Evidence for mutation showers

Abstract

Mutants in the Big Blue transgenic mouse system show spontaneous clustered multiple mutations with unexpectedly high frequency, consistent with chronocoordinate events. We tested the prediction that the multiple mutations seen within the lacI mutation target sometimes occur in the context of chronocoordinate multiple mutations spanning multiple kilobases (mutation showers). Additional sequencing of mutants was performed in regions immediately flanking the lacI region (total of 10.7 kb). Nineteen additional mutations were found outside the lacI region (''ectomutations'') from 10 mutants containing two or more lacI mutations, whereas only one ectomutation was found in 130 mutants with a single mutation (P < 0.0001). The mutation showers had an average of approximately one mutation per 3 kb. Four mutants showed closely spaced double mutations in the new sequence, and analysis of the spacing between these mutations revealed significant clustering (P ‫؍‬ 0.0098). To determine the extent of the mutation showers, regions (8.5 kb total) remote from the lacI region (Ϸ16 -17 kb away) were sequenced. Only two additional ectomutations were found in these remote regions, consistent with mutation showers that generally do not extend more than Ϸ30 kb. We conclude that mutation showers exist and that they constitute at least 0.2% and possibly 1% or more of mutational events observed in this system. The existence of mutation showers has implications for oncogenesis and evolution, raising the possibilities of ''cancer in an instant'' and ''introns as sponges to reduce the deleterious impact of mutation showers.'' Big Blue mouse ͉ lacI transgene ͉ multiple mutations ͉ mutation clusters ͉ transient hypermutability

APOBEC3 genes: retroviral restriction factors to cancer drivers

“…These clusters were also characterized by strand-coordinated mutations at C:G base pairs. Noting the similarity of these clusters to the multikilobase chronocoordinate mutation showers previously described in transgenic mice expressing a lacl reporter gene (and predicted to occur in cancer) [33], they termed them kataegis (after the Greek kataegisa meaning thunder shower, or tempest) [32]. Both studies [31,32] noticed that the predominant mutations occurring in these clusters were C>T or C>G substitutions within the optimal substrate motif (TpCpW, where W = A or T) for a subset of 'TC-specific' A3s including A3A, A3B, A3C, A3F and A3H.…”

Damage-induced localized hypermutability

“…Multiple mutations that appear to be simultaneous or coordinated in time (chronocoordinate) have been detected in normal mouse and human tissues 15,16 and in tumors. [17][18][19] While the fraction of mutations that appear to be chronocoordinate is small, they may play bigger roles in some types of cancers, especially those associated with a high density of DNA damage (see below).…”

Too Many Mutants with Multiple Mutations

“…Subsequently, 65 such multiples were subjected to resequencing over about 20 kb outside of the reporter sequence, and ten were found to contain additional mutations (Wang et al, 2007). (When 130 singles were thusly sequenced, only one had a single mutation in the outside regions.)…”