Skip to main content
SpringerLink
Log in

Transcriptome Analysis as a Tool for Investigation of Pathogenesis of Chromosomal Diseases

  • REVIEW AND THEORETICAL ARTICLES
  • Published:
Russian Journal of Genetics Aims and scope Submit manuscript

Abstract

The aspects of transcriptional profiles of cells with chromosomal imbalance are discussed. There are certain difficulties in the assessment of phenotypic manifestations of chromosomal and genomic mutations. The data on the use of whole transcriptome analysis as an important new tool for investigation of the pathogenesis of chromosomal diseases related to aneuploidies, as well as microdeletion and microduplication syndromes, are described. The general patterns of gene expression changes in cells with chromosomal imbalance are highlighted: global dysregulation of gene expression; the similarity of transcriptional changes in cells with different aneuploidies or reciprocal copy number variations; common biological pathways and processes affected by mutations; the accumulation of transcriptional changes during ontogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Lebedev, I.N., Chromosomal diseases, Nasledstvennye bolezni: natsional’noe rukovodstvo (Inherited Diseases: National Guidelines), Moscow: GEOTAR-Media, P. 555–609.

  2. Kashevarova, A.A., Lebedev, I.N., and Nazarenko, L.P., Arkhitektura genoma i khromosomnye bolezni: sindromy retsiproknykh mikrodeletsii i mikroduplikatsii (Genome Architecture and Chromosomal Diseases: Reciprocal Microdeletion and Microduplication Syndromes), Tomsk: Pechatnaya Manufaktura, 2014.

  3. Galassi, F.M., Armocida, E., and Rühli, F.J., Angelman syndrome in the portrait of a child with a drawing by Giovanni F. Caroto, JAMA Pediatr., 2016, vol. 170, no. 9, p. 831. https://doi.org/10.1001/jamapediatrics.2016.0581

    Article  PubMed  Google Scholar 

  4. Oranges, C.M., Christ-Crain, M., and Schaefer, D.J., “La Monstrua Desnuda”: an artistic textbook representation of Prader—Willi syndrome in a painting of Juan Carreño de Miranda (1680), J. Endocrinol. Invest., 2017, vol. 40, no. 6, pp. 691—692. https://doi.org/10.1007/s40618-017-0639-5

    Article  CAS  PubMed  Google Scholar 

  5. Eblovi, D. and Clardy, C., Charles Dickens and Barnaby Rudge: the first description of Williams syndrome? Pediatr. Ann., 2016, vol. 45, no. 2, pp. e67—e69. https://doi.org/10.3928/00904481-20160113-03

    Article  PubMed  Google Scholar 

  6. Esquirol, J.E.D., Des maladies mentales considerées sous le rapport médicale, hygiènique et médico-legal, in 2 volumes and atlas, Paris: Baillière, 1838.

  7. Seguin, E., Traitement moral, hygiène et éducation des idiots, Paris: Baillière, 1846.

    Google Scholar 

  8. Down, J.H.L., The Mongolian Idiocy, vol. 3 of London Hospital Clinical Lectures and Adjournments (Transfers), 1866.

  9. Ellis, H., John Langdon Down: Down’s syndrome, J. Perioper. Pract., 2013, vol. 23, no. 12, pp. 296—297. https://doi.org/10.1177/175045891302301206

    Article  PubMed  Google Scholar 

  10. Karamanou, M., Kanavakis, E., Mavrou, A., et al., Jérôme Lejeune (1926—1994): father of modern genetics, Acta Med. Hist. Adriat., 2012, vol. 10, no. 2, pp. 311—316.

    PubMed  Google Scholar 

  11. Ford, C.E., Jones, K.W., Polani, P.E., et al., A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome), Lancet, 1959, vol. 1, no. 7075, pp. 711—713. https://doi.org/10.1016/S0140-6736(59)91893-8

    Article  CAS  PubMed  Google Scholar 

  12. Jacobs, P.A. and Strong, J.A., A case of human intersexuality having a possible XXY sex-determining mechanism, Nature, 1959, vol. 183, no. 4657, pp. 302—303. https://doi.org/10.1038/183302a0

    Article  CAS  PubMed  Google Scholar 

  13. Jacobs, P.A., Baikie, A.G., Brown, W.M., et al., Evidence for the existence of the human “super female”, Lancet, 1959, vol. 2, no. 7100, pp. 423—425. https://doi.org/10.1016/S0140-6736(59)90415-5

    Article  CAS  PubMed  Google Scholar 

  14. Patau, K., Smith, D.W., Therman, E., et al., Multiple congenital anomaly caused by an extra autosome, Lancet, 1960, vol. 1, no. 7128, pp. 790—793. https://doi.org/10.1016/S0140-6736(60)90676-0

    Article  CAS  PubMed  Google Scholar 

  15. Edwards, J.H., Harnden, D.G., Cameron, A.H., et al., A new trisomic syndrome, Lancet, 1960, vol. 1, no. 7128, pp. 787—790. https://doi.org/10.1016/S0140-6736(60)90674-7

    Article  CAS  PubMed  Google Scholar 

  16. Hirschhorn, K. and Cooper, H., Apparent deletion of short arms of one chromosome (4 or 5) in a child with defects of midline fusion, Hum. Chromosom. Newslett., 1961, vol. 4, no. 14.

  17. Hirschhorn, K., A short history of the initial discovery of the Wolf—Hirschhorn syndrome, Am. J. Med. Genet.,Part C, 2008, vol. 148, no. 4, pp. 244—245. https://doi.org/10.1002/ajmg.c.30186

    Article  Google Scholar 

  18. Watson, C.T., Tomas, M.-B., Sharp, A.J., and Mefford, H.C., The genetics of microdeletion and microduplication syndromes: an update, Annu. Rev. Genomics Hum. Genet., 2014, vol. 15, no. 1, pp. 215—244. https://doi.org/10.1146/annurev-genom-091212-153408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ewart, A.K., Morris, C.A., Atkinson, D., et al., Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome, Nat. Genet., 1993, vol. 5, no. 1, pp. 11—16. https://doi.org/10.1038/ng0993-11

    Article  CAS  PubMed  Google Scholar 

  20. Berdon, W.E., Clarkson, P.M., and Teele, R.L., Williams—Beuren syndrome: historical aspects, Pediatr. Radiol., 2011, vol. 41, no. 2, pp. 262—266. https://doi.org/10.1007/s00247-010-1908-z

    Article  PubMed  Google Scholar 

  21. Izumi, K. and Krantz, I.D., Pallister—Killian syndrome, Am. J. Med. Genet.,Part C, 2014, vol. 166, no. 4, pp. 406—413. https://doi.org/10.1002/ajmg.c.31423

    Article  Google Scholar 

  22. Powis, Z., Kang, S.-H.L., Cooper, M.L., et al., Mosaic tetrasomy 12p with triplication of 12p detected by array-based comparative genomic hybridization of peripheral blood DNA, Am. J. Med. Genet., Part A, 2007, vol. 143, no. 24, pp. 2910—2915. https://doi.org/10.1002/ajmg.a.31959

    Article  Google Scholar 

  23. Truty, R., Paul, J., Kennemer, M., et al., Prevalence and properties of intragenic copy-number variation in Mendelian disease genes, Genet. Med., 2019, vol. 21, no. 1, pp. 114—123. https://doi.org/10.1038/s41436-018-0033-5

    Article  CAS  PubMed  Google Scholar 

  24. Grinberg, K.N. and Kukharenko, V.I., Realization of the phenotypic effect of chromosomal aberrations in humans, Vavilovskii Zh. Genet. Sel., 2013, vol. 17, no. 1, pp. 32—39.

    Google Scholar 

  25. Taylor, A.I., Autosomal trisomy syndromes: a detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome, J. Med. Genet., 1968, vol. 5, no. 3, pp. 227—252. https://doi.org/10.1136/jmg.5.3.227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kloosterman, W.P. and Hochstenbach, R., Deciphering the pathogenic consequences of chromosomal aberrations in human genetic disease, Mol. Cytogenet., 2014, vol. 7, no. 1:100, p. 12. https://doi.org/10.1186/s13039-014-0100-9

  27. Hindley, D. and Medakkar, S., Diagnosis of Down’s syndrome in neonates, Arch. Dis. Child. Fetal Neonatal Ed., 2002, vol. 87, no. 3, pp. F220—F221. https://doi.org/10.1136/fn.87.3.f220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sivakumar, S. and Larkins, S., Accuracy of clinical diagnosis in Down’s syndrome, Arch. Dis. Child., 2004, vol. 89, no. 7, pp. 691—693. https://doi.org/10.1136/adc.2003.046565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Popadin, K., Peischl, S., Garieri, M., et al., Slightly deleterious genomic variants and transcriptome perturbations in Down syndrome embryonic selection, Genome Res., 2018, vol. 28, no. 1, pp. 1—10. https://doi.org/10.1101/gr.228411.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Volk, M., Maver, A., Hodžić, A., et al., Transcriptome profiling uncovers potential common mechanisms in fetal trisomies 18 and 21, OMICS, 2017, vol. 21, no. 10, pp. 565—570. https://doi.org/10.1089/omi.2017.0123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kaur, M., Izumi, K., Wilkens, A.B., et al., Genome-wide expression analysis in fibroblast cell lines from probands with Pallister Killian syndrome, PLoS One, 2014, vol. 9, no. 10, p. 12. e108853. https://doi.org/10.1371/journal.pone.0108853

    Article  PubMed  PubMed Central  Google Scholar 

  32. Takahashi, K. and Yamanaka, S., Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell, 2006, vol. 126, no. 4, pp. 663—676. https://doi.org/10.1016/j.cell.2006.07.024

    Article  CAS  PubMed  Google Scholar 

  33. Wernig, M., Meissner, A., Foreman, R., et al., In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state, Nature, 2007, vol. 448, no. 7151, pp. 318—324. https://doi.org/10.1038/nature05944

    Article  CAS  PubMed  Google Scholar 

  34. Yamanaka, S., Strategies and new developments in the generation of patient-specific pluripotent stem cells, Cell Stem Cell, 2007, vol. 1, no. 1, pp. 39—49. https://doi.org/10.1016/j.stem.2007.05.012

    Article  CAS  PubMed  Google Scholar 

  35. Nekrasov, E.D., Lebedeva, O.S., and Chestkov, I.V., Obtaining and characteristics of human induced pluripotent stem cells from skin fibroblasts of patients with neurodegenerative diseases, Kletochnaya Transplantol.Tkanevaya Inzh., 2011, vol. 6, no. 4, pp. 82—88.

    Google Scholar 

  36. Xie, Y.Z. and Zhang, R.X., Neurodegenerative diseases in a dish: the promise of iPSC technology in disease modeling and therapeutic discovery, Neurol. Sci., 2015, vol. 36, no. 1, pp. 21—27. https://doi.org/10.1007/s10072-014-1989-9

    Article  CAS  PubMed  Google Scholar 

  37. Ross, C.A. and Akimov, S.S., Human-induced pluripotent stem cells: potential for neurodegenerative diseases, Hum. Mol. Genet., 2014, vol. 23, no. R1, pp. R17—R26. https://doi.org/10.1093/hmg/ddu204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. McKinney, C., Using induced pluripotent stem cells derived neurons to model brain diseases, Neural Regen. Res., 2017, vol. 12, no. 7, pp. 1062—1067. https://doi.org/10.4103/1673-5374.211180

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hung, S.S.C., Khan, S., Lo, C.Y., et al., Drug discovery using induced pluripotent stem cell models of neurodegenerative and ocular diseases, Pharmacol. Ther., 2017, vol. 177, pp. 32—43. https://doi.org/10.1016/j.pharmthera.2017.02.026

    Article  CAS  PubMed  Google Scholar 

  40. Korecka, J.A., Levy, S., and Isacson, O., In vivo modeling of neuronal function, axonal impairment and connectivity in neurodegenerative and neuropsychiatric disorders using induced pluripotent stem cells, Mol. Cell. Neurosci., 2016, vol. 73, pp. 3—12. https://doi.org/10.1016/j.mcn.2015.12.004

    Article  CAS  PubMed  Google Scholar 

  41. Gillentine, M.A., Yin, J., Bajic, A., et al., Functional consequences of CHRNA7 copy-number alterations in induced pluripotent stem cells and neural progenitor cells, Am. J. Hum. Genet., 2017, vol. 101, no. 6, pp. 874—887. https://doi.org/10.1016/j.ajhg.2017.09.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Malakhova, A.A., Sorokin, M.A., Sorokina, A.E., et al., Using genome editing techniques to create isogenic cell lines that model Huntington’s disease in vitro, Geny Kletki, 2016, vol. 11, pp. 106—113.

    Google Scholar 

  43. Nekrasov, E.D., Vigont, V.A., Klyushnikov, S.A., et al., Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons, Mol. Neurodegener., 2016, vol. 11, no. 27, p. 15. https://doi.org/10.1186/s13024-016-0092-5

    Article  CAS  Google Scholar 

  44. Kovalenko, V.R., Khabarova, E.A., Rzaev, D.A., and Medvedev, S.P., Cellular models, genomic technologies and clinical practice: a synthesis of knowledge for the study of mechanisms, diagnostics and treatment of Parkinson’s disease, Geny Kletki, 2017, vol. 12, no. 2, pp 11—28. https://doi.org/10.23868/201707012

    Article  Google Scholar 

  45. Lebedin, M.Yu., Mayorova, K.S., Maksimov, V.V., et al., Somatic cells reprogramming and genome editing for the Stargardt disease modeling, investigation, and treatment, Geny Kletki, 2017, vol. 12, no. 2, pp. 62—70. https://doi.org/10.23868/201707021

    Article  Google Scholar 

  46. Chestkov, E.V., Vasil’eva, E.A., Illarioshkin, S.N., et al., Generation of cell model system of amyotrophic lateral sclerosis based on patient-specific induced pluripotent stem cells, Kletochnaya Transplantol.Tkanevaya Inzh., 2013. vol. 8, no. 3, pp. 58—59.

    Google Scholar 

  47. Grigor'eva, E.V. Valetdinova, K.R., Ust’yantseva, E.I., et al., Neural differentiation of patient-specific induced pluripotent stem cells derived from patients with a hereditary spinal muscular atrophy, Geny Kletki, 2016, vol. 11, no. 2, pp. 70—81.

    Google Scholar 

  48. Khattak, S., Brimble, E., Zhang, W., et al., Human induced pluripotent stem cell derived neurons as a model for Williams—Beuren syndrome, Mol. Brain, 2015, vol. 8, no. 1(77), p. 11. https://doi.org/10.1186/s13041-015-0168-0

  49. Li, L.B., Chang, K.-H., Wang, P.-R., et al., Trisomy correction in down syndrome induced pluripotent stem cells, Cell Stem Cell, 2012, vol. 11, no. 5, pp. 615—619. https://doi.org/10.1016/j.stem.2012.08.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Weick, J.P., Held, D.L., Bonadurer, G.F., et al., Deficits in human trisomy 21 iPSCs and neurons, Proc. Natl. Acad. Sci. U.S.A., 2013, vol. 110, no. 24, pp. 9962—9967. https://doi.org/10.1073/pnas.1216575110

    Article  PubMed  PubMed Central  Google Scholar 

  51. Jiang, J., Jing, Y., Cost, G.J., et al., Translating dosage compensation to trisomy 21, Nature, 2013, vol. 500, no. 7462, pp. 296—300. https://doi.org/10.1038/nature12394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hibaoui, Y., Grad, I., Letourneau, A., et al., Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21, EMBO Mol. Med., 2014, vol. 6, no. 2, pp. 259—277. https://doi.org/10.1002/emmm.201302848

    Article  CAS  PubMed  Google Scholar 

  53. Letourneau, A., Santoni, F.A., Bonilla, X., et al., Domains of genome-wide gene expression dysregulation in Down’s syndrome, Nature, 2014, vol. 508, no. 7496, pp. 345—350. https://doi.org/10.1038/nature13200

    Article  CAS  PubMed  Google Scholar 

  54. Gonzales, P.K., Roberts, C.M., Fonte, V., et al., Transcriptome analysis of genetically matched human induced pluripotent stem cells disomic or trisomic for chromosome 21, PLoS One, 2018, vol. 13, no. 3, p. 22. e0194581. https://doi.org/10.1371/journal.pone.0194581

    Article  PubMed  PubMed Central  Google Scholar 

  55. Adamo, A., Atashpaz, S., Germain, P.-L., et al., 7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages, Nat. Genet., 2015, vol. 47, no. 2, pp. 132—141. https://doi.org/10.1038/ng.3169

    Article  CAS  PubMed  Google Scholar 

  56. Germain, N.D., Chen, P.-F., Plocik, A.M., et al., Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1, Mol. Autism, 2014, vol. 5, no. 1(44), p. 19. https://doi.org/10.1186/2040-2392-5-44

    Article  PubMed  PubMed Central  Google Scholar 

  57. Chen, J., Lin, M., Hrabovsky, A., et al., ZNF804A transcriptional networks in differentiating neurons derived from induced pluripotent stem cells of human origin, PLoS One, 2015, vol. 10, no. 4, p. 23. e0124597. https://doi.org/10.1371/journal.pone.0124597

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kashevarova, A.A., Nazarenko, L.P., Schultz-Pedersen, S., et al., Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability, Mol. Cytogenet., 2014, vol. 7, no. 1:97. https://doi.org/10.1186/s13039-014-0097-0

  59. Lopatkina, M.E., Fishman, V.S., Gridina, M.M., et al., Patterns of gene expression in neurons derived from induced pluripotent stem cells of patients with reciprocal 3p26.3 microdeletion and microduplication, Comp. Cytogenet., 2018, vol. 12, no. 3, pp. 320—321. https://doi.org/10.3897/CompCytogen.v12i3.27448

    Article  Google Scholar 

  60. Gridina, M.M., Matveeva, N.M., Fishman, V.S., et al., Allele-specific biased expression of the CNTN6 gene in iPS cell-derived neurons from a patient with intellectual disability and 3p26.3 microduplication involving the CNTN6 gene, Mol. Neurobiol., 2018, vol. 55, no. 8, pp. 6533—6546. https://doi.org/10.1007/s12035-017-0851-5

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was carried out as part of the Russian Science Foundation grant no. 14-15-00772 and the topic of the state assignment of the Research Institute of Medical Genetics of the Tomsk National Research Medical Center, Russian Academy of Sciences (state registration number R&D AAAA-A19-119020890005-5).

Author information

Authors and Affiliations

  1. Research Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050, Tomsk, Russia

    M. E. Lopatkina & I. N. Lebedev

Authors
  1. M. E. Lopatkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. N. Lebedev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. E. Lopatkina.

Ethics declarations

COMPLIANCE WITH ETHICAL STANDARDS

This study does not contain any research involving humans or animals as research objects.

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lopatkina, M.E., Lebedev, I.N. Transcriptome Analysis as a Tool for Investigation of Pathogenesis of Chromosomal Diseases. Russ J Genet 56, 548–561 (2020). https://doi.org/10.1134/S1022795420050099

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1022795420050099

Keywords:

Search

Navigation