Skip to main content
SpringerLink
Log in
Book cover

Tandem Repeat Polymorphisms pp 1–9Cite as

Tandem Repeat Polymorphisms

Mediators of Genetic Plasticity, Modulators of Biological Diversity and Dynamic Sources of Disease Susceptibility

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB))

Abstract

Tandem repetitive DNA elements (tandem repeats), including microsatellites and simple sequence repeats, are extremely common throughout the genomes of a wide range of species. Tandem repeat expansions have been found to cause a range of monogenic diseases, such as Huntington’s disease, various ataxias and other neurological diseases. The human genome contains hundreds of thousands of distinct tandem repeats, many of which appear to have evolved to regulate specific aspects of gene expression, RNA function and protein function. Tandem repeat polymorphisms (TRPs) provide a unique source of genetic variability that has an extended digital distribution, asopposed to theusual binary natureofsinglenucleotidepolymorphisms. In this chapter I will review studies in which tandem repeats have been implicated in a multitude of molecular and cellular processes associated with the development, behavior and evolution of a variety of animal species, including mammals. Recent data suggesting that these repetitive sequences can increase the ‘evolvability’ of genomes provides further evidence that TRPs not only have functional consequences but also provide a rich source of genetic diversity that can facilitate evolutionary processes. I propose that a readily mutable subclass of tandem repeats may provide an important template for stochastic genetic variation, which could in turn generate diversity in epigenetics, development and organismal function, thus impacting upon evolution. Furthermore, the distinctive characteristics of TRPs also uniquely position them as contributors to complex polygenic disorders. Ultimately, there is much to be gained from systematic analysis of the ‘repeatome’, defined as the entire set of tandem repeats and other repetitive DNA in a genome, as well as their transcribed and translated expression products. Applying such approaches not only to the human genome but to other species will yield new insights into the genetic regulation of a wide range of biological processes in healthy and diseased states.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Nithianantharajah J, Hannan AJ. Dynamic mutations as digital genetic modulators of brain development, function and dysfunction. Bioessays 2007; 29:525–535.

    Article  CAS  Google Scholar 

  2. Hannan AJ. Tandem repeat polymorphisms: modulators of disease susceptibility and candidates for ‘missing heritability’. Trends Genet 2010; 26:59–65.

    Article  CAS  Google Scholar 

  3. King DG. Evolution of simple sequence repeats as mutable sites. In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/ Springer Science+Business Media, 2012:10–25.

    Chapter  Google Scholar 

  4. Sawaya SM, Bagshaw ATB, Buschiazzo E et al. Promoter microsatellites as modulators of human gene expression. In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/Springer Science+Business Media, 2012:41–54.

    Chapter  Google Scholar 

  5. Hamada H, Seidman M, Howard BH et al. Enhanced gene expression by the poly(dT-dG) poly(dC-dA) sequence. Mol Cell Biol 1984; 4:2622–2630.

    Article  CAS  Google Scholar 

  6. Kashi Y, King D, Soller M. Simple sequence repeats as a source of quantitative genetic variation. Trends Genet 1997; 13:74–78.

    Article  CAS  Google Scholar 

  7. Faux NG, Bottomley SP, Lesk AM et al. Functional insights from the distribution and role of homopeptide repeat-containing proteins. Genome Res 2005; 15:537–551.

    Article  CAS  Google Scholar 

  8. Verstrepen KJ, Jansen A, Lewitter F et al. Intragenic tandem repeats generate functional variability. Nat Genet 2005; 37:986–990.

    Article  CAS  Google Scholar 

  9. Roberts J, Scott AC, Howard MR et al. Differential regulation of the serotonin transporter gene by lithium is mediated by transcription factors, CCCTC binding protein and Y-Box binding protein 1, through the polymorphic intron 2 variable number tandem repeat. J Neurosci 2007; 27:2793–2801.

    Article  CAS  Google Scholar 

  10. Salichs E, Ledda A, Mularoni L et al. Genome-wide analysis of histidine repeats reveals their role in the localization of human proteins to the nuclear speckles compartment. PloS Genet 2009; 5: e 1000397.

    Article  Google Scholar 

  11. Mattick JS, Taft RJ, Faulkner GJ. A global view of genomic information — moving beyond the gene and the master regulator. Trends Genet 2010; 26:21–28.

    Article  CAS  Google Scholar 

  12. Kashi Y, King DG. Simple sequence repeats as advantageous mutators in evolution. Trends Genet 2006; 22:253–259.

    Article  CAS  Google Scholar 

  13. Richard GF, Kerrest A, Dujon B. Comparative genomics and molecular dynamics of DNA repeats in eukaryotes. Microbiol Mol Biol Rev 2008; 72:686–727.

    Article  CAS  Google Scholar 

  14. Conrad DF, Pinto D, Redon R et al. Origins and functional impact of copy number variation in the human genome. Nature 2010; 464:704–712.

    Article  CAS  Google Scholar 

  15. Richards RI. Dynamic mutations: a decade of unstable expanded repeats in human genetic disease. Hum Mol Genet 2001; 10:2187–2194.

    Article  CAS  Google Scholar 

  16. Fondon JW III, Hammock EA, Hannan AJ et al. Simple sequence repeats: genetic modulators of brain function and behavior. Trends Neurosci 2008; 31:328–334.

    Article  CAS  Google Scholar 

  17. Usdin K. The biological effects of simple tandem repeats: lessons from the repeat expansion diseases. Genome Res 2008; 18:1011–1019.

    Article  CAS  Google Scholar 

  18. Van Eyk CL, Richards RI. Dynamic mutations: where are they now? In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/ Springer Science+Business Media, 2012:55–77.

    Google Scholar 

  19. Bauer PO, Nukina N. The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies. J Neurochem 2009; 110:1737–1765.

    Article  CAS  Google Scholar 

  20. Polling S, Hill AF, Hatters DM. Polyglutamine aggregation in Huntington and related diseases. In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/Springer Science+Business Media, 2012:125–140.

    Chapter  Google Scholar 

  21. Robertson AL, Bottomley SP. Molecular pathways to polyglutamine aggregation. In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/Springer Science+Business Media, 2012:115–124.

    Chapter  Google Scholar 

  22. Moseley ML, Zu T, Ikeda Y et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet 2006; 38:758–769.

    Article  CAS  Google Scholar 

  23. Wilburn B, Rudnicki DD, Zhao J et al. An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington’s disease-like 2 mice. Neuron 2011; 70:427–440.

    Article  CAS  Google Scholar 

  24. Waldvogel H, Thu D, Hogg V et al. Selective neurodegeneration, neuropathology and symptom profiles in Huntington’s disease. In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/Springer Science+Business Media, 2012:141–152.

    Chapter  Google Scholar 

  25. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms andpotential therapeutical targets in Huntington’s disease. Physiol Rev 2010; 90:905–981.

    Article  CAS  Google Scholar 

  26. Raymond LA, André VM, Cepeda C et al. Pathophysiology of Huntington’s disease: time-dependent alterations in synaptic and receptor function. Neuroscience. 2011; 198:252–273.

    Article  CAS  Google Scholar 

  27. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011; 10:83–98.

    Article  CAS  Google Scholar 

  28. Zajac JD, Fui MNT. Kennedy’s disease: clinical significance of tandem repeats in the androgen receptor. In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/Springer Science+Business Media, 2012:153–168.

    Chapter  Google Scholar 

  29. Zu T, Gibbens B, Doty NS et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci USA 2011; 108:260–265.

    Article  CAS  Google Scholar 

  30. Pearson CE. Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities! PLoS Genet 2011; 7(3):e1002018.

    Article  CAS  Google Scholar 

  31. Messaed C, Rouleau GA. Molecular mechanisms underlying polyalanine diseases. Neurobiol Dis 2009; 34:397–405.

    Article  CAS  Google Scholar 

  32. Shoubridge C, Gecz J. Polyalanine tract disorders and neurocognitive phenotypes. In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/Springer Science+Business Media, 2012:185–204.

    Chapter  Google Scholar 

  33. Brouwer JR, Willemsen R, Oostra BA. Microsatellite repeat instability and neurological disease. Bioessays 2009; 31:71–83.

    Article  CAS  Google Scholar 

  34. Kumari D, Usdin K. Chromatin remodeling in the noncoding repeat expansion diseases. J Biol Chem 2009; 284:7413–7417.

    Article  CAS  Google Scholar 

  35. Schmucker S, Puccio H. Understanding the molecular mechanisms of Friedreich’s ataxia to develop therapeutic approaches. Hum Mol Genet 2010; 19: R103–R110.

    Article  CAS  Google Scholar 

  36. Loesch D, Hagerman R. Unstable mutations in the FMR1 gene and the phenotypes. In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/Springer Science+Business Media, 2012:78–114.

    Chapter  Google Scholar 

  37. Corben LA, Georgiou-Karistianis N, Bradshaw JL. Characterisingtheneuropathologyandneurobehavioural phenotype in Friedreich ataxia: A systematic review. In: Hannan AJ, ed. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease. Austin/New York: Landes Bioscience/Springer Science+Business Media, 2012:169–184.

    Chapter  Google Scholar 

  38. Li LB, Bonini NM. Roles of trinucleotide-repeat RNA in neurological disease and degeneration. Trends Neurosci 2010; 33:292–298.

    Article  CAS  Google Scholar 

  39. Nakamori M, Thornton C. Epigenetic changes andnoncoding expanded repeats. NeurobiolDis 2010; 39:21–27.

    CAS  Google Scholar 

  40. Todd PK, Paulson HL. RNA-mediated neurodegeneration in repeat expansion disorders. Ann Neurol 2010; 67:291–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Fondon JW III, Garner HR. Molecular origins of rapid and continuous morphological evolution. Proc Natl Acad Sci USA 2004; 101:18058–18063.

    Article  CAS  Google Scholar 

  42. Gerber HP, Scipel K, Georgiev O et al. Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 1994; 263:808–881.

    Article  CAS  Google Scholar 

  43. Faux NG, Huttley GA, Mahmood K et al. RCPdb: An evolutionary classification and codon usage database for repeat-containing proteins. Genome Res. 2007; 17:1118–1127.

    Article  CAS  Google Scholar 

  44. Matsushima N, Tanaka T, Kretsinger RH. Non-globular structures of tandem repeats in proteins. Protein Pept Lett 2009; 16:1297–1322.

    Article  CAS  Google Scholar 

  45. Riley DE, Krieger JN. Embryonic nervous system genes predominate in searches for dinucleotide simple sequence repeats flanked by conserved sequences. Gene 2009; 429:74–79.

    Article  CAS  Google Scholar 

  46. Hammock EAD, Young LJ. Microsatellite instability generates diversity in brain and sociobehavioral traits. Science 2005; 308:1630–1634.

    Article  CAS  Google Scholar 

  47. Rubinsztein DC, Amos B, Cooper G. Microsatellite and trinucleotide-repeat evolution: evidence for mutational bias and different rates of evolution in different lineages. Philos Trans R Soc Lond B Biol Sci 1999; 354:1095–1099.

    Article  CAS  Google Scholar 

  48. Zeitlin S, Liu JP, Chapman DL et al. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet 1995; 11:155–163.

    Article  CAS  Google Scholar 

  49. Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet 2000; 26:300–306.

    Article  CAS  Google Scholar 

  50. Zheng S, Clabough EB, Sarkar S et al. Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice. PLoS Genet 2010; 6(2):e1000838.

    Article  Google Scholar 

  51. Manolio TA, Collins FS, Cox NJ et al. Finding the missing heritability of complex diseases. Nature 2009; 461:747–753.

    Article  CAS  Google Scholar 

  52. Singleton AB, Hardy J, Traynor BJ et al. Towards a complete resolution of the genetic architecture of disease. Trends Genet 2011; 26:438–442.

    Article  Google Scholar 

  53. Elden AC, Kim HJ, Hart MP et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 2010; 466:1069–1075.

    Article  CAS  Google Scholar 

  54. Dejesus-Hernandez M, Mackenzie IR, Boeve BF et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-Linked FTD and ALS. Neuron 2011; 72:245–256.

    Article  CAS  Google Scholar 

  55. Renton AE, Majounie E, Waite A et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72:257–268.

    Article  CAS  Google Scholar 

  56. Gonitel R, Moffitt H, Sathasivam K et al. DNA instability in postmitotic neurons. Proc Natl Acad Sci USA 2008; 105:3467–3472.

    Article  CAS  Google Scholar 

  57. Haberman Y, Amariglio N, Rechavi G et al. Trinucleotide repeats are prevalent among cancer-related genes. Trends Genet 2008; 24:14–18.

    Article  CAS  Google Scholar 

  58. Vinces MD, Legendre M, Caldara M et al. Unstable tandem repeats in promoters confer transcriptional evolvability. Science 2009; 324:1213–1216.

    Article  CAS  Google Scholar 

  59. Gemayel R, Vinces MD, Legendre M et al. Variable tandem repeats accelerate evolution of coding and regulatory sequences. Annu Rev Genet 2010; 44:445–477.

    Article  CAS  Google Scholar 

  60. Feinberg AP, Irizarry RA. Evolution in health and medicine Sackler colloquium: Stochastic epigenetic variation as a driving force of development, evolutionary adaptation and disease. Proc Natl Acad Sci USA 2010; 107 Suppl 1:1757–1764.

    Article  Google Scholar 

  61. O’Dushlaine CT, Shields DC. Marked variation in predicted and observed variability of tandem repeat loci across the human genome. BMC Genomics 2008; 9:175.

    Article  Google Scholar 

  62. Hannan AJ. TRPing up the genome: Tandem repeat polymorphisms as dynamic sources of genetic variability in health and disease. Discov Med 2010; 10:314–321.

    PubMed  Google Scholar 

  63. Baillie JK, Barnett MW, Upton KR et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature 2011; 479:534–537.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Florey Neuroscience Institutes, Melbourne Brain Centre, University of Melbourne, Parkville, Australia

    Anthony J. Hannan

Authors
  1. Anthony J. Hannan
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Florey Neuroscience Institutes, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia

    Anthony J. Hannan Phd

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Hannan, A.J. (2012). Tandem Repeat Polymorphisms. In: Hannan, A.J. (eds) Tandem Repeat Polymorphisms. Advances in Experimental Medicine and Biology. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5434-2_1

Download citation

Publish with us

Policies and ethics

Search

Navigation