High levels of transcription are associated with increased mutation rates in 
Saccharomyces cerevisiae, a phenomenon termed transcription-associated mutation 
(TAM). To obtain insight into the mechanism of TAM, we obtained LYS2 forward 
mutation spectra under low- versus high-transcription conditions in which LYS2 
was expressed from either the low-level pLYS2 promoter or the strong pGAL1-10 
promoter, respectively. Because of the large size of the LYS2 locus, forward 
mutations first were mapped to specific LYS2 subregions, and then those 
mutations that occurred within a defined 736-bp target region were sequenced. In 
the low-transcription strain base substitutions comprised the majority (64%) of 
mutations, whereas short insertion-deletion mutations predominated (56%) in the 
high-transcription strain. Most notably, deletions of 2 nucleotides (nt) 
comprised 21% of the mutations in the high-transcription strain, and these 
events occurred predominantly at 5'-(G/C)AAA-3' sites. No -2 events were present 
in the low-transcription spectrum, thus identifying 2-nt deletions as a unique 
mutational signature for TAM.