Russian Journal of Genetics

, Volume 53, Issue 6, pp 703–711 | Cite as

Viability of carriers of chromosomal abnormalities depends on genomic dosage of active ribosomal genes (rRNA genes)

  • N. A. Lyapunova
  • L. N. Porokhovnik
  • N. V. Kosyakova
  • I. A. Mandron
  • T. G. Tsvetkova
Human Genetics


The genomic dosage of active (transcription-capable) ribosomal genes (AcRG) was determined in the genomes of 172 individuals, carriers of various chromosomal abnormalities: 116 individuals with numerical autosomal abnormalities (Down syndrome and Robertson translocations), 36 individuals with numerical abnormalities of gonosomes (Klinefelter, Turner, trisomy X, and disomy Y syndromes), and 20 carriers of various structural abnormalities of chromosomes. In the control sample of healthy individuals with a normal karyotype (N = 318), the AcRG number varied from 120 to 190 copies with mean of 150 ± 1 copies per diploid genome. In all the studied samples of carriers of chromosomal abnormalities, the genomic dosage (GD) of AcRG does not exceed the limits of variation of this feature in the control sample. However, in all the samples, the characteristic differences in the GD of AcRG were revealed. In accordance with the expectation, in patients with Down syndrome, the mean GD of AcRG was 10% higher, and in carriers of Robertson translocations, the maximum AcRG dose was 20% less than in the control. It can be concluded that about 10% of patients with Down syndrome and up to 50% of carriers of Robertsonian translocations die in the prenatal or early postnatal period because of excess or deficiency of AcRG in their genomes. A significant narrowing of the limits of the variation of the GD of AcRG in a sample of age-specific (over 10 years) patients with Down syndrome in comparison with the newborns was revealed. Obviously, Down syndrome carriers with low and high doses of AcRG predominantly die during the first years of life. The GD of AcRG of carriers of numerical anomalies of gonosomes predominantly fall into the region of medium, adaptive doses, and the carriers of structural chromosomal abnormalities predominantly survive when the dose of AcRG in the genome is greater than the mean in the control sample. For the first time, data on the association of the viability of carriers of different variants of chromosomal abnormalities with the number of active copies of rRNA genes in their genomes are presented.


ribosomal genes genomic dosage chromosomal abnormalities (CA) syndromes with aneuploidy of autosomes and gonosomes structural CA viability of CA carriers 


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  1. 1.
    Bochkov, N.P., Puzyrev, V.P., and Smirnikhina, S.A., Klinicheskaya genetika (Clinical Genetics), Moscow: GEOTAR-Media, 2011, 4th ed.Google Scholar
  2. 2.
    Larson, D.E., Zahradka, P., and Sells, B.H., Control points in eukaryotic ribosome biogenesis, Biochem. Cell Biol., 1991, vol. 69, no. 1, pp. 5–22.CrossRefPubMedGoogle Scholar
  3. 3.
    Long, E.O. and David, J.B., Repeated genes in eukaryotes, Ann. Rev. Biochem., 1980, vol. 49, pp. 729–764.CrossRefGoogle Scholar
  4. 4.
    Bross, K. and Krone, W., On the number of ribosomal RNA genes in man, Humangenetik, 1972, vol. 14, no. 2, pp. 137–141.CrossRefPubMedGoogle Scholar
  5. 5.
    Bross, K., Dittes, H., Krone, W., et al., Biochemical and cytogenetic studies on the nucleolus organizing regions (NOR) of man: 1. Comparison of trisomy 21 with balanced translocations t(DqGq), Humangenetik, 1973, vol. 20, no. 3, pp. 223–229.CrossRefPubMedGoogle Scholar
  6. 6.
    Gibbons, J.G., Branco, A.T., Yu, S., and Lemos, B., Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans, Nat. Commun., 2014, vol. 5, no. 4850. doi 10.1038/ncomms5850Google Scholar
  7. 7.
    Santoro, R., The epigenetics of the nucleolus: structure and function of active and silent ribosomal RNA genes, in The Nucleolus, Protein Reviews 15, Olson, M.O.J., Ed., Springer Science, 2011, pp. 57–82.Google Scholar
  8. 8.
    Conconi, A., Widmer, R.M., Koller, T., and Sogo, J.M., Two different chromatin structures coexist in ribosomal RNA genes throughout the cell cycle, Cell, 1989, vol. 57, no. 5, pp. 753–761.CrossRefPubMedGoogle Scholar
  9. 9.
    Stefanovsky, V. and Moss, T., Regulation of rRNA synthesis in human and mouse cells is not determined by changes in active gene count, Cell Cycle, 2006, vol. 5, no. 7, pp. 735–739.CrossRefPubMedGoogle Scholar
  10. 10.
    Veiko, N.N., Karpukhin, A.L., Salimov, A.G., et al., Biotining of DNA using a photoactivated M-(4-azido- 2-nitrobenzene)-1,7-diaminoheptane, Biotekhnologia, 1989, vol. 5, pp. 414–419.Google Scholar
  11. 11.
    Veiko, N.N., Lyapunova, N.A., Kosyakova, N.V., and Spitkovskii, D.M., Variation in chromatin structure of the rDNA transcribed region in human peripheral blood lymphocytes, Mol. Biol. (Moscow), 2001, vol. 35, no. 1, pp. 45–55.CrossRefGoogle Scholar
  12. 12.
    Li, J., Santoro, R., Koberna, K., and Grummt, I., The chromatin remodeling complex NoRC controls replication timing of rRNA genes, EMBO J., 2005, vol. 24, no. 1, pp. 120–127.CrossRefPubMedGoogle Scholar
  13. 13.
    Lyapunova, N.A. and Veiko, N.N., Ribosomal genes in the human genome: identification of four fractions, their organization in the nucleolus and metaphase chromosomes, Russ. J. Genet., 2010, vol. 46, no. 9, pp. 1070–1073.CrossRefGoogle Scholar
  14. 14.
    Veiko, N.N., Lyapunova, N.A., Bogush, L.V., et al., Estimation of the number of ribosomal genes in individual human genomes: a comparison of the results of molecular and cytogenetic analyses, Mol. Biol. (Moscow), 1996, vol. 30, no. 5, pp. 1076–1085.Google Scholar
  15. 15.
    Veiko, N.N., Structural and functional organization of the human ribosomal repeats, Doctoral (Biol.) Dissertation, Moscow: Medical Genetic Scientific Center of the Russian Academy of Medical Sciences, 2001.Google Scholar
  16. 16.
    Howell, W.M. and Black, D.A., Controlled silverstaining of nucleolus organizer regions with a protective colloidal developer: a 1-step method, Experientia, 1980, vol. 36, pp. 1014–1015.CrossRefPubMedGoogle Scholar
  17. 17.
    Miller, D.A., Dev, V.G., Tantravahi, R., and Miller, O.J., Suppression of human nucleolus organizer activity in mouse—human somatic hybrid cells, Exp. Cell Res., 1976, vol. 101, pp. 235–243.CrossRefPubMedGoogle Scholar
  18. 18.
    Hubbell, H.R., Silver staining as an indicator of active ribosomal genes, Stain. Technol., 1985, vol. 60, no. 5, pp. 285–294.CrossRefPubMedGoogle Scholar
  19. 19.
    Taylor, E.F. and Martin-DeLeon, P.A., Familial silver staining patterns of human nucleolus organizer regions (NORs), Am. J. Hum. Genet., 1981, vol. 33, pp. 67–76.PubMedPubMedCentralGoogle Scholar
  20. 20.
    de Capoa, A., Aleixandre, C., Felli, M.P., et al., Inheritance of ribosomal gene activity and level of DNA methylation of individual gene clusters in a three generation family, Hum. Genet., 1991, vol. 88, pp. 146–152.CrossRefPubMedGoogle Scholar
  21. 21.
    Velazquez, M., Visedo, G., Ludena, P., et al., Cytogenetic analysis of a human familial 15p+ marker chromosome, Genome, 1991, vol. 34, no. 5, pp. 827–829.CrossRefPubMedGoogle Scholar
  22. 22.
    Verma, R.S., Benjamin, C., Rodriguez, J., and Dosik, H., Population heteromorphisms of Ag-stained nucleolus organizer regions (NORs) in the acrocentric chromosomes of East Indians, Hum Genet., 1981, vol. 59, no. 4, pp. 412–415.CrossRefPubMedGoogle Scholar
  23. 23.
    Bernstein, R. and Griffiths, J., Human inherited chromosome 22 short-arm enlargement: investigation of rDNA gene multiplicity, Ag-band size, and acrocentric association, Hum. Genet., 1981, vol. 58, no. 2, pp. 135–139.CrossRefPubMedGoogle Scholar
  24. 24.
    Lyapunova, N.A., Egolina, N.A., Mkhitarova, E.V., and Viktorov, V.V., Interindividual and intercellular differences in the total activity of ribosomal genes, revealed by Ag-staining of the nucleolus-forming regions of human acrocenter chromosomes, Genetika (Moscow), 1988, vol. 24, no. 7, pp. 1282–1288.Google Scholar
  25. 25.
    Lyapunova, N.A., Kravets-Mandron, I.A., and Tsvetkova, T.G., Cytogenetics of the nucleolus organizer regions (NORs) of human chromosomes: the identification, individual variation, and chromosome distribution of four morphological functional variants of NORs, Russ. J. Genet., 1998, vol. 34, no. 9, pp. 1095–1102.Google Scholar
  26. 26.
    Lyapunova, N.A., Egolina, N.A., Tsvetkova, T.G., et al., Nucleolus organizer regions (NORs) of human chromosomes: the quantitative cytological and molecular analysis, Biol. Membr., 2001, vol. 18, no. 3, pp. 189–199.Google Scholar
  27. 27.
    Porokhovnik, L.N., Viktorov, V.V., Egolina, N.A., et al., Cluster size polymorphism of active human ribosomal genes and simulation of the conditions of its stability through generations, Russ. J. Genet., 2011, vol. 47, no. 12, pp. 1479–1476. doi 10.1134/S1022795411120106CrossRefGoogle Scholar
  28. 28.
    Hammer, O., Harper, D.A.T., and Ryan, P.D., PAST: paleontological statistics software package for education and data analysis, Palaeontol. Electron., 2001, vol. 4, no. 1, pp. 1–9.Google Scholar
  29. 29.
    Baird, P.A. and Sadovnick, A.D., Life tables for Down syndrome, Hum. Genet., 1989, vol. 82, no. 3, pp. 291–292.CrossRefPubMedGoogle Scholar
  30. 30.
    Glasson, E.J., Jacques, A., Wong, K., et al., Improved survival in Down syndrome over the last 60 years and the impact of perinatal factors in recent decades, J. Pediatr., 2016, vol. 169, pp. 214–220.CrossRefPubMedGoogle Scholar
  31. 31.
    Harris, D.J., Hankins, L., and Begleiter, M.L., Reproductive risk of t(13q14q) carriers: case report and review, Am. J. Med. Genet., 1979, vol. 3, no. 2, pp. 175–181.CrossRefPubMedGoogle Scholar
  32. 32.
    Golovataya, E.I., Pribushenya, O.V., Lazyuk, G.I., and Boisha, A.S., Pregnancy outcomes in families with carriers of Robertsonian translocations, Med. Genet., 2013, no. 7, pp. 41–46.Google Scholar
  33. 33.
    Julian-Reynier, C., Aurran, Y., Dumaret, A., et al., Attitudes towards Down’s syndrome: follow up of a cohort of 280 cases, J. Med. Genet., 1995, vol. 32, no. 8, pp. 597–599.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Roizen, N.J. and Patterson, D., Down’s syndrome, Lancet, 2003, vol. 361, no. 9365, pp. 1281–1289.CrossRefPubMedGoogle Scholar
  35. 35.
    Piccoli, C., Izzo, A., Scrima, R., et al., Chronic prooxidative state and mitochondrial dysfunctions are more pronounced in fibroblasts from Down syndrome foeti with congenital heart defects, Hum. Mol. Genet., 2013, vol. 22, no. 6, pp. 1218–1232.CrossRefPubMedGoogle Scholar
  36. 36.
    Espinola-Zavaleta, N., Soto, M.E., Romero-Gonzalez, A., et al., Prevalence of congenital heart disease and pulmonary hypertension in Down’s syndrome: an echocardiographic study, J. Cardiovasc. Ultrasound., 2015, vol. 23, no. 2, pp. 72–77.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Bermudez, B.E., Medeiros, S.L., Bermudez, M.B., et al., Down syndrome: prevalence and distribution of congenital heart disease in Brazil, Sao Paulo Med. J., 2015, vol. 133, no. 6, pp. 521–524.CrossRefPubMedGoogle Scholar
  38. 38.
    Veiko, N.N., Terekhov, S.M., Shubaeva, N.O., et al., Early and late responses to oxidative stress in human dermal fibroblasts of healthy donors and rheumatoid arthritis patients: relationship between the cell death rate and the genomic dosage of active ribosomal genes, Mol. Biol. (Moscow), 2005, vol. 39, no. 2, pp. 234–243.CrossRefGoogle Scholar
  39. 39.
    Jacob, S.T., Regulation of ribosomal gene transcription, Biochem. J., 1995, vol. 306, no. 3, pp. 617–626.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2017

Authors and Affiliations

  • N. A. Lyapunova
    • 1
  • L. N. Porokhovnik
    • 1
  • N. V. Kosyakova
    • 1
  • I. A. Mandron
    • 1
  • T. G. Tsvetkova
    • 1
  1. 1.Research Center for Medical GeneticsMoscowRussia

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