GENOMIC INSTABILITY IN THE BRAIN: ETIOLOGY, PATHOGENESIS AND NEW BIOLOGICAL MARKERS OF PSYCHIATRIC DISORDERS

Cover Page

Abstract


The latest advances in molecular medicine, medical genetics and neurobiology have provided for a new look at processes occurring in cells of the brain and have allowed to discover previously unknown phenomena associated with mental traits and to propose new biomedical direction which include genomics, psychiatry and neurobiology ― brain genomics. The application of modern molecular and cellular technologies of genome analysis in the brain in common psychiatric disorders (autism, schizophrenia and Alzheimer’s disease) has shown that genomic instability is a phathogenetic mechanism of central nervous system abnormalities and plays a role in the brain development. Genomic disbalance alters neural homeostasis leads to cell death and is an important biological marker of psychiatric disorders which determine genomic pathways. These alterations lead to synaptic disfunction and neurodegeneration. In the present review, the main advances of brain genomics and potential application in diagnostic, clinical and therapeutic practice.

 


A. S. Tiganov

Research Center of Mental Health of Russian Academy of Medical Sciences, Moscow

Author for correspondence.
Email: ncpz@ncpz.ru

Russian Federation доктор медицинских наук, профессор, академик РАМН, директор ФГБУ «Научный центр психического здоровья» РАМН Адрес: 115522, Москва, Каширское шоссе, д. 34 Тел.: (499) 617-8147

Yu. B. Yurov

Research Center of Mental Health of Russian Academy of Medical Sciences, Moscow

Email: y_yurov@yahoo.com

Russian Federation профессор, доктор биологических наук, заведующий лабораторией цитогенетики и гено- мики психических заболеваний ФГБУ «Научный центр психического здоровья» РАМН Адрес: 115522, Москва, Каширское шоссе, д. 34

S. G. Vorsanova

Research Center of Mental Health of Russian Academy of Medical Sciences, Moscow
Institute of Pediatrics and Children Surgey, Moscow

Email: svorsanova@mail.ru

Russian Federation профессор, доктор биологических наук, главный научный сотрудник ФГБУ «Научный центр психического здоровья» РАМН, заведующая лабораторией молекулярной цитогенетики нервно- психических болезней ФБГУ «Московский НИИ педиатрии и детской хирургии» Минздравсоцразвития России Адрес: 115522, Москва, Каширское шоссе, д. 34

I.Y Yu. Yurov

Research Center of Mental Health of Russian Academy of Medical Sciences, Moscow

Email: ivan.iourov@gmail.ru

Russian Federation доктор биологических наук, исполняющий обязанности заведующего лабораторией молеку- лярной генетики мозга ФГБУ «Научный центр психического здоровья» РАМН Адрес: 115522, Москва, Каширское шоссе, д. 34

  1. Stankiewicz P., Lupski J.R. Structural variation in the human genome and its role in disease. Ann. Rev. Med. 2010; 61: 437−455.
  2. Zhang F., Gu W., Hurles M.E., Lupski J.R. Copy number variation in human health, disease, and evolution. Ann. Rev. Genomics Hum. Genet. 2009; 10: 451−481.
  3. Gordon D.J., Resio B., Pellman D. Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 2012; 13 (3): 189−203.
  4. Iourov I.Y., Vorsanova S.G., Yurov Y.B. Intercellular gnomic (chromosomal) variations resulting in somatic mosaicism: mechanisms and consequences. Curr. Genomics. 2006; 7: 435−446.
  5. Iourov I.Y., Vorsanova S.G., Yurov Y.B. Somatic genome variations in health and disease. Curr Genomics. 2010; 11 (6): 420−425. Available at: http://www.els.net
  6. Yurov Y.B., Iourov I.Y., Monakhov V.V., Soloviev I.V., Vostrikov V.M., Vorsanova S.G. The variation of aneuploidy frequency in the developing and adult human brain revealed by an interphase FISH study. J. Histochem. Cytochem. 2005; 53: 385−390.
  7. Yurov Y.B., Iourov I.Y., Vorsanova S.G., Lieh, T., Kolotii A.D., Kutsev S.I., Pellestor F., Beresheva A.K., Demidova I.A., Kravets V.S., Monakhov V.V., Soloviev I.V. Aneuploidy and confined chromosomal mosaicism in the developing human brain. PLoS ONE. 2007; 2: e558.
  8. Vanneste E., Voet T., Le Caignec C., Ampe M., Konings P., Melotte C., Debrock S., Amyere M., Vikkula M., Schuit F., Fryns J.P., Verbeke G., D'Hooghe T., Moreau Y., Vermeesch J.R. Chromosome instability is common in human cleavage-stage embryos. Nat Med. 2009; 15: 577−583.
  9. Iourov I.Y., Vorsanova S.G., Yurov Y.B. Chromosomal variation in mammalian neuronal cells: known facts and attractive hypotheses. Int. Rev. Cytol. 2006; 249: 143−191.
  10. Iourov I.Y., Vorsanova S.G., Yurov Y.B. Chromosomal mosaicism goes global. Mol. Cytogenet. 2008; 1: 26.
  11. Iourov I.Y., Liehr T., Vorsanova S.G., Kolotii A.D., Yurov Y.B. Visualization of interphase chromosomes in postmitotic cells of the human brain by multicolour banding (MCB). Chromosome Res. 2006; 14: 223−229.
  12. Yurov Y.B., Vostrikov V.M., Vorsanova S.G., Monakhov V.V., Iourov I.Y. Multicolor fluorescent in situ hybridization on post-mortem brain in schizophrenia as an approach for identification of low-level chromosomal aneuploidy in neuropsychiatric diseases. Brain Dev. 2001; 23: 186−190.
  13. Vorsanova S.G., Yurov I.Yu., Demidova I.A., Voinova-Ulas V.Yu., Kravets V.S., Solov'ev I.V., Gorbachevskaya N.L., Yurov Yu.B. Variabel'nost' geterokhromatinovykh raionov khromosom i khromosomnye anomalii u detei s autizmom: identifikatsiya geneticheskikh markerov autisticheskikh rasstroistv. Zhurnal nevrologii i psikhiatrii im. S. S. Korsakova. 2006; 106 (6): 52−57.
  14. Yurov Y.B., Vorsanova S.G., Iourov I.Y., Demidova I.A., Beresheva A.K., Kravetz V.S., Monakhov V.V., Kolotii A.D., Voinova-Ulas V.Y., Gorbachevskaya N.L. Unexplained autism is frequently associated with low-level mosaic aneuploidy. J. Med. Genet. 2007; 44: 521−525.
  15. Iourov I.Y., Vorsanova S.G., Yurov Y.B. Molecular cytogenetics and cytogenomics of brain diseases. Curr. Genomics. 2008; 9: 452−465.
  16. Yurov Y.B., Iourov I.Y., Vorsanova S.G., Demidova I.A., Kravets V.S., Beresheva A.K., Kolotii A.D., Monakhov V.V., Uranova N.A., Vostrikov V.M., Soloviev I.V., Liehr T. The schizophrenia brain exhibits low-level aneuploidy involving chromosome 1. Schizophr Res. 2008; 98: 139−147.
  17. Dierssen M., Herault Y., Estivill X. Aneuploidy: from a physiological mechanism of variance to Down syndrome. Physiol. Rev. 2009; 89: 887−920.
  18. Iourov I.Y., Vorsanova S.G., Liehr T., Yurov Y.B. Aneuploidy in the normal, Alzheimer's disease and ataxia-telangiectasia brain: differential expression and pathological meaning. Neurobiol. Dis. 2009; 34: 212−220.
  19. Ly D.H., Lockhar D.J., Lerne R.A., Schultz P.G. Mitotic misregulation and human aging. Science. 2000; 287: 2486−2492.
  20. Leach N.T., Rehder D., Jensen K., Holt S., Jackson-Cook C. Human chromosomes with shorter telomeres and large heterochromatin regions have a higher frequency of acquired somatic cell aneuploidy. Mech. Ageing Dev. 2004; 125: 563−573.
  21. Finkel T., Serrano M., Blasco M.A. The common biology of cancer and ageing. Nature. 2007; 448: 767−774.
  22. Yuro Y.B., Vorsanova S.G., Iourov I.Y. GIN'n'CIN hypothesis of brain aging: deciphering the role of somatic genetic instabilities and neural aneuploidy during ontogeny. Mol. Cytogenet. 2009; 2: 23.
  23. Yurov Y.B., Vorsanova S.G., Iourov I.Y. Ontogenetic variation of the human genome. Current Genomics. 2010; 11 (6): 420−425.
  24. Yurov I.Yu., Vorsanova S.G., Yurov Yu.B. Molekulyarnaya neirotsitogenetika: nestabil'nost' genoma v mozge pri psikhicheskikh zabolevaniyakh. Psikhiatriya. 2007; 28 (4): 36−43.
  25. Yurov I.Yu., Vorsanova S.G., Yurov Yu.B. Variabel'nost' i nestabil'nost' genoma v kletkakh golovnogo mozga pri psikhicheskikh i neirodegenerativnykh zabolevaniyakh. Psikhiatriya. 2010; 3: 7−12.
  26. Yurov Yu.B., Vorsanova S.G., Solov'ev I.Yu., Yurov I.Yu. Nestabil'nost' khromosom v nervnykh kletkakh cheloveka v norme i pri nervno-psikhicheskikh zabolevaniyakh. Genetika. 2010; 46 (10): 1352−1355.
  27. Iourov I.Y., Vorsanova S.G., Yurov Yu.B. Somatic genome variations in health and disease. Current Genomics. 2010; 11 (6): 387−396.
  28. Vorsanova S.G., Yurov Y.B., Soloviev I.V., Iourov I.Y. Molecular cytogenetic diagnosis and somatic genome variations. Current Genomics. 2010; 11 (6): 440−446.
  29. Yurov Yu.B., Vorsanova S.G. Molekulyarno-tsitogeneticheskie issledovaniya khromosomnykh anomalii i narushenii pri nervno-psikhicheskikh zabolevaniyakh: poisk biologicheskikh markerov dlya diagnostiki. Vestnik RAMN. 2001; 7: 26−31.
  30. Boeras D.I., Granic A., Padmanabhan J., Crespo N.C., Rojiani A.M., Potter H. Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy. Neurobiol Aging. 2008; 29: 319−328.
  31. Granic A., Padmanabhan J., Norden M., Potte H. Alzheimer Abeta peptide induces chromosome mis-segregation and aneuploidy, including trisomy 21: requirement for tau and APP. Mol. Biol. Cell. 2010; 21: 511−520.
  32. Los F.J., van Opstal D., van den Berg C. The development of cytogenetically normal, abnormal and mosaic embryos: a theoretical model. Hum. Reprod. Update. 2004; 10: 79−94.
  33. Hultеn M.A., Patel S.D., Westgren M., Papadogiannaki N., Jonsso A.M., Jonasson J., Iwarsson E. On the paternal origin of trisomy 21 Down syndrome. Mol. Cytogenet. 2010; 3: 4.
  34. Hassold T., Hall H., Hunt P. The origin of human aneuploidy: where we have been, where we are going. Hum. Mol. Genet. 2007; 16: 203−208.
  35. Weier J.F., Ferlatte C., Baumgartner A., Jung C.J., Nguyen H.N., Chu L.W., Pedersen R.A., Fisher S.J., Weier H.U. Molecular cytogenetic studies towards the full karyotype analysis of human blastocysts and cytotrophoblasts. Cytogenet Genome Res. 2006; 114: 302−311.
  36. Vorsanova S.G., Kolotii A.D., Iourov I.Y., Monakhov V.V., Kirillova E.A., Soloviev I.V., Yurov Y.B. Evidence for high frequency of chromosomal mosaicism in spontaneous abortions revealed by interphase FISH analysis. J. Histochem. Cytochem. 2005; 53: 375−380.
  37. Vorsanova S.G., Yurov I.Y., Demidova I.A., Voinova-Ulas V.Y., Kravets V.S., Soloviev I.V., Gorbachevskaya N.L., Yurov Y.B. Variability in the heterochromatin regions of the chromosomes and chromosomal anomalies in children with autism: identification of genetic markers of autistic spectrum disorders. Neurosci Behav. Physiol. 2007; 37: 553−558.
  38. Kalousek D.K., Vekemans M. Confined placental mosaicism and genomic imprinting. Baillieres Best Pract. Res. Clin. Obstet Gynaecol. 2000; 1: 723−730.
  39. Fickelscher I., Starke H., Schulze E., Ernst G., Kosyakova N., Mkrtchyan H., MacDermont K., Sebire N., Liehr T. A further case with a small supernumerary marker chromosome (sSMC) derived from chromosome 1 — evidence for high variability in mosaicism in different tissues of sSMC carriers. Prenat. Diagn. 2007; 27: 783−785.
  40. Weier J.F., Weier H.U., Jung C.J., Gormley M., Zhou Y., Chu L.W., Genbacev O., Wright A.A., Fisher S.J. Human cytotrophoblasts acquire aneuploidies as they differentiate to an invasive phenotype. Dev. Biol. 2005; 279: 420−432.
  41. Iourov I.Y., Vorsanova S.G., Liehr T., Kolotii A.D., Yurov Y.B. Increased chromosome instability dramatically disrupts neural genome integrity and mediates cerebellar degeneration in the ataxia-telangiectasia brain. Hum. Mol. Genet. 2009; 18: 2656−2669.
  42. Vorsanova S.G., Iourov I.Y., Beresheva A.K., Demidova I.A., Monakhov V.V., Kravets V.S., Bartseva O.B., Goyko E.A., Soloviev I.V., Yurov Y.B. Non-disjunction of chromosome 21, alphoid DNA variation, and sociogenetic features of Down syndrome. Tsitol. Genet. 2005; 39 (6): 30−36.
  43. Vorsanova S.G., Yurov Y.B., Iourov I.Y. Human interphase chromosomes: a review of available molecular cytogenetic technologies. Mol. Cytogenet. 2010; 3: 1.
  44. Erickson R.P. Somatic gene mutation and human disease other than cancer: An update. Mutat Res. 2010; 705 (2): 96–106.
  45. Nowinski G.P., van Dyke D.L., Tilley B.C., Jacobsen G., Babu V.R., Worsham M.J., Wilson G.N., Weiss L. The frequency of aneuploidy in cultured lymphocytes is correlated with age and gender but not with reproductive history. Am. J. Hum. Genet. 1990; 46: 1101−1111.
  46. Guttenbach M., Koschorz B., Bernthaler U., Grimm T., Schmid M. Sex chromosomes loss and aging: in situ hybridization studies on human interphase nuclei. Am. J. Hum. Genet. 1995; 57: 1143−1150.
  47. Geigl J.B., Langer S., Barwisch S., Pfleghaar K., Lederer G., Speicher M.R. Analysis of gene expression patterns and chromosomal changes associated with aging. Cancer Res. 2004; 64: 8850−8557.
  48. Russel L.M., Strike P., Browne C.E., Jacobs P.A. X chromosome loss and aging. Cytogenet Genome Res. 2007; 116: 181−185.
  49. Kipling D., Davis T., Ostler E.L., Faragher R.G. What can progeroid syndromes tell us about human aging? Science. 2004; 305: 1426−1431.
  50. Neveling K., Bechtold A., Hoehn H. Genetic instability syndromes with progeroid features. Z. Gerontol. Geriatr. 2007; 40: 339−348.
  51. Vorsanova S.G. Dynamics of changes in anomalous human cells during prolonged cultivation in the stationary phase. Trisomy 7 cells. Biull. Eksp. Biol. Med. 1977; 3: 742−744.
  52. Liehr T. Cytogenetic contribution to uniparental disomy (UPD). Mol. Cytogenet. 2010; 3: 8.
  53. Soloviev I.V., Yurov Y.B., Vorsanova S.G., Fayet F., Roizes G., Malet P. Prenatal diagnosis of trisomy 21 using interphase fluorescence in situ hybridization of postreplicated cells with sitespecific cosmid and cosmid contig probes. Prenat. Diagn. 1995; 15: 237–248.
  54. Vorsanova S.G., Yurov Y.B., Koloti A.D., Soloviev I.V. FISH analysis of replication and transcription of chromosome X loci: new approach for genetic analysis of Rett syndrome. Brain Dev. 2001; 23: 191−195.
  55. Yeshaya J., Amir I., Rimon A., Freedman J., Shohat M., Avivi L. Microdeletion syndromes disclose replication timing alterations of genes unrelated to the missing DNA. Mol. Cytogenet. 2009; 2: 11.
  56. Yang Y., Herrup K. Cell division in the CNS: protective response or lethal event in post-mitotic neurons? Biochim Biophys Acta. 2007; 1772: 457−466.
  57. Iourov I.Y., Vorsanova S.G., Yurov Y.B. Genomic landscape of the Alzheimer’s disease brain: chromosome instability — aneuploidy, but not tetraploidy — mediates neurodegeneration. Neurodegener Dis. 2010; 8: 35−37.
  58. Federoff N., Botstein D. (eds). The dynamic genome: Barbara McClintock’s ideas in the century of genetics. Cold Spring Harbor Lab. Press, Plainview, New-York. 1992.
  59. Sgaramella V., Astolfi P.A. Somatic genome variations interact with environment, genome and epigenome in the determination of the phenotype: a paradigm shift in genomics? DNA Repair. 2010; 9: 470−473.
  60. Gericke G.S. An integrative view of dynamic genomic elements influencing human brain evolution and individual neurodevelopment. Med Hypotheses. 2008; 71: 360−373.
  61. Iourov I.Y., Vorsanova S.G., Yurov Y.B. Developmental neural chromosome instability as a possible cause of childhood brain cancers. Med Hypotheses. 2009; 72: 615−616.
  62. Little M.P. Cancer models, genomic instability and somatic cellular Darwinian evolution. Biol Direct. 2010; 5: 19.
  63. Iourov I.Y., Vorsanova S.G., Yurov Y.B. Single cell genomics of the brain: focus on neuronal diversity and neuropsychiatric diseases. Current Genomics. 2012; 13 (6): 477−488.
  64. Yurov Y.B., Iourov I.Y. Editorial: Somatic genome variations. Current Genomics. 2010; 11: 377−378.
  65. Vorsanova S.G., Demidova I.A., Ulas V.Y. et al. Cytogenetic and molecular-cytogenetic investigation of Rett syndrome. Analysis of 31 cases. NeuroReport. 1996; 7:187−189.
  66. Vorsanova S.G., Yurov Y.B., Ulas V.Y. et al. Cytogenetic and molecular-cytogenetic studies of Rett syndrome (RTT): a retrospective analysis of a Russian cohort of RTT patients (the investigation of 57 girls and three boys). Brain Dev. 2001; 23:196−201.
  67. Vorsanova S.G., Voinova V.Yu., Yurov I.Yu., Kurinnaya O.S., Demidova I.A., Yurov Yu.B. Cytogenetic, molecular-cytogenetic, and clinical-genealogical studies of the mothers of children with autism: a search for familial genetic markers for autistic disorders. Neurosciense and Behavioral Physiology. 2010; 40: 745−756.
  68. Yurov Y.B., Vorsanova S.G., Kolotii A.D., Liehr T., Iourov I.Y. Aneuploidy in the autistic brain: the first molecular cytogenetic study. Balkan Journal of Medical Genetics. 2011; 14: 73.
  69. Yurov I.Yu., Vorsanova S.G., Kolotii A.D. i dr. Mozaichnaya aneuploidiya v kletkakh golovnogo mozga pri ataksii-teleangiektazii (sindrom Lui-Bar). Med. genetika. 2008; 73: 22−26.
  70. Yurov Y.B., Vorsanova S.G., Iourov I.Y. The DNA replication stress hypothesis of Alzheimer's disease. Scientific World Journal. 2011; 11: 2602−2612.

Views

Abstract - 28

PDF (Russian) - 7

Cited-By


PlumX

Dimensions



Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies