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Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence

Nature Genetics volume 7, pages 525–530 (1994)Cite this article

Abstract

Huntington's disease (HD) correlates with abnormal expansion in a block of CAG repeats in the Huntington's disease gene. We have investigated HD evolution by typing CAG alleles in several human populations and in a variety of primates. We find that human alleles have expanded from a shorter ancestral state and exhibit unusual asymmetric length distributions. Computer simulations are used to show that the human state can be derived readily from a primate ancestor, without the need to invoke natural selection. The key element is a simple length–dependent mutational bias towards longer alleles. Our model can explain a number of empirical observations, and predicts an ever–increasing incidence of HD.

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Authors and Affiliations

  1. East Anglian Regional Genetics Service Molecular Genetics Laboratory and Department of Clinical Genetics, Addenbrooke's NHS Trust, Box 158, Hills Road, Cambridge, CB2 2QQ, UK

    David C. Rubinsztein, Jayne Leggo, Sandy Goodburn, Robert McMahon, David E. Barton & Malcolm A. Ferguson-Smith

  2. Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK

    William Amos

  3. Department of Human Genetics, University of Cape Town, Observatory, 7925, South Africa

    Rajkumar S. Ramesar

  4. Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    John Old

  5. Medical Biological Laboratories TNO, PO Box 5815HV, 2280, Rijswijk, The Netherlands

    Ronald Bontrop

  6. Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK

    Malcolm A. Ferguson-Smith

Authors
  1. David C. Rubinsztein
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  2. William Amos
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  3. Jayne Leggo
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  4. Sandy Goodburn
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  5. Rajkumar S. Ramesar
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  6. John Old
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  7. Ronald Bontrop
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  8. Robert McMahon
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  9. David E. Barton
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  10. Malcolm A. Ferguson-Smith
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Rubinsztein, D., Amos, W., Leggo, J. et al. Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence. Nat Genet 7, 525–530 (1994). https://doi.org/10.1038/ng0894-525

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