Single sperm analysis of the trinucleotide repeats in the Huntington’s disease gene: quantification of the mutation frequency spectrum
Abstract
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 (> or = 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.
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STR instability is known to occur in the germline, but tissue-specific somatic variation in STR tract length has been reported.
“STR instability is known to occur in the germline, but tissue-specific somatic variation in STR tract length has been reported (Leeflang et al., 1995; Telenius et al., 1994; Wohrle et al., 1993; Wong et al., 1995; Zhang et al., 1994).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Leeflang et al., 1995
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Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries
Sun, J. H., Zhou, L., Emerson, D. J., Phyo, S. A., Titus, K. R., Gong, W., Gilgenast, T. G., Beagan, J. A., Davidson, B. L., Tassone, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.005 · Cited by 249 · see citing works
“STR instability is known to occur in the germline, but tissuespecific somatic variation in STR tract length has been reported (Leeflang et al., 1995; Telenius et al., 1994; Wöhrle et al., 1993; Wong et al., 1995; Zhang et al., 1994).”
BackgroundBrock, G. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.6.1061 · Cited by 122 · see citing works
Takiyama, Y. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.7.1063 · Cited by 66 · see citing works
- Authors
- P.Leeflang, E., Zhang, L., Tavare, S., Hubert, R., Srinidhi, J., E.MacDonald, M., H.Myers, R., Young, M. D., S.Wexler, N., F.Gusella, J., & Arnheim, N.
- Affiliations
- Massachusetts General Hospital (US)
- Corresponding author
- Arnheim, Norman
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1995
- Volume
- 4
- Issue
- 9
- Pages
- 1519-1526
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2138167972
- Cited by
- 182
- References
- 27
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 7 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 2 · 2013: 5 · 2012: 6
- FWCI
- 4.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Science Foundation
- National Institute of General Medical Sciences (R37 GM37645)
- National Institute of Neurological Disorders and Stroke (R01NS022031, NS 16367, NS22031)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Huntington's disease, CAG trinucleotide repeat, trinucleotide repeat expansion, repeat contraction, repeat number
- MeSH terms
- Alleles, Base Sequence, Gene Frequency, Humans, Huntington Disease, Male, Molecular Sequence Data, Mutation, Spermatozoa, DNA Primers, Trinucleotide Repeats
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