Tandem Repeat Instability and Genome Evolution


Evolvability is the potential for a biological system to produce variation that can be acted upon by natural selection. Processes that promote selectable variation can facilitate adaptation to dynamic environments. Microsatellite repeats – sequences composed of repeated sets of up to nine nucleotides – provide one source of adaptive variation. Repeats mutate by the addition or loss of their unit nucleotide sequence, up to 100 000 times more frequently than point mutations. In a number of species, including humans, repeat mutations can cause disease (including neurological and skeletal disorders) as well as exert subtle and quantitative consequences on gene function, morphology, behaviour and life history traits. Understanding the underlying properties of repeat mutation – including causes and mechanisms – is critical for understanding trait variation, adaptation and a growing list of human disorders.

Key Concepts:

  • Recent discoveries in molecular genetics are challenging current dogma that claims independence between selection and mutation.

  • Tandem repeats in the genome are highly mutable, sometimes at frequencies of up to 100 000 times more than point mutations.

  • Nearly all aspects of DNA processing, and even transcription and stress, contribute to repeat mutation, making repeats important markers for genomic instability.

  • Microsatellite repeats encode their own mutability, thereby enabling local manipulation of mutation rates.

  • Changes in the lengths of tandem repeats can subtly and quantitatively modulate gene function, traits and disease.

  • Many genomic regions, including tandem repeats, mutate during cellular stress, suggesting that the genome is far more dynamic and susceptible to environmental processes than previously recognised.

Keywords: evolvability; stress‐induced mutagenesis; genome instability; tandem repeats; microsatellites; triplet repeat disorders; Hsp90 chaperone; genome evolution; natural selection


Albà MM, Santibáñez‐Koref MF and Hancock JM (1999) Conservation of polyglutamine tract size between mice and humans depends on codon interruption. Molecular Biology and Evolution 16: 1641–1644.

Albrecht AN, Kornak U, Boddrich A et al. (2004) A molecular pathogenesis for transcription factor associated poly‐alanine tract expansions. Human Molecular Genetics 13: 2351–2359.

Cairns J and Foster PL (1991) Adaptive reversion of a frameshift mutation in Escherichia coli. Genetics 128: 695–701.

Caporale LH (2003) Natural selection and the emergence of a mutation phenotype: an update of the evolutionary synthesis considering mechanisms that affect genome variation. Annual Review of Microbiology 57: 467–485.

Caporale LH (2006) The Implicit Genome. Oxford, New York: Oxford University Press. pp. xi, 385 p.

Carone BR, Fauquier L, Habib N et al. (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143: 1084–1096.

Chen G, Bradford WD, Seidel CW and Li R (2012) Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482: 246–250.

Chen LS, Tassone F, Sahota P and Hagerman PJ (2003) The (CGG)n repeat element within the 5′ untranslated region of the FMR1 message provides both positive and negative cis effects on in vivo translation of a downstream reporter. Human Molecular Genetics 12: 3067–3074.

Coyle S and Kroll E (2008) Starvation induces genomic rearrangements and starvation‐resilient phenotypes in yeast. Molecular Biology and Evolution 25: 310–318.

Davis AP and Capecchi MR (1996) A mutational analysis of the 5′ HoxD genes: dissection of genetic interactions during limb development in the mouse. Development 122: 1175–1185.

Di Marco S, Hel Z, Lachance C, Furneaux H and Radzioch D (2001) Polymorphism in the 3′‐untranslated region of TNFalpha mRNA impairs binding of the post‐transcriptional regulatory protein HuR to TNFalpha mRNA. Nucleic Acids Research 29: 863–871.

Elanko N, Sibbring JS, Metcalfe KA et al. (2001) A survey of TWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals. Human Mutation 18: 535–541.

Fondon JW 3rd, Mele GM, Brezinschek RI et al. (1998) Computerized polymorphic marker identification: experimental validation and a predicted human polymorphism catalog. Proceedings of the National Academy of Sciences of the USA 95: 7514–7519.

Fondon JWR and Garner HR (2004) Molecular origins of rapid and continuous morphological evolution. Proceedings of the National Academy of Sciences of the USA 101: 18058–18063.

Forche A, Abbey D, Pisithkul T et al. (2011) Stress alters rates and types of loss of heterozygosity in Candida albicans. MBio 2: e00129–11. doi:10.1128/mBio.00129‐11.

Galhardo RS, Hastings PJ and Rosenberg SM (2007) Mutation as a stress response and the regulation of evolvability. Critical Reviews in Biochemistry and Molecular Biology 42: 399–435.

Gerber HP, Seipel K, Georgiev O et al. (1994) Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 263: 808–811.

Gersappe A and Pintel DJ (1999) CA‐ and purine‐rich elements form a novel bipartite exon enhancer which governs inclusion of the minute virus of mice NS2‐specific exon in both singly and doubly spliced mRNAs. Molecular and Cellular Biology 19: 364–375.

Goodman FR, Mundlos S, Muragaki Y et al. (1997) Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. Proceedings of the National Academy of Sciences of the USA 94: 7458–7463.

Gorbunova V, Seluanov A, Dion V et al. (2003) Selectable system for monitoring the instability of CTG/CAG triplet repeats in mammalian cells. Molecular and Cellular Biology 23: 4485–4493.

Gould SJ (2002) The Structure of Evolutionary Theory. Cambridge: Belknap Press of Harvard University Press.

Hale CS, Herring WO, Shibuya H et al. (2000) Decreased growth in angus steers with a short TG‐microsatellite allele in the P1 promoter of the growth hormone receptor gene. Journal of Animal Science 78: 2099–2104.

Hall BG (1999) Transposable elements as activators of cryptic genes in E. coli. Genetica 107: 181–187.

Hammock EA and Young LJ (2005) Microsatellite instability generates diversity in brain and sociobehavioral traits. Science 308: 1630–1634.

Kelkar YD, Tyekucheva S, Chiaromonte F and Makova KD (2008) The genome‐wide determinants of human and chimpanzee microsatellite evolution. Genome Research 18: 30–38.

King DG (2012) Indirect selection of implicit mutation protocols. Annals of the New York Academy of Sciences 1267: 45–52.

Korol A, Rashkovetsky E, Iliadi K and Nevo E (2006) Drosophila flies in ‘Evolution Canyon’ as a model for incipient sympatric speciation. Proceedings of the National Academy of Sciences of the USA 103: 18184–18189.

Laidlaw J, Gelfand Y, Ng K‐W et al. (2007) Elevated basal slippage mutation rates among the Canidae. Journal of Heredity 98: 452–460.

Legendre M, Pochet N, Pak T and Verstrepen KJ (2007) Sequence‐based estimation of minisatellite and microsatellite repeat variability. Genome Research 17: 1787–1796.

Levy DD and Cebula TA (2001) Fidelity of replication of repetitive DNA in mutS and repair proficient E. coli. Mutation Research 474: 1–14.

Lopez Castel A, Cleary JD and Pearson CE (2010) Repeat instability as the basis for human diseases and as a potential target for therapy. Nature Reviews Molecular Cell Biology 11: 165–170.

Mancuso M, Sammarco MC and Grabczyk E (2010) Transposon Tn7 preferentially inserts into GAA*TTC triplet repeats under conditions conducive to Y*R*Y triplex formation. PloS One 5: e11121.

Mirkin SM (2007) Expandable DNA repeats and human disease. Nature 447: 932–940.

Mittelman D and Wilson JH (2010) Stress, genomes, and evolution. Cell Stress and Chaperones 15: 463–466.

Mrazek J, Guo X and Shah A (2007) Simple sequence repeats in prokaryotic genomes. Proceedings of the National Academy of Sciences of the USA 104: 8472–8477.

Mundlos S, Otto F, Mundlos C et al. (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89: 773–779.

Orr HT and Zoghbi HY (2007) Trinucleotide repeat disorders. Annual Reviews of Neuroscience 30: 575–621.

Rando OJ and Verstrepen KJ (2007) Timescales of genetic and epigenetic inheritance. Cell 128: 655–668.

Ritz D, Lim J, Reynolds CM, Poole LB and Beckwith J (2001) Conversion of a peroxiredoxin into a disulfide reductase by a triplet repeat expansion. Science 294: 158–160.

Rockman MV and Wray GA (2002) Abundant raw material for cis‐regulatory evolution in humans. Molecular Biology Evolution 19: 1991–2004.

Sawyer LA, Hennessy JM, Peixoto AA et al. (1997) Natural variation in a Drosophila clock gene and temperature compensation. Science 278: 2117–2120.

Scally A and Durbin R (2012) Revising the human mutation rate: implications for understanding human evolution. Nature Reviews Genetics 13: 745–753.

Streelman JT and Kocher TD (2002) Microsatellite variation associated with prolactin expression and growth of salt‐challenged tilapia. Physiological Genomics 9: 1–4.

Sun JX, Helgason A, Masson G et al. (2012) A direct characterization of human mutation based on microsatellites. Nature 44: 1161–1165.

Utsch B, Becker K, Brock D et al. (2002) A novel stable polyalanine [poly(A)] expansion in the HOXA13 gene associated with hand–foot–genital syndrome: proper function of poly(A)‐harbouring transcription factors depends on a critical repeat length? Human Genetics 110: 488–494.

Verstrepen KJ, Jansen A, Lewitter F and Fink GR (2005) Intragenic tandem repeats generate functional variability. Nature Genetics 37: 986–990.

Vinces MD, Legendre M, Caldara M, Hagihara M and Verstrepen KJ (2009) Unstable tandem repeats in promoters confer transcriptional evolvability. Science 324: 1213–1216.

Wren JD, Forgacs E, Fondon JW et al. (2000) Repeat polymorphisms within gene regions: phenotypic and evolutionary implications. American Journal of Human Genetics 67: 345–356.

Yant SR, Wu X, Huang Y et al. (2005) High‐resolution genome‐wide mapping of transposon integration in mammals. Molecular and Cellular Biology 25: 2085–2094.

Zhang Z and Saier MHJ (2009) A novel mechanism of transposon‐mediated gene activation. PLoS Genetics 5: e1000689.

Further Reading

Caporale LH (2012) Overview of the creative genome: effects of genome structure and sequence on the generation of variation and evolution. Annals of the New York Academy of Sciences 1267(1): 1–10.

Fonville NC, Ward RM and Mittelman D (2011) Stress‐induced modulators of repeat instability and genome evolution. Journal of Molecular Microbiology and Biotechnology 21(1–2): 36–44.

Hannan AJ (2010) TRPing up the genome: tandem repeat polymorphisms as dynamic sources of genetic variability in health and disease. Discovery Medicine 10(53): 314–321.

Mittelman D (ed.) (2013) Stress‐induced Mutagenesis. New York: Springer.

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Matthew Ward, R, and Mittelman, David(Feb 2013) Tandem Repeat Instability and Genome Evolution. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024945]