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Single Amino Acid and Trinucleotide Repeats

Function and Evolution
  • Noel Faux
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB)

Abstract

The most well known effect of single amino acid repeat expansion, beyond a certain threshold, is the development of a specific disease, depending on the protein in which the expansion has occurred. For example, the expansion of the glutamine repeat in huntingtin leads to the debilitating neurodegenerative disease, Huntington’s disease. Similarly, there are a range of other disorders caused by trinucleotide repeat expansions encoding polyglutamine or polyalanine tracts. The age of onset of the polyglutamine-induced neurodegenerative diseases is usually negatively correlated with the length of expanded CAG/glutamine repeat. However, recent studies have given evidence that single amino acid repeats may also play critical roles in normal protein function and that changes in the length of single amino acid repeats is likely to play a beneficial role in evolution. This chapter will look at the prevalence, function and possible role single amino acid repeats have in evolution and other biological processes.

Keywords

Single Amino Acid Codon Position Trinucleotide Repeat Spinocerebellar Ataxia Amino Acid Repeat 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Lander ES, Linton LM, Birren B et al. Initial sequencing and analysis of the human genome. Nature 2001; 409(6822):860–921.CrossRefGoogle Scholar
  2. 2.
    Cooper DN. Nature encyclopedia of the human genome. Nature Publ Group; 2003.Google Scholar
  3. 3.
    Karlin S, Burge C. Trinucleotide repeats and long homopeptides in genes and proteins associated with nervous system disease and development. Proc Natl Acad Sci U S A 1996; 93(4):1560–1565.CrossRefGoogle Scholar
  4. 4.
    Green H, Wang N. Codon reiteration and the evolution of proteins. Proc Natl Acad Sci U S A 1994; 91(10):4298–4302.CrossRefGoogle Scholar
  5. 5.
    Faux NG, Bottomley SP, Lesk AM et al. Functional insights from the distribution and role of homopeptide repeat-containing proteins. Genome Res 2005; 15(4):537–551.CrossRefGoogle Scholar
  6. 6.
    Jorda J, Kajava AV. Protein homorepeats sequences, structures, evolution, and functions. Adv Protein Chem Struct Biol 2010; 79:59–88.CrossRefGoogle Scholar
  7. 7.
    Huntley MA, Golding GB. Neurological proteins are not enriched for repetitive sequences. Genetics 2004; 166(3):1141–1154.CrossRefGoogle Scholar
  8. 8.
    Karlin S, Brocchieri L, Bergman A et al. Amino acid runs in eukaryotic proteomes and disease associations. Proc Natl Acad Sci U S A 2002; 99(1):333–338.CrossRefGoogle Scholar
  9. 9.
    Albà MM, Guigó R. Comparative analysis of amino acid repeats in rodents and humans. Genome Res 2004; 14(4):549–554.CrossRefGoogle Scholar
  10. 10.
    Mar Alba M, Santibanez-Koref MF, Hancock JM. Amino acid reiterations in yeast are overrepresented in particular classes of proteins and show evidence of a slippage-like mutational process. J Mol Evol 1999; 49(6):789–797.CrossRefGoogle Scholar
  11. 11.
    Holtzman JL. Amyloid-β vaccination for Alzheimer’s dementia. The Lancet 2008; 372(9647):1381–1381.CrossRefGoogle Scholar
  12. 12.
    Kreil D, Kreil G. Asparagine repeats are rare in mammalian proteins. Trends Biochem Sci 2000; 25(6):270–271.CrossRefGoogle Scholar
  13. 13.
    Sumiyama K, Washio-Watanabe K, Saitou N et al. Class III POU genes: generation of homopolymeric amino acid repeats under GC pressure in mammals. J Mol Evol 1996; 43(3):170–178.CrossRefGoogle Scholar
  14. 14.
    Nakachi Y, Hayakawa T, Oota H et al. Nucleotide compositional constraints on genomes generate alanine-,glycine-, and proline-rich structures in transcription factors. Mol Biol Evol 1997; 14(10): 1042–1049.CrossRefGoogle Scholar
  15. 15.
    Cocquet J, de Baere E, Caburet S et al. Compositional biases and polyalanine runs in humans. Genetics 2003; 165(3):1613–1617.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Veitia R. Amino acids runs and genomic compositional biases in vertebrates. Genomics 2004; 83(3):502–507.CrossRefGoogle Scholar
  17. 17.
    Bernardi G. The compositional evolution of vertebrate genomes. Gene 2000;259(1–2):31–43.CrossRefGoogle Scholar
  18. 18.
    Caburet S, Vaiman D, Veitia R. A genomic basis for the evolution of vertebrate transcription factors containing amino acid runs. Genetics 2004; 167(4):1813–1820.CrossRefGoogle Scholar
  19. 19.
    Hancock J, Worthey E, Santibanez-Koref M. Arole for selection inregulatingthe evolutionary emergence of disease-causing and other coding CAGrepeats inhumans and mice. Mol Biol Evol 2001; 18(6):1014–1023.CrossRefGoogle Scholar
  20. 20.
    Hancock JM, Simon M. Simple sequence repeats in proteins and their significance for network evolution. Gene 2005; 345(1): 113–118.CrossRefGoogle Scholar
  21. 21.
    Ogasawara M, Imanishi T, Moriwaki K et al. Length variation of CAG/CAA triplet repeats in 50 genes among 16 inbred mouse strains. Gene 2005; 349:107–119.CrossRefGoogle Scholar
  22. 22.
    Faux N, Huttley G, Mahmood K et al. RCPdb: An evolutionary classification and codon usage database for repeat-containing proteins. Genome Res 2007; 17(7):1118–1127.CrossRefGoogle Scholar
  23. 23.
    Alba MM, Santibanez-Koref MF, Hancock JM. Conservation of polyglutamine tract size between mice and humans depends on codon interruption. Mol Biol Evol 1999; 16(11): 1641–1644.CrossRefGoogle Scholar
  24. 24.
    Alba MM, Santibanez-Koref MF, Hancock JM. The comparative genomics of polyglutamine repeats: extreme differences in the codon organization of repeat-encoding regions between mammals and Drosophila. J Mol Evol 2001; 52(3):249–259.CrossRefGoogle Scholar
  25. 25.
    Oma Y, Kino Y, Sasagawa N et al. Intracellular localization of homopolymeric amino acid-containing proteins expressed in mammalian cells. J Biol Chem 2004; 279(20):21217–21222.CrossRefGoogle Scholar
  26. 26.
    Dorsman J, Pepers B, Langenberg D et al. Strong aggregation and increased toxicity of polyleucine over polyglutamine stretches in mammalian cells. Hum Mol Genet 2002; 11(13):1487–1496.CrossRefGoogle Scholar
  27. 27.
    Waldvogel HJ, 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 29.
    Woods KS, Cundall M, Turton J et al. Over-and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet 2005; 76(5):833–849.CrossRefGoogle Scholar
  30. 30.
    Brito M, Malta-Vacas J, Carmona B et al. Polyglycine expansions in eRF3/GSPTl are associated with gastric cancer susceptibility. Carcinogenesis 2005; 26(12):2046–2049.CrossRefGoogle Scholar
  31. 31.
    McKusick-Nathans Institute for Genetic Medicine J. Online Mendelian Inheritance in Man, OMIM (TM).Google Scholar
  32. 32.
    Peri S, Navarro J, Kristiansen T et al. Human protein reference database as a discovery resource for proteomics. Nucleic Acids Res 2004; 32(Database issue):D497–D501.CrossRefGoogle Scholar
  33. 33.
    Brown LY, Odent S, David V et al. Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Hum Mol Genet 2001; 10(8):791–796.CrossRefGoogle Scholar
  34. 34.
    Rudnicki DD, Holmes SE, Lin MW et al. Huntington’s disease-like 2 is associated with CUGrepeat-containing RNA foci. Ann Neurol 2007; 61(3):272–282.CrossRefGoogle Scholar
  35. 35.
    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(3):427–440.CrossRefGoogle Scholar
  36. 36.
    Shoubridge C, Gecz J. 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.CrossRefGoogle Scholar
  37. 37.
    Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000; 23:217–247.CrossRefGoogle Scholar
  38. 38.
    Wexler NS, Lorimer J, Porter J et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci U S A 2004; 101(10):3498–3503.CrossRefGoogle Scholar
  39. 39.
    van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ. Delaying the onset of Huntington’s in mice. Nature 2000; 404(6779):721–722.CrossRefGoogle Scholar
  40. 40.
    Mitchell PJ, Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science 1989; 245(4916):371–378.CrossRefGoogle Scholar
  41. 41.
    Perutz MF, Johnson T, Suzuki M, Finch JT. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci U S A 1994; 91(12):5355–5358.CrossRefGoogle Scholar
  42. 42.
    Kazemi-Esfarjani P, Trifiro MA, Pinsky L. Evidence for arepressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance forthe (CAG)n-expanded neuronopathies. Hum Mol Genet 1995; 4(4):523–527.CrossRefGoogle Scholar
  43. 43.
    Galant R, Carroll SB. Evolution of a transcriptional repression domain in an insect Hox protein. Nature 2002; 415(6874):910–913.CrossRefGoogle Scholar
  44. 44.
    Gerber H-P, Scipel K, Georgiev O et al. Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 1994; 263(5148):808–811.CrossRefGoogle Scholar
  45. 45.
    Ren R, Mayer B, Cicchetti P et al. Identification of a ten-amino acid proline-rich SH3 binding site. Science 1993; 259(5098):1157–1161.CrossRefGoogle Scholar
  46. 46.
    Liu YF, Deth RC, Devys D. SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes. J Biol Chem 1997; 272(13):8121–8124.CrossRefGoogle Scholar
  47. 47.
    Sittler A, Wälter S, Wedemeyer N et al. SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol Cell 1998; 2(4):427–436.CrossRefGoogle Scholar
  48. 48.
    Inoue K, Keegstra K. A polyglycine stretch is necessary for proper targeting of the protein translocation channel precursor to the outer envelope membrane of chloroplasts. Plant J 2003; 34(5):661–669.CrossRefGoogle Scholar
  49. 49.
    Calnan B, Tidor B, Biancalana S et al. Arginine-mediated RNA recognition: the arginine fork. Science 1991; 252(5010):1167–1171.CrossRefGoogle Scholar
  50. 50.
    Nam YS, Petrovic A, Jeong KS et al. Exchange of the basic domain of human immunodeficiency virus type 1 Rev for a polyarginine stretch expands the RNA binding specificity, and a minimal arginine cluster is required for optimal RRE RNA binding affinity, nuclear accumulation, and trans-activation. J Virol 2001;75(6):2957–2971.CrossRefGoogle Scholar
  51. 51.
    Uritani M, Nakano K, Aoki Y et al. Polyamino acids that inhibit the interaction of yeast translational elongation factor-3 (EF-3) with ribosomes. J Biochem (Tokyo) 1994; 115(5):820–824.CrossRefGoogle Scholar
  52. 52.
    Shimohata T, Nakajima T, Yamada M et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 2000; 26(l):29–36.CrossRefGoogle Scholar
  53. 53.
    Fondon J, Garner H. Molecular origins of rapid and continuous morphological evolution. Proc Natl Acad Sci U S A 2004; 101(52): 18058–18063.CrossRefGoogle Scholar
  54. 54.
    Ellegren H. Microsatellite mutations in the germline: implications for evolutionary inference. Trends Genet 2000; 16(12):551–558.CrossRefGoogle Scholar
  55. 55.
    Ellegren H. Microsatellites: simple sequences with complex evolution. Nat Rev Genet 2004; 5(6):435–445.CrossRefGoogle Scholar
  56. 56.
    Cleary J, Pearson C. The contribution of cis-elements to disease-associated repeat instability: clinical and experimental evidence. Cytogenet Genome Res 2003; 100(1–4): 25–55.CrossRefGoogle Scholar
  57. 57.
    Robertson KD. DNA methylation and human disease. Nat Rev Genet 2005; 6(8):597–610.CrossRefGoogle Scholar
  58. 58.
    Gutierrez JC, Callejas S, Borniquel S et al. DNA methylation in ciliates: implications in differentiation processes. Int Microbiol 2000; 3(3): 139–146.PubMedGoogle Scholar
  59. 59.
    Gowher H, Leismann O, Jeltsch A. DNA of Drosophila melanogaster contains 5-methylcytosine. EMBO J 2000; 19(24):6918–6923.CrossRefGoogle Scholar
  60. 60.
    Lyko F, Ramsahoye BH, Jaenisch R. DNA methylation in Drosophila melanogaster. Nature 2000; 408(6812):538–540.CrossRefGoogle Scholar
  61. 61.
    Marhold J, Rothe N, Pauli A et al. Conservation of DNA methylation in dipteran insects. Insect Mol Biol 2004; 13(2):117–123.CrossRefGoogle Scholar
  62. 62.
    Hattman S, Kenny C, Berger L et al. Comparative study of DNA methylation in three unicellular eucaryotes. J Bacteriol 1978; 135(3):1156–1157.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Vanyushin BF. Enzymatic DNA methylation is an epigenetic control for genetic functions of the cell. Biochemistry (Mosc) 2005; 70(5):488–499.CrossRefGoogle Scholar
  64. 64.
    Rogers SD, Rogers ME, Saunders G et al. Isolation of mutants sensitive to 2-aminopurine and alkylating agents and evidence for the role of DNA methylation in Penicillium chrysogenum. Curr Genet 1986; 10(7):557–560.CrossRefGoogle Scholar
  65. 65.
    Zhang X, Yazaki J, Sundaresan A et al. Genome-wide high-resolution mapping and functional analysis of DNA methylation in arabidopsis. Cell 2006; 126(6):1189–1201.CrossRefGoogle Scholar
  66. 66.
    Wang Y, Jorda M, Jones PL et al. Functional CpG methylation system in a social insect. Science 2006; 314(5799):645–647.CrossRefGoogle Scholar
  67. 67.
    Varriale A, Bernardi G. DNA methylation and body temperature in fishes. Gene 2006; 385:111–121.CrossRefGoogle Scholar
  68. 68.
    Varriale A, Bernardi G. DNA methylation in reptiles. Gene 2006;385:122–127.CrossRefGoogle Scholar
  69. 69.
    Steward N, Ito M, Yamaguchi Y et al. Periodic DNA methylation in maize nucleosomes and demethylation by environmental stress. J Biol Chem 2002; 277(40):37741–37746.CrossRefGoogle Scholar
  70. 70.
    Wada Y, Miyamoto K, Kusano T et al. Association between up-regulation of stress-responsive genes and hypomethylation of genomic DNA in tobacco plants. Mol Genet Genomics 2004; 271(6):658–666.CrossRefGoogle Scholar
  71. 71.
    O’Neill RJ, O’Neill MJ, Graves JA. Undermethylation associated with retroe lement activation and chromosome remodelling in an interspecific mammalian hybrid. Nature 1998; 393(6680):68–72.CrossRefGoogle Scholar
  72. 72.
    Ruden DM, Garfinkel MD, Xiao L et al. Epigenetic regulation of trinucleotide repeat expansions and contractions and the “biased embryos” hypothesis for rapid morphological evolution. Current Genomics 2005; 6:145–155.CrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Noel Faux
    • 1
    • 2
  1. 1.Mental Health Research InstituteThe University of MelbourneParkvilleAustralia
  2. 2.National Neuroscience FacilityCarltonAustralia

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