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Mathematical Modelling of Mycobacterium tuberculosis VNTR Loci Estimates a Very Slow Mutation Rate for the Repeats

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Abstract

Minisatellites are highly variable tandem repeats used for over 20 years in humans for DNA fingerprinting. In prokaryotes fingerprinting techniques exploiting VNTR (variable number of tandem repeats) polymorphisms have become widely used recently in bacterial typing. However although many investigations into the mechanisms underlying minisatellite variation in humans have been performed, relatively little is known about the processes that mediate bacterial minisatellite polymorphism. An understanding of this is important since it will influence how the results from VNTR experiments are interpreted. The minisatellites of Mycobacterium tuberculosis are well characterized since they are some of the few polymorphic loci in what is otherwise a very homogeneous organism. Using VNTR results from a well-defined and characterized set of M. tuberculosis strains we show that the repeats at a locus are likely to evolve by stepwise contraction or expansion in the number of repeats. A stochastic continuous-time population mathematical model was developed to simulate the evolution of the repeats. This allowed estimation of the tendency of the repeats to increase or decrease and the rate at which they change. The majority of loci tend to lose rather than gain repeats. All of the loci mutate extremely slowly, with an average rate of 2.3 × 10−8, which is 350 times slower than that of a set of VNTR repeats with similar diversity observed experimentally in Escherichia coli. This suggests that the VNTR profile of a strain of M. tuberculosis will be indicative of its clonal lineage and will be unlikely to vary in epidemiologically-related strains.

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References

  • Adams JL (1991) A computer experiment to evaluate regression strategies. Proc Comput Sect Am Stat Assoc 55–62

  • Armitage P, Berry G, Matthews JNS (2002) Statistical methods in medical research. Blackwell

  • Arnold C, Thorne N, Underwood A, Baster K, Gharbia S (2006) Evolution of short sequence repeats in Mycobacterium tuberculosis. FEMS Microbiol Lett 256:340–346

    Article  PubMed  CAS  Google Scholar 

  • Ayares D, Chekuri L, Song K, Kucherlapati R (1986) Sequence homology requirements for intermolecular recombination in mammalian cells. Proc Natl Acad Sci USA 83:5199–5203

    Google Scholar 

  • Bartlett S (1960) Stochastic population models in ecology and epidemiology Methuen, London

    Google Scholar 

  • Becker N (1989) Analysis of infectious disease data. Chapman and Hall, London

    Google Scholar 

  • Bichara M, Wagner J, Lambert I (2006) Mechanisms of tandem repeat instability in bacteria. Mutat Res 598:144–163

    PubMed  CAS  Google Scholar 

  • Brosch R, Gordon SV, Marmiesse M, Brodin P, Buchrieser C, Eiglmeier K, Garnier T, Gutierrez C, Hewinson G, Kremer K, Parsons LM, Pym AS, Samper S, van Soolingen D, Cole ST (2002) A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA 99:3684–3689

    Article  PubMed  CAS  Google Scholar 

  • Bzymek M, Lovett S (2001) Instability of repetitive DNA sequences: the role of replication in multiple mechanisms. Proc Natl Acad Sci USA 98:8319–8325

    Google Scholar 

  • De Bolle X, Bayliss CD, Field D, van de Ven T, Saunders NJ, Hood DW, Moxon ER (2000) The length of a tetranucleotide repeat tract in Haemophilus influenzae determines the phase variation rate of a gene with homology to type III DNA methyltransferases. Mol Microbiol 35:211–222

    Article  PubMed  Google Scholar 

  • Durret R, Kruglyak S (1999) A new stochastic model of microsatellite evolution. J Appl Probab 36:621–631

    Article  Google Scholar 

  • Filliol I, Driscoll JR, Van Soolingen D, Kreiswirth BN, Kremer K, Valetudie G, Anh DD, Barlow R, Banerjee D, Bifani PJ, Brudey K, Cataldi A, Cooksey RC, Cousins DV, Dale JW, Dellagostin OA, Drobniewski F, Engelmann G, Ferdinand S, Gascoyne-Binzi D, Gordon M, Gutierrez MC, Haas WH, Heersma H, Kallenius G, Kassa-Kelembho E, Koivula T, Ly HM, Makristathis A, Mammina C, Martin G, Mostrom P, Mokrousov I, Narbonne V, Narvskaya O, Nastasi A, Niobe-Eyangoh SN, Pape JW, Rasolofo-Razanamparany V, Ridell M, Rossetti ML, Stauffer F, Suffys PN, Takiff H, Texier-Maugein J, Vincent V, De Waard JH, Sola C, Rastogi N (2002) Global distribution of Mycobacterium tuberculosis spoligotypes. Emerg Infect Dis 8:1347–1349

  • Frothingham R, Meeker-O’Connell W (1998) Genetic diversity in the Mycobacterium tuberculosis complex based on variable numbers of tandem DNA repeats. Microbiology (Reading, England) 144(Pt 5):1189–1196

    CAS  Google Scholar 

  • Gutcker M, Mathema B, Soini H, Shashkina E, Kreiswirth B, Graviss E, Musser J (2006) Single-nucleotide polymorphism-based population genetic analysis of Mycobacterium tuberculosis strains from 4 geographic sites. J Infect Dis 193:121–128

    Article  PubMed  CAS  Google Scholar 

  • Harding RM, Boyce AJ, Clegg JB (1992) The evolution of tandemly repetitive DNA: recombination rules. Genetics 132:847–859

    PubMed  CAS  Google Scholar 

  • Hayashi T, Makino K, Ohnishi M, Kurokawa K, Ishii K, Yokoyama K, Han CG, Ohtsubo E, Nakayama K, Murata T, Tanaka M, Tobe T, Iida T, Takami H, Honda T, Sasakawa C, Ogasawara N, Yasunaga T, Kuhara S, Shiba T, Hattori M, Shinagawa H (2001) Complete genome sequence of enterohemorrhagic Escherichia coli O157:H7 and genomic comparison with a laboratory strain K-12. DNA Res 8:11–22

    Article  PubMed  CAS  Google Scholar 

  • Hughes A, Friedman R, Murray M (2002) Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis. Emerg Infect Dis 8:1342–1346

    PubMed  CAS  Google Scholar 

  • Jeffreys AJ, Wilson V, Thein SL (1985a) Hypervariable ‘minisatellite’ regions in human DNA. Nature 314:67–73

    Article  PubMed  CAS  Google Scholar 

  • Jeffreys AJ, Wilson V, Thein SL (1985b) Individual-specific ‘fingerprints’ of human DNA. Nature 316:76–79

    Article  PubMed  CAS  Google Scholar 

  • Kato-Maeda M, Bifani P, Kreiswirth B, Small P (2001) The nature and consequence of genetic variability within Mycobacterium tuberculosis. J Clin Invest 107:533–537

    Article  PubMed  CAS  Google Scholar 

  • Kokoska RJ, Stefanovic L, Tran HT, Resnick MA, Gordenin DA, Petes TD (1998) Destabilization of yeast micro- and minisatellite DNA sequences by mutations affecting a nuclease involved in Okazaki fragment processing (rad27) and DNA polymerase delta (pol3-t). Mol Cell Biol 18:2779–2788

    PubMed  CAS  Google Scholar 

  • Lindstedt BA (2005) Multiple-locus variable number tandem repeats analysis for genetic fingerprinting of pathogenic bacteria. Electrophoresis 26:2567–2582

    Article  PubMed  CAS  Google Scholar 

  • Linhart H, Zucchini W (1986) Model selection. John Wiley, New York

    Google Scholar 

  • Romero D, Palacios R (1997) Gene amplification and genomic plasticity in prokaryotes. Ann Rev Genet 31:91–111

    Article  PubMed  CAS  Google Scholar 

  • Rubnitz J, Subramani S (1984) The minimum amount of homology required for homologous recombination in mammalian cells. Mol Cell Biol 4:2253–2258

    PubMed  CAS  Google Scholar 

  • Savine E, Warren RM, van der Spuy GD, Beyers N, van Helden PD, Locht C, Supply P (2002) Stability of variable-number tandem repeats of mycobacterial interspersed repetitive units from 12 loci in serial isolates of Mycobacterium tuberculosis. J Clin Microbiol 40:4561–4566

    Article  PubMed  CAS  Google Scholar 

  • Smith NH, Dale J, Inwald J, Palmer S, Gordon SV, Hewinson RG, Smith JM (2003) The population structure of Mycobacterium bovis in Great Britain: clonal expansion. Proc Natl Acad Sci USA 100:15271–15275

    Article  PubMed  CAS  Google Scholar 

  • Sreevatsan S, Pan X, Stockbauer KE, Connell ND, Kreiswirth BN, Whittam TS, Musser JM (1997) Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proc Natl Acad Sci USA 94:9869–9874

    Article  PubMed  CAS  Google Scholar 

  • Supply P, Mazars E, Lesjean S, Vincent V, Gicquel B, Locht C (2000) Variable human minisatellite-like regions in the Mycobacterium tuberculosis genome. Mol Microbiol 36:762–771

    Article  PubMed  CAS  Google Scholar 

  • Supply P, Warren RM, Banuls AL, Lesjean S, Van Der Spuy GD, Lewis LA, Tibayrenc M, Van Helden PD, Locht C (2003) Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area. Mol Microbiol 47:529–538

    Article  PubMed  CAS  Google Scholar 

  • Supply P, Allix C, Lesjean S, Cardoso-Oelemann M, Rusch-Gerdes S, Willery E, Savine E, de Haas P, van Deutekom H, Roring S, Bifani P, Kurepina N, Kreiswirth B, Sola C, Rastogi N, Vatin V, Gutierrez MC, Fauville M, Niemann S, Skuce R, Kremer K, Locht C, van Soolingen D (2006) Proposal for standardization of optimized mycobacterial interspersed repetitive unit-variable-number tandem repeat typing of Mycobacterium tuberculosis. J Clin Microbiol 44:4498–4510

    Google Scholar 

  • Thorne N, Underwood A, Gharbia S, Arnold C (2007) Evolutionary clues from comparative analysis of Mycobacterium tuberculosis variable-number tandem repeat sequences within genetic families. Infect Genet Evol 7:239–246

    Article  PubMed  CAS  Google Scholar 

  • van Belkum A (1999) Short sequence repeats in microbial pathogenesis and evolution. Cell Mol Life Sci 56:729–734

    Article  PubMed  Google Scholar 

  • van Embden J, van Gorkom T, Kremer K, Jansen R, van Der Zeijst B, Schouls L (2000) Genetic variation and evolutionary origin of the direct repeat locus of Mycobacterium tuberculosis complex bacteria. J Bacteriol 182:2393–2401

    Article  PubMed  Google Scholar 

  • Vergnaud G, Denoeud F (2000) Minisatellites: mutability and genome architecture. Genome Res 10:899–907

    Article  PubMed  CAS  Google Scholar 

  • Vogler A, Keys C, Nemoto Y, Colman R, Jay Z, Keim P (2006) Effect of repeat copy number on variable-number tandem repeat mutations in Escherichia coli O157:H7. J Bacteriol 188:4253–4263

    Article  PubMed  CAS  Google Scholar 

  • Vogler A, Keys C, Allender C, Bailey I, Girard J, Pearson T, Smith K, Wagner D, Keim P (2007) Mutations, mutation rates, and evolution at the hypervariable VNTR loci of Yersinia pestis. Mutat Res 616:145–158

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported in part by a PhD studentship funded by Biotage AB.

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Authors and Affiliations

  1. Statistics Unit, Statistics, Modelling and Bioinformatics Department, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London, NW9 5EQ, UK

    Andrew Grant

  2. Applied and Functional Genomics Unit, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London, NW9 5EQ, UK

    Catherine Arnold & Saheer Gharbia

  3. Molecular Identification Services Unit, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London, NW9 5EQ, UK

    Nicola Thorne

  4. Bioinformatics Unit, Statistics, Modelling and Bioinformatics Department, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London, NW9 5EQ, UK

    Anthony Underwood

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  1. Andrew Grant
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  2. Catherine Arnold
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  3. Nicola Thorne
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  4. Saheer Gharbia
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  5. Anthony Underwood
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Correspondence to Anthony Underwood.

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Grant, A., Arnold, C., Thorne, N. et al. Mathematical Modelling of Mycobacterium tuberculosis VNTR Loci Estimates a Very Slow Mutation Rate for the Repeats. J Mol Evol 66, 565–574 (2008). https://doi.org/10.1007/s00239-008-9104-6

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  • DOI: https://doi.org/10.1007/s00239-008-9104-6

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