Nature Genetics
7, 525 - 530 (1994)
doi:10.1038/ng0894-525
Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalenceDavid C. Rubinsztein1, 7, William Amos2, Jayne Leggo1, Sandy Goodburn1, Rajkumar S. Ramesar3, John Old4, Ronald Bontrop5, Robert McMahon1, David E. Barton1
& Malcolm A. Ferguson-Smith1, 6
1East Anglian Regional Genetics Service Molecular Genetics Laboratory and Department of Clinical Genetics, Box 158, Addenbrooke's NHS Trust, Hills Road, Cambridge CB2 2QQ, UK
2University of Cambridge Department of Genetics, Cambridge CB2 3EH, UK
3Department of Human Genetics, University of Cape Town, Observatory, 7925, South Africa
4Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK
5Medical Biological Laboratories TNO, PO Box 5815HV, 2280, Rijswijk, The Netherlands
6University of Cambridge Department of Pathology, Cambridge CB2 1QP, UK
7Correspondence should be addressed to D.C.R. 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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