© 1995 Oxford University Press
RESEARCH-ARTICLE |
Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum
1Molecular Biology Program 2Department of Mathematics, University of Southern California Los Angeles, CA, 90089 3The Molecular Neurogenetics Unit, Massachusetts General Hospital Boston, MA, 02129 4Department of Neurology, Boston University Medical School Boston MA, 02118, USA 5Association of Friends of Families with Huntington's Disease Maracaibo, Zulia, Venezuela 6Department of Neurology, Columbia University New York, NY, 10032, and Hereditary Disease Foundation 1427 7th St. Suite 2, Santa Monica, CA 90401, USA
*To whom correspondence be addressed
Revised June 2, 1995; Accepted June 2, 1995
The CAG triplet repeat region of the Huntington's disease gene was amplified in 923 single sperm from three affected and two normal individuals. Average-size alleles (15–18 repeats) showed only three contraction mutations among 475 sperm (0.6%). A 30 repeat normal allele showed an 11% mutation frequency. The mutation frequency of a 36 repeat intermediate allele was 53% with 8% of all gametes having expansions which brought the allele size into the HD disease range (38 repeats). Disease alleles (38–51 repeats) showed a very high mutation frequency (92–99%). As repeat number increased there was a marked elevation in the frequency of expansions, in the mean number of repeats added per expansion and the size of the largest observed expansion. Contraction frequencies also appeared to increase with allele size but decreased as repeat number exceeded 36. Our sperm typing data are of a discrete nature rather than consisting of smears of PCR product from pooled sperm. This allowed the observed mutation frequency spectra to be compared to the distribution calculated using discrete stochastic models based on current molecular ideas of the expansion process. An excellent fit was found when the model specified that a random number of repeats are added during the progression of the polymerase through the repeated region.
+Present address: Medical Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
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