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Spontaneous multiple mutations show both proximal spacing consistent with chronocoordinate events and alterations
Kathleen A Hill1, Jicheng Wang, Kelly D Farwell
1Department of Molecular Genetics and Molecular Diagnosis, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
Mutation Research
|September 29, 2004
Summary
Spontaneous multiple mutations occur more frequently than expected and are closely spaced, suggesting coordinated events. Doublet mutation frequency increases with age and is elevated in p53-deficient mice, potentially contributing to cancer risk.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Spontaneous multiple mutations (doublets) in Big Blue mice were previously found to be more frequent than expected by chance.
- The spacing of mutations in doublets was closer than random, suggesting a non-random process.
Purpose of the Study:
- To analyze a larger dataset of spontaneous mutations to confirm and expand upon previous findings regarding doublets.
- To investigate the factors influencing the frequency, spacing, and patterns of doublets and multiplets (domuplets), including age, tissue type, p53-deficiency, and neoplasia.
Main Methods:
- Analysis of 2658 additional spontaneous mutants in Big Blue mice.
- Statistical examination of mutation spacing, frequency, and patterns in relation to various biological factors.
- Comparison of mutation patterns in normal and tumor tissues, particularly in p53-deficient models.
Main Results:
- Doublets were confirmed to be significantly enhanced relative to chance expectation.
- Mutation spacing in doublets was non-random and closely spaced (half-life of 120 nucleotides), consistent with chronocoordinate events.
- Doublet frequency increased with age, was potentially lower in the male germline, and was elevated in somatic tissues of p53-deficient mice.
Conclusions:
- Spontaneous doublets and multiplets likely arise from transient error-prone conditions, not primarily from Y family polymerases.
- The enhancement of doublets in p53-deficient mice may be a contributing factor to cancer risk.
- Mutation patterns differ between singlets and doublets in tumors from p53-deficient mice.