Journal
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Volume 554, Issue 1-2, Pages 223-240Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2004.05.005
Keywords
Big Blue mouse; lacI transgene; Li-fraumini cancer syndrome; mutation frequency; mutator phenotype; error-prone polymerase; nucleotide pool imbalance
Funding
- NIA NIH HHS [R01 AG 19784] Funding Source: Medline
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Analysis of spontaneous multiple mutations in normal and tumor cells may constrain hypotheses about the mechanisms responsible for multiple mutations and provide insight into the mutator phenotype. In a previous study, spontaneous doublets in Big Blue(R) mice were dramatically more frequent than expected by chance and exhibited a mutation pattern similar to that observed for single mutations [Mutat. Res. 452 (2000) 219]. The spacing between mutations in doublets was generally closer than expected by chance and the distribution of mutation spacing fit an exponential, albeit with substantial scatter. We now analyze 2658 additional mutants and confirm that doublets are enhanced dramatically relative to chance expectation. The spacing, frequency and pattern of spontaneous doublets and multiplets (domuplets) are examined as a function of age, tissue type, p53-deficiency and neoplasia in the new and combined data. The new and combined data confirm that the distribution of the spacing between mutations in doublets is non-random with the mutations more closely spaced than expected by chance (P < 0.0005; combined data), consistent with temporally coordinate (chronocoordinate) events. An exponential provides an excellent fit to the distribution (R-2 = 0.98) and estimates that half of doublets have mutations separated by 120 nucleotides or less (the half-Life of mutation spacing). We make several novel observations: (i) singlets and doublets show similar overall increases in frequency with age (ii) doublet frequency may be lower in the male germline, consistent with the generally reduced mutation frequency in the male germline (iii) doublet frequencies are elevated in somatic tissues of p53-deficient mice (Li-Fraumini cancer syndrome model; P = 0.005) and (iv) doublets and singlets in tumors from p53-deficient mice have a different mutation pattern (P = 0.007). The observations are consistent with chronocoordinate occurrence of spontaneous doublets and multiplets due to a transient error-prone condition and do not suggest a major role for the recently discovered Y family of error-prone polymerases. The enhancement of doublets in p53-deficient mice may contribute to cancer risk. (C) 2004 Elsevier B.V. All rights reserved.
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