциональную организацию генома, транскриптом и протеом как клетки, так и целого организма. Несмотря на то что при анеуплоидии уровень экспрессии для большинства генов коррелирует с измененным числом копий генов в клетке, были описаны случаи дозовой компенсации, при которой уровень транскриптов генов, расположенных на анеуплоидной хромосоме, оставался неизменным. В обзоре приводятся результаты последних исследований, посвященных изучению компенсаторных механизмов дозовой компенсации изменения количества продуктов генов на посттранскрипционных и пострансляционных уровнях, снижающих негативный эффект анеуплоидии на гомеостаз клетки, а также влиянию экстрахромосом на пространственную организацию генома, изменению паттернов экспрессии генов вследствие ее наличия. Кроме того, отдельно обсуждаются варианты сегментных анеуплоидий и изменения числа копий участков генома. Рассмотрено не только значение их состава, но также его локализация в хромосоме и в разных компартментах интерфазного ядра. Решение поднятых вопросов может внести большой вклад в совершенствование цитогеномной диагностики и в создание необходимой базы данных для корректной интерпретации выявленных случаев и сегментной анеуплоидии, и варьирующих по числу копий участков генома.

1. Auwerx C., Lepamets M., Sadler M.C., Patxot M., Stojanov M., Baud D., Mägi R.; Estonian Biobank Research Team; Porcu E., Reymond A., Kutalik Z. The individual and global impact of copynumber variants on complex human traits. Am J Hum Genet. 2022; 109(4):647-668. https://doi.org/10.1016/j.ajhg.2022.02.010

2. Baker D.E., Harrison N.J., Maltby E., Smith K., Moore H.D., Shaw P.J., Heath P.R., Holden H., Andrews P.W. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol. 2007;25(2):207-215. https://doi.org/10.1038/nbt1285

3. Balaton B.P., Cotton A.M., Brown C.J. Derivation of consensus inactivation status for X-linked genes from genome-wide studies. Biol Sex Differ. 2015;6:35. https://doi.org/10.1186/s13293-015-0053-7

4. Berglund A., Stochholm K., Gravholt C.H. The epidemiology of sex chromosome abnormalities. Am J Med Genet C Semin Med Genet. 2020;184(2):202-215. https://doi.org/10.1002/ajmg.c.31805

5. Birchler J.A. Aneuploidy in plants and flies: the origin of studies of genomic imbalance. Semin Cell Dev Biol. 2013;24(4):315-319. https://doi.org/10.1016/j.semcdb.2013.02.004

6. Birchler J.A., Veitia R.A. Gene balance hypothesis: connecting issues of dosage sensitivity across biological disciplines. Proc Natl Acad Sci USA. 2012;109(37):14746-14753. https://doi.org/10.1073/pnas.1207726109

7. Birchler J.A., Bhadra U., Bhadra M.P., Auger D.L. Dosage-dependent gene regulation in multicellular eukaryotes: implications for dosage compensation, aneuploid syndromes, and quantitative traits. Dev Biol. 2001;234(2):275-288. https://doi.org/10.1006/dbio.2001.0262

8. Borel C., Ferreira P.G., Santoni F., Delaneau O., Fort A., Popadin K.Y., Garieri M., Falconnet E., Ribaux P., Guipponi M., Padioleau I., Carninci P., Dermitzakis E.T., Antonarakis S.E. Biased allelic expression in human primary fibroblast single cells. Am J Hum Genet. 2015;96(1):70-80. https://doi.org/10.1016/j.ajhg.2014.12.001

9. Bouwman A.C., Hulsegge I., Hawken R.J., Henshall J.M., Veerkamp R.F., Schokker D., Kamphuis C. Classifying aneuploidy in genotype intensity data using deep learning. J Anim Breed Genet. 2023;140(3):304-315. https://doi.org/10.1111/jbg.12760

10. Braun R., Ronquist S., Wangsa D., Chen H., Anthuber L., Gemoll T., Wangsa D., Koparde V., Hunn C., Habermann J.K., HeselmeyerHaddad K., Rajapakse I., Ried T. Single chromosome aneuploidy induces genome-wide perturbation of nuclear organization and gene expression. Neoplasia. 2019;21(4):401-412. https://doi.org/10.1016/j.neo. 2019.02.003

11. Burrell R.A., McClelland S.E., Endesfelder D., Groth P., Weller M.C., Shaikh N., Domingo E., Kanu N., Dewhurst S.M., Gronroos E., Chew S.K., Rowan A.J., Schenk A., Sheffer M., Howell M., Kschischo M., Behrens A., Helleday T., Bartek J., Tomlinson I.P., Swanton C. Replication stress links structural and numerical cancer chromosomal instability. Nature. 2013;494(7438):492-496. https://doi.org/10.1038/nature11935

12. Carrel L., Willard H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434(7031): 400-404. https://doi.org/10.1038/nature03479

13. Chester M., Gallagher J.P., Symonds V.V., Cruz da Silva A.V., Mavrodiev E.V., Leitch A.R., Soltis P.S., Soltis D.E. Extensive chromosomal variation in a recently formed natural allopolyploid species, Tragopogon miscellus (Asteraceae). Proc Natl Acad Sci USA. 2012; 109(4):1176-1181. https://doi.org/10.1073/pnas.1112041109

14. Chikashige Y., Tsutsumi C., Okamasa K., Yamane M., Nakayama J., Niwa O., Haraguchi T., Hiraoka Y. Gene expression and distribution of Swi6 in partial aneuploids of the fission yeast Schizosaccharomyces pombe. Cell Struct Funct. 2007;32(2):149-161. https://doi.org/10.1247/ csf.07036

15. Chunduri N.K., Menges P., Zhang X., Wieland A., Gotsmann V.L., Mardin B.R., Buccitelli C., Korbel J.O., Willmund F., Kschischo M., Raeschle M., Storchova Z. Systems approaches identify the consequences of monosomy in somatic human cells. Nat Commun. 2021; 12:5576. https://doi.org/10.1038/s41467-021-25288-x

16. Colnaghi R., Carpenter G., Volker M., O’Driscoll M. The consequences of structural genomic alterations in humans: genomic disorders, genomic instability and cancer. Semin Cell Dev Biol. 2011;22(8): 875-885. https://doi.org/10.1016/j.semcdb.2011.07.010

17. Cremer M., Küpper K., Wagler B., Wizelman L., Hase J., Weiland Y., Kreja L., Diebold J., Speicher M.R., Cremer T. Inheritance of gene density-related higher order chromatin arrangements in normal and tumor cell nuclei. J Cell Biol. 2003;162(5):809-820. https://doi.org/10.1083/jcb.200304096

18. Cremer M., Brandstetter K., Maiser A., Rao S.S.P., Schmid V.J., Guirao-Ortiz M., Mitra N., Mamberti S., Klein K.N., Gilbert D.M., Leonhardt H., Cardoso M.C., Aiden E.L., Harz H., Cremer T. Cohesin depleted cells rebuild functional nuclear compartments after endomitosis. Nat Commun. 2020;11(1):6146. https://doi.org/10.1038/s41467020-19876-6

19. Cremer T., Cremer C. Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nat Rev Genet. 2001;2(4): 292-301. https://doi.org/10.1038/35066075

20. Cremer T., Cremer M. Chromosome territories. Cold Spring Harb Perspect Biol. 2010;2(3):a003889. https://doi.org/10.1101/cshperspect.a003889

21. Croft J.A., Bridger J.M., Boyle S., Perry P., Teague P., Bickmore W.A. Differences in the localization and morphology of chromosomes in the human nucleus. J Cell Biol. 1999;145(6):1119-1131. https://doi.org/10.1083/jcb.145.6.1119

22. Dekker J., Rippe K., Dekker M., Kleckner N. Capturing chromosome conformation. Science. 2002;295(5558):1306-1311. https://doi.org/10.1126/science.1067799

23. Deng Q., Ramsköld D., Reinius B., Sandberg R. Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells. Science. 2014;343(6167):193-196. https://doi.org/10.1126/science.1245316

24. Deng X., Berletch J., Nguyen D., Disteche C.M. X chromosome regulation: diverse patterns in development, tissues and disease. Nat Rev Genet. 2014;15:367-378. https://doi.org/10.1038/nrg3687

25. Duncan A.W., Hanlon Newell A.E., Smith L., Wilson E.M., Olson S.B., Thayer M.J., Strom S.C., Grompe M. Frequent aneuploidy among normal human hepatocytes. Gastroenterology. 2012;142(1):25-28. https://doi.org/10.1053/j.gastro.2011.10.029

26. Dürrbaum M., Storchová Z. Effects of aneuploidy on gene expression: implications for cancer. FEBS J. 2016;283(5):791-802. https://doi.org/10.1111/febs.13591

27. Edwards J.H., Harnden D.G., Cameron A.H., Crosse V.M., Wolff O.H. A new trisomic syndrome. Lancet. 1960;1(7128):787-790. https://doi.org/10.1016/s0140-6736(60)90675-9

28. Fournier R.E., Ruddle F.H. Microcell-mediated transfer of murine chromosomes into mouse, Chinese hamster, and human somatic cells. Proc Natl Acad Sci USA. 1977;74(1):319-323. https://doi.org/10.1073/pnas.74.1.319

29. Garieri M., Stamoulis G., Blanc X., Falconnet E., Ribaux P., Borel C., Santoni F., Antonarakis S.E. Extensive cellular heterogeneity of X inactivation revealed by single-cell allele-specific expression in human fibroblasts. Proc Natl Acad Sci USA. 2018;115(51):1301513020. https://doi.org/10.1073/pnas.1806811115

30. Gasch A.P., Hose J., Newton M.A., Sardi M., Yong M., Wang Z. Further support for aneuploidy tolerance in wild yeast and effects of dosage compensation on gene copy-number evolution. eLife. 2016;5:e14409. https://doi.org/10.7554/eLife.14409

31. Graham E.J., Vermeulen M., Vardarajan B., Bennett D., De Jager P., Pearse R.V. 2nd, Young-Pearse T.L., Mostafavi S. Somatic mosaicism of sex chromosomes in the blood and brain. Brain Res. 2019; 1721:146345. https://doi.org/10.1016/j.brainres.2019.146345

32. Gravholt C.H., Viuff M.H., Brun S., Stochholm K., Andersen N.H. Turner syndrome: mechanisms and management. Nat Rev Endocrinol. 2019;15:601-614. https://doi.org/10.1038/s41574-019-0224-4

33. Guo M., Birchler J.A. Trans-acting dosage effects on the expression of model gene systems in maize aneuploids. Science. 1994;266(5193): 1999-2002. https://doi.org/10.1126/science.266.5193.1999

34. Guttenbach M., Koschorz B., Bernthaler U., Grimm T., Schmid M. Sex chromosome loss and aging: in situ hybridization studies on human interphase nuclei. Am J Hum Genet. 1995;57(5):1143-1150

35. Hose J., Yong C.M., Sardi M., Wang Z., Newton M.A., Gasch A.P. Dosage compensation can buffer copy-number variation in wild yeast. eLife. 2015;4:e05462. https://doi.org/10.7554/eLife.05462

36. Hsieh T.S., Cattoglio C., Slobodyanyuk E., Hansen A.S., Rando O.J., Tjian R., Darzacq X. Resolving the 3D landscape of transcriptionlinked mammalian chromatin folding. Mol Cell. 2020;78(3):539553.e8. https://doi.org/10.1016/j.molcel.2020.03.002

37. Huettel B., Kreil D.P., Matzke M., Matzke A.J. Effects of aneuploidy on genome structure, expression, and interphase organization in Arabidopsis thaliana. PLoS Genet. 2008;4(10):e1000226. https://doi.org/10.1371/journal.pgen.1000226

38. Jones K.J., Jones M.C., del Campo M. Smith’s Recognizable Patterns of Human Malformation. Elsevier Health Sciences, 2022

39. Kemeny S., Tatout C., Salaun G., Pebrel-Richard C., Goumy C., Ollier N., Maurin E., Pereira B., Vago P., Gouas L. Spatial organization of chromosome territories in the interphase nucleus of trisomy 21 cells. Chromosoma. 2018;127(2):247-259. https://doi.org/10.1007/s00412-017-0653-6

40. Knouse K.A., Wu J., Whittaker C.A., Amon A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci USA. 2014;111(37):13409-13414. https://doi.org/10.1073/pnas.1415287111

41. Krivega M., Stiefel C.M., Storchova Z. Consequences of chromosome gain: a new view on trisomy syndromes. Am J Hum Genet. 2022; 109(12):2126-2140. https://doi.org/10.1016/j.ajhg.2022.10.014

42. Kvitek D.J., Will J.L., Gasch A.P. Variations in stress sensitivity and genomic expression in diverse S. cerevisiae isolates. PLoS Genet. 2008;4(10):e1000223. https://doi.org/10.1371/journal.pgen.1000223

43. Lachaud L., Bourgeois N., Kuk N., Morelle C., Crobu L., Merlin G., Bastien P., Pagès M., Sterkers Y. Constitutive mosaic aneuploidy is a unique genetic feature widespread in the Leishmania genus. Microbes Infect. 2014;16(1):61-66. https://doi.org/10.1016/j.micinf.2013.09.005

44. Lambuta R.A., Nanni L., Liu Y., Diaz-Miyar J., Iyer A., Tavernari D., Katanayeva N., Ciriello G., Oricchio E. Whole-genome doubling drives oncogenic loss of chromatin segregation. Nature. 2023; 615(7954):925-933. https://doi.org/10.1038/s41586-023-05794-2

45. Larsson A.J.M., Johnsson P., Hagemann-Jensen M., Hartmanis L., Faridani O.R., Reinius B., Segerstolpe Å., Rivera C.M., Ren B., Sandberg R. Genomic encoding of transcriptional burst kinetics. Nature. 2019;565(7738):251-254. https://doi.org/10.1038/s41586-018-0836-1

46. Larsson A.J.M., Ziegenhain C., Hagemann-Jensen M., Reinius B., Jacob T., Dalessandri T., Hendriks G.J., Kasper M., Sandberg R. Transcriptional bursts explain autosomal random monoallelic expression and affect allelic imbalance. PLoS Comput Biol. 2021; 17(3):e1008772. https://doi.org/10.1371/journal.pcbi.1008772

47. Leibowitz M.L., Papathanasiou S., Doerfler P.A., Blaine L.J., Sun L., Yao Y., Zhang C.Z., Weiss M.J., Pellman D. Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing. Nat Genet. 2021;53(6):895-905. https://doi.org/10.1038/s41588-021-00838-7

48. Lejeune J., Gautier M., Turpin R. Study of somatic chromosomes from 9 mongoloid children. C R Hebd Seances Acad Sci. 1959;248(11): 1721-1722

49. Letourneau A., Santoni F., Bonilla X., Sailani M.R., Gonzalez D., Kind J., Chevalier C., Thurman R., Sandstrom R.S., Hibaoui Y., Garieri M., Popadin K., Falconnet E., Gagnebin M., Gehrig C., Vannier A., Guipponi M., Farinelli L., Robyr D., Migliavacca E., Borel C., Deutsch S., Feki A., Stamatoyannopoulos J.A., Herault Y., van Steensel B., Guigo R., Antonarakis S.E. Domains of genomewide gene expression dysregulation in Down’s syndrome. Nature. 2014;508(7496):345-350. https://doi.org/10.1038/nature13200

50. Li G., Fullwood M.J., Xu H., Mulawadi F.H., Velkov S., Vega V., Ariya ratne P.N., Mohamed Y.B., Ooi H.S., Tennakoon C., Wei C.L., Ruan Y., Sung W.K. ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing. Genome Biol. 2010;11(2):R22. https://doi.org/10.1186/gb-2010-11-2-r22

51. Li R., Zhu J. Effects of aneuploidy on cell behaviour and function. Nat Rev Mol Cell Biol. 2022;23(4):250-265. https://doi.org/10.1038/s41580-021-00436-9

52. Liao W.W., Asri M., Ebler J., Doerr D., Haukness M., Hickey G., Lu S., … Garrison E., Marschall T., Hall I.M., Li H., Paten B. A draft human pangenome reference. Nature. 2023;617(7960):312-324. https://doi.org/10.1038/s41586-023-05896-x

53. Machiela M.J., Zhou W., Karlins E., Sampson J.N., Freedman N.D., Yang Q., Hicks B., … Rothman N., Tucker M., Dean M.C., Yeager M., Chanock S.J. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat Commun. 2016;7:11843. https://doi.org/10.1038/ncomms11843

54. Mallick S., Li H., Lipson M., Mathieson I., Gymrek M., Racimo F., Zhao M., … Thangaraj K., Pääbo S., Kelso J., Patterson N., Reich D. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature. 2016;538(7624):201-206. https://doi.org/10.1038/nature18964

55. Mayer R., Brero A., von Hase J., Schroeder T., Cremer T., Dietzel S. Common themes and cell type specific variations of higher order chromatin arrangements in the mouse. BMC Cell Biol. 2005;6:44. https://doi.org/10.1186/1471-2121-6-44

56. McConnell M.J., Moran J.V., Abyzov A., Akbarian S., Bae T., CortesCiriano I., Erwin J.A., … Kidd J.M., Park P.J., Pevsner J., Vaccarino F.M.; Brain Somatic Mosaicism Network. Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. Science. 2017;356(6336):eaal1641. https://doi.org/10.1126/science.aal1641

57. Meaburn K.J., Misteli T. Cell biology: chromosome territories. Nature. 2007;445(7126):379-781. https://doi.org/10.1038/445379a

58. Meharena H.S., Marco A., Dileep V., Lockshin E.R., Akatsu G.Y., Mullahoo J., Watson L.A., Ko T., Guerin L.N., Abdurrob F., Rengarajan S., Papanastasiou M., Jaffe J.D., Tsai L.H. Down-syndromeinduced senescence disrupts the nuclear architecture of neural progenitors. Cell Stem Cell. 2022;29(1):116-130.e7. https://doi.org/10.1016/j.stem. 2021.12.002

59. Miga K.H. From complete genomes to pangenomes. Am J Hum Genet. 2024;111(7):1265-1268. https://doi.org/10.1016/j.ajhg.2024.05.012

60. Minks J., Robinson W.P., Brown C.J. A skewed view of X chromosome inactivation. J Clin Invest. 2008;118(1):20-23. https://doi.org/10.1172/JCI34470

61. Modi D., Berde P., Bhartiya D. Down syndrome: a study of chromosomal mosaicism. Reprod Biomed Online. 2003;6(4):499-503. https://doi.org/10.1016/s1472-6483(10)62174-8

62. Muenzner J., Trébulle P., Agostini F., Zauber H., Messner C.B., Steger M., Kilian C., Lau K., Barthel N., Lehmann A., Textoris-Taube K., Caudal E., Egger A.S., Amari F., De Chiara M., Demichev V., Gossmann T.I., Mülleder M., Liti G., Schacherer J., Selbach M., Berman J., Ralser M. Natural proteome diversity links aneuploidy tolerance to protein turnover. Nature. 2024;630(8015):149-157. https://doi.org/10.1038/s41586-024-07442-9

63. Nagano T., Lubling Y., Stevens T.J., Schoenfelder S., Yaffe E., Dean W., Laue E.D., Tanay A., Fraser P. Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature. 2013;502(7469):59-64. https://doi.org/10.1038/nature12593

64. Nawata H., Kashino G., Tano K., Daino K., Shimada Y., Kugoh H., Oshimura M., Watanabe M. Dysregulation of gene expression in the artificial human trisomy cells of chromosome 8 associated with transformed cell phenotypes. PLoS One. 2011;6(9):e25319. https://doi.org/10.1371/journal.pone.0025319

65. Noormohammadi A., Calculli G., Gutierrez-Garcia R., Khodakarami A., Koyuncu S., Vilchez D. Mechanisms of protein homeostasis (proteostasis) maintain stem cell identity in mammalian pluripotent stem cells. Cell Mol Life Sci. 2018;75(2):275-290. https://doi.org/10.1007/s00018-017-2602-1

66. Nurk S., Koren S., Rhie A., Rautiainen M., Bzikadze A.V., Mikheenko A., Vollger M.R., … Zook J.M., Schatz M.C., Eichler E.E., Miga K.H., Phillippy A.M. The complete sequence of a human genome. Science. 2022;376(6588):44-53. https://doi.org/10.1126/science.abj6987

67. Oji A., Choubani L., Miura H., Hiratani I. Structure and dynamics of nuclear A/B compartments and subcompartments. Curr Opin Cell Biol. 2024;90:102406. https://doi.org/10.1016/j.ceb.2024.102406

68. Olson L.E., Richtsmeier J.T., Leszl J., Reeves R.H. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science. 2004;306(5696):687-690. https://doi.org/10.1126/science.1098992

69. Patau K., Smith D.W., Therman E., Inhorn S.L., Wagner H.P. Multiple congenital anomaly caused by an extra autosome. Lancet. 1960; 1(7128):790-793. https://doi.org/10.1016/s0140-6736(60)90676-0

70. Pavelka N., Rancati G., Zhu J., Bradford W.D., Saraf A., Florens L., Sanderson B.W., Hattem G.L., Li R. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast.

71. Nature. 2010;468(7321):321-325. https://doi.org/10.1038/nature09529

72. Pavlicek J., Soucek O., Vrtel R., Klaskova E., Hana V., Stara V., Adamova K., Fürst T., Hana V., Jr., Kapralova S., Prochazka M., Snajderova M., Tomaskova H., Tüdös Z., Vrbicka D., Vrtel P., Zapletalova J., Tauber Z., Lebl J. Karyotyping of lymphocytes and epithelial cells of distinct embryonic origin does not help to predict the Turner syndrome features. Horm Res Paediatr. 2022;95(5):465-475. https://doi.org/10.1159/000525823

73. Pinkel D., Segraves R., Sudar D., Clark S., Poole I., Kowbel D., Collins C., Kuo W.L., Chen C., Zhai Y., Dairkee S.H., Ljung B.M., Gray J.W., Albertson D.G. High resolution analysis of DNA copy number variation using comparative genomic hybridization to micro arrays. Nat Genet. 1998;20(2):207-211. https://doi.org/10.1038/2524

74. Pires J.C., Conant G.C. Robust yet fragile: expression noise, protein misfolding, and gene dosage in the evolution of genomes. Annu Rev Genet. 2016;50:113-131. https://doi.org/10.1146/annurev-genet-120215- 035400

75. Ramsköld D., Hendriks G.J., Larsson A.J.M., Mayr J.V., Ziegenhain C., Hagemann-Jensen M., Hartmanis L., Sandberg R. Single-cell new RNA sequencing reveals principles of transcription at the resolution of individual bursts. Nat Cell Biol. 2024;26(10):1725-1733. https://doi.org/10.1038/s41556-024-01486-9

76. Rana B., Lambrese K., Mendola R., Xu J., Garrisi J., Miller K., Marin D., Treff N.R. Identifying parental and cell-division origins of aneuploidy in the human blastocyst. Am J Hum Genet. 2023;110(4): 565-574. https://doi.org/10.1016/j.ajhg.2023.03.003

77. Razin S.V., Ulianov S.V. Genome-directed cell nucleus assembly. Biology. 2022;11(5):708. https://doi.org/10.3390/biology11050708

78. Raznahan A., Parikshak N.N., Chandran V., Blumenthal J.D., Clasen L.S., Alexander-Bloch A.F., Zinn A.R., Wangsa D., Wise J., Murphy D.G.M., Bolton P.F., Ried T., Ross J., Giedd J.N., Geschwind D.H. Sex-chromosome dosage effects on gene expression in humans. Proc Natl Acad Sci USA. 2018;115(28):7398-7403. https://doi.org/10.1073/pnas.1802889115

79. Rehen S.K., Yung Y.C., McCreight M.P., Kaushal D., Yang A.H., Almeida B.S., Kingsbury M.A., Cabral K.M., McConnell M.J., Anliker B., Fontanoz M., Chun J. Constitutional aneuploidy in the normal human brain. J Neurosci. 2005;25(9):2176-2180. https://doi.org/10.1523/JNEUROSCI.4560-04.2005

80. Reinius B., Sandberg R. Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation. Nat Rev Genet. 2015;16(11):653-664. https://doi.org/10.1038/nrg3888

81. Rustchenko E. Chromosome instability in Candida albicans. FEMS Yeast Res. 2007;7(1):2-11. https://doi.org/10.1111/j.1567-1364.2006.00150.x

82. Rutledge S.D., Cimini D. Consequences of aneuploidy in sickness and in health. Curr Opin Cell Biol. 2016;40:41-46. https://doi.org/10.1016/j.ceb.2016.02.003

83. Santaguida S., Vasile E., White E., Amon A. Aneuploidy-induced cellular stresses limit autophagic degradation. Genes Dev. 2015;29(19): 2010-2021. https://doi.org/10.1101/gad.269118.115

84. Santoni F.A., Stamoulis G., Garieri M., Falconnet E., Ribaux P., Borel C., Antonarakis S.E. Detection of imprinted genes by single-cell allelespecific gene expression. Am J Hum Genet. 2017;100(3):444-453. https://doi.org/10.1016/j.ajhg.2017.01.028

85. Shah P.P., Keough K.C., Gjoni K., Santini G.T., Abdill R.J., Wickramasinghe N.M., Dundes C.E., Karnay A., Chen A., Salomon R.E.A., Walsh P.J., Nguyen S.C., Whalen S., Joyce E.F., Loh K.M., Dubois N., Pollard K.S., Jain R. An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype. Genome Biol. 2023;24(1):16. https://doi.org/10.1186/s13059-023-02849-5

86. Shao Y., Lu N., Wu Z., Cai C., Wang S., Zhang L.-L., Zhou F., Xiao S., Liu L., Zeng X., Zheng H., Yang C., Zhao Z., Zhao G., Zhou J.- Q., Xue X., Qin Z. Creating a functional single-chromosome yeast. Nature. 2018;560(7718):331-335. https://doi.org/10.1038/s41586-018-0382-x

87. Sheltzer J.M., Torres E.M., Dunham M.J., Amon A. Transcriptional consequences of aneuploidy. Proc Natl Acad Sci USA. 2012; 109(31):12644-12649. https://doi.org/10.1073/pnas.1209227109

88. Solovei I., Wang A.S., Thanisch K., Schmidt C.S., Krebs S., Zwerger M., Cohen T.V., Devys D., Foisner R., Peichl L., Herrmann H., Blum H., Engelkamp D., Stewart C.L., Leonhardt H., Joffe B. LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell. 2013;152(3):584-598. https://doi.org/10.1016/j.cell.2013.01.009

89. Stamoulis G., Garieri M., Makrythanasis P., Letourneau A., Guipponi M., Panousis N., Sloan-Béna F., Falconnet E., Ribaux P., Borel C., Santoni F., Antonarakis S.E. Single cell transcriptome in aneuploidies reveals mechanisms of gene dosage imbalance. Nat Commun. 2019;10:4495. https://doi.org/10.1038/s41467-019-12273-8

90. Starostik M.R., Sosina O.A., McCoy R.C. Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism. Genome Res. 2020;30(6):814-825. https://doi.org/10.1101/gr.262774.120

91. Sterkers Y., Lachaud L., Crobu L., Bastien P., Pagès M. FISH analysis reveals aneuploidy and continual generation of chromosomal mosaicism in Leishmania major. Cell Microbiol. 2011;13(2):274-283. https://doi.org/10.1111/j.1462-5822.2010.01534.x

92. Sterkers Y., Lachaud L., Bourgeois N., Crobu L., Bastien P., Pagès M. Novel insights into genome plasticity in eukaryotes: mosaic aneuploidy in Leishmania. Mol Microbiol. 2012;86(1):15-23. https://doi.org/10.1111/j.1365-2958.2012.08185.x

93. Stingele S., Stoehr G., Peplowska K., Cox J., Mann M., Storchova Z. Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Mol Syst Biol. 2012;8:608. https://doi.org/10.1038/msb.2012.40

94. Storchová Z. Cells cope with altered chromosome numbers by enhancing protein breakdown. Nature. 2024;630(8015):41-43. https://doi.org/10.1038/d41586-024-01360-6

95. Sullivan K.D., Lewis H.C., Hill A.A., Pandey A., Jackson L.P., Cabral J.M., Smith K.P., Liggett L.A., Gomez E.B., Galbraith M.D., DeGregori J., Espinosa J.M. Trisomy 21 consistently activates the interferon response. eLife. 2016;5:e16220. https://doi.org/10.7554/eLife.16220

96. Tallaksen H.B.L., Johannsen E.B., Just J., Viuff M.H., Gravholt C.H., Skakkebæk A. The multi-omic landscape of sex chromosome abnormalities: current status and future directions. Endocr Connect. 2023; 12(9):e230011. https://doi.org/10.1530/EC-23-0011

97. Tanabe H., Müller S., Neusser M., von Hase J., Calcagno E., Cremer M., Solovei I., Cremer C., Cremer T. Evolutionary conservation of chromosome territory arrangements in cell nuclei from higher primates. Proc Natl Acad Sci USA. 2002;99(7):4424-4429. https://doi.org/10.1073/pnas.072618599

98. Tang Y.C., Amon A. Gene copy-number alterations: a cost-benefit analysis. Cell. 2013;152(3):394-405. https://doi.org/10.1016/j.cell.2012.11.043

99. Taylor A.M.R., Rothblum-Oviatt C., Ellis N.A., Hickson I.D., Meyer S., Crawford T.O., Smogorzewska A., Pietrucha B., Weemaes C., Stewart G.S. Chromosome instability syndromes. Nat Rev Dis Primers. 2019;5(1):64. https://doi.org/10.1038/s41572-019-0113-0

100. The 1000 Genomes Project Consortium; Auton A., Brooks L.D., Durbin R.M., Garrison E.P., Kang H.M., Korbel J.O., Marchini J.L., McCarthy S., McVean G.A., Abecasis G.R. A global reference for human genetic variation. Nature. 2015;526(7571):68-74. https://doi.org/10.1038/nature15393

101. Thomas R., Marks D.H., Chin Y., Benezra R. Whole chromosome loss and associated breakage-fusion-bridge cycles transform mouse tetraploid cells. EMBO J. 2018;37(2):201-218. https://doi.org/10.15252/embj.201797630

102. Thompson S.L., Bakhoum S.F., Compton D.A. Mechanisms of chromosomal instability. Curr Biol. 2010;20(6):R285-R295. https://doi.org/10.1016/j.cub.2010.01.034

103. Torres E.M. Consequences of gaining an extra chromosome. Chromosome Res. 2023;31(3):24. https://doi.org/10.1007/s10577-023-09732-w

104. Torres E.M., Sokolsky T., Tucker C.M., Chan L.Y., Boselli M., Dunham M.J., Amon A. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science. 2007;317(5840):916-924. https://doi.org/10.1126/science.1142210

105. Truong M.A., Cané-Gasull P., Lens S.M.A. Modeling specific aneuploidies: from karyotype manipulations to biological insights. Chromosome Res. 2023;31(3):25. https://doi.org/10.1007/s10577-023-09735-7

106. van Berkum N.L., Lieberman-Aiden E., Williams L., Imakaev M., Gnirke A., Mirny L.A., Dekker J., Lander E.S. Hi-C: a method to study the three-dimensional architecture of genomes. J Vis Exp. 2010;39:1869. https://doi.org/10.3791/1869

107. van Steensel B., Belmont A.S. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell. 2017;169(5):780-791. https://doi.org/10.1016/j.cell.2017.04.022

108. Veitia R.A., Potier M.C. Gene dosage imbalances: action, reaction, and models. Trends Biochem Sci. 2015;40(6):309-317. https://doi.org/10.1016/j.tibs.2015.03.011

109. Veitia R.A., Bottani S., Birchler J.A. Gene dosage effects: nonlinearities, genetic interactions, and dosage compensation. Trends Genet. 2013;29(7):385-393. https://doi.org/10.1016/j.tig.2013.04.004

110. Vernot B., Tucci S., Kelso J., Schraiber J.G., Wolf A.B., Gittelman R.M., Dannemann M., Grote S., McCoy R.C., Norton H., Scheinfeldt L.B., Merriwether D.A., Koki G., Friedlaender J.S., Wakefield J., Pääbo S., Akey J.M. Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals. Science. 2016;352(6282):235-239. https://doi.org/10.1126/science.aad9416

111. Wang S., Leng L., Wang Q., Gu Y., Li J., An Y., Deng Q., Xie P., Cheng C., Chen X., Zhou Q., Lu J., Chen F., Liu L., Yang H., Wang J., Xu X., Hou Y., Gong F., Hu L., Lu G., Shang Z., Lin G. A single-cell transcriptome atlas of human euploid and aneuploid blastocysts. Nat Genet. 2024;56(7):1468-1481. https://doi.org/10.1038/s41588-024-01788-6

112. Wang Y., Qu Z., Fang Y., Chen Y., Peng J., Song J., Li J., Shi J., Zhou J.- Q., Zhao Y. Chromosome territory reorganization through artificial chromosome fusion is compatible with cell fate determination and mouse development. Cell Discov. 2023;9(1):11. https://doi.org/10.1038/s41421-022-00511-1

113. Werner J.M., Hover J., Gillis J. Population variability in X-chromosome inactivation across 10 mammalian species. Nat Commun. 2024;15(1):8991. https://doi.org/10.1038/s41467-024-53449-1

114. Williams B.R., Amon A. Aneuploidy: cancer’s fatal flaw? Cancer Res. 2009;69(13):5289-5291. https://doi.org/10.1158/0008-5472.CAN-09-0944

115. Williams B.R., Prabhu V.R., Hunter K.E., Glazier C.M., Whittaker C.A., Housman D.E., Amon A. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science. 2008; 322(5902):703-709. https://doi.org/10.1126/science.1160058

116. Xiao R., Xu D., Zhang M., Chen Z., Cheng L., Du S., Lu M., Zhou T., Li R., Bai F., Huang Y. Aneuploid embryonic stem cells drive teratoma metastasis. Nat Commun. 2024;15(1):8883. https://doi.org/10.1038/s41467-024-53288-0

117. Yurov Y.B., Vorsanova S.G., Iourov I.Y., Demidova I.A., Beresheva A.K., Kravetz V.S., Monakhov V.V., Kolotii A.D., VoinovaUlas V.Y., Gorbachevskaya N.L. Unexplained autism is frequently associated with low‐level mosaic aneuploidy. J Med Genet. 2007; 44(8):521-525. https://doi.org/10.1136/jmg.2007.049312

118. Zadesenets K.S., Rubtsov N.B. B chromosomes in free-living flatworms of the genus Macrostomum (Platyhelminthes, Macrostomorpha). Int J Mol Sci. 2021;22(24):13617. https://doi.org/10.3390/ijms222413617

119. Zadesenets K.S., Vizoso D.B., Schlatter A., Konopatskaia I.D., Bere zikov E., Schärer L., Rubtsov N.B. Evidence for karyotype polymorphism in the free-living flatworm, Macrostomum lignano, a model organism for evolutionary and developmental biology. PLoS One. 2016;11(10):e0164915. https://doi.org/10.1371/journal.pone.0164915

120. Zadesenets K.S., Ershov N.I., Berezikov E., Rubtsov N.B. Chromosome evolution in the free-living flatworms: first evidence of intrachromosomal rearrangements in karyotype evolution of Macrostomum lignano (Platyhelminthes, Macrostomida). Genes (Basel). 2017a;8(11):298. https://doi.org/10.3390/genes8110298

121. Zadesenets K.S., Schärer L., Rubtsov N.B. New insights into the karyotype evolution of the free-living flatworm Macrostomum lignano (Platyhelminthes, Turbellaria). Sci Rep. 2017b;7(1):6066. https://doi.org/10.1038/s41598-017-06498-0

122. Zadesenets K.S., Jetybayev I.Y., Schärer L., Rubtsov N.B. Genome and karyotype reorganization after whole genome duplication in freeliving flatworms of the genus Macrostomum. Int J Mol Sci. 2020; 21(2):680. https://doi.org/10.3390/ijms21020680

123. Zadesenets K.S., Ershov N.I., Bondar N.P., Rubtsov N.B. Unraveling the unusual subgenomic organization in the neopolyploid free-living flatworm Macrostomum lignano. Mol Biol Evol. 2023;40(12): msad250. https://doi.org/10.1093/molbev/msad250

124. Zhai F., Kong S., Song S., Guo Q., Ding L., Zhang J., Wang N., Kuo Y., Guan S., Yuan P., Yan L., Yan Z., Qiao J. Human embryos harbor complex mosaicism with broad presence of aneuploid cells during Conflict of interest. The authors declare no conflict of interest. early development. Cell Discov. 2024;10(1):98. https://doi.org/10.1038/ s41421-024-00719-3

125. Zhang F., Gu W., Hurles M.E., Lupski J.R. Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet. 2009;10:451-481. https://doi.org/10.1146/annurev.genom.9.081307.164217

126. Zhang X.M., Yan M., Yang Z., Xiang H., Tang W., Cai X., Wu Q., Liu X., Pei G., Li J. Creation of artificial karyotypes in mice reveals robustness of genome organization. Cell Res. 2022;32(11):10261029. https://doi.org/10.1038/s41422-022-00722-x

127. Zhegalova I.V., Vasiluev P.A., Flyamer I.M., Shtompel A.S., Glazyrina E., Shilova N., Minzhenkova M., Markova Z., Petrova N.V., Dashinimaev E.B., Razin S.V., Ulianov S.V. Trisomies reorganize human 3D genome. Int J Mol Sci. 2023;24(22):6044. https://doi.org/10.3390/ijms242216044