title: Spontaneous tandem-base mutations (TBM) show dramatic tissue, age, pattern and spectrum specificity.
abstract: To supplement a previous analysis of spontaneous tandem-base mutations (TBM) in the lacI gene of Big Blue((R)) mice, 2658 additional mutants were sequenced from 13 tissues and 44 spontaneous TBM were identified (tripling the sample size). Previous findings were confirmed and generalized and several new observations were made. TBM differ from single and other double mutations in that TBM frequency varies dramatically with tissue type. In certain tissues, most notably male germ cells, no TBM are observed despite screening as many as 26 million plaque forming units. TBM are most frequent in kidney and liver (3.45 and 2x10(-6), respectively), accounting for 7.6 and 4.8% of all mutational events in kidney and liver, respectively. There is a trend for elevated TBM frequency in thymic lymphomas in p53-deficient mice. TBM are more frequent in old age in both liver and kidney. TBM differ from single mutations and other double mutations because they display a marked difference in pattern and dramatic tissue specificity for target sequence. Five of the 78 possible TBM outcomes comprise 79% of those observed, and mutations at GG/CC predominate. TBM in mice were compared with TBM found in human mutation databases. TBM are also rare in the human germline (one in 5133 germline mutations reported in five human mutation databases). In general, the types of somatic TBM are similar in mice and humans except for an excess of TG/CA to CA/TG TBM in humans (TBM related to ultraviolet light-induced skin cancer were excluded). TBM may be the result of unknown mechanisms that may have some similarities in mice and humans.
authors.affiliation: Department of Molecular Genetics, Beckman Research Institute/City of Hope, Duarte, CA 91010-0269, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Hill
authors.forename: Jicheng
authors.initials: J
authors.lastname: Wang
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Farwell
authors.forename: Steve S
authors.initials: SS
authors.lastname: Sommer
mesh_terms: D000367:Age Factors; D000818:Animals; D001426:Bacterial Proteins; D020029:Base Pairing; D001483:Base Sequence; D030541:Databases, Genetic; D029968:Escherichia coli Proteins / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000502:physiology; D056968:Lac Repressors; D008099:Liver / Q000502:physiology; D008223:Lymphoma / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009928:Organ Specificity; D011897:Random Allocation; D012097:Repressor Proteins / Q000235:genetics; D013094:Spermatozoa / Q000502:physiology; D013953:Thymus Neoplasms / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53