Reporter gene assays have demonstrated both transcription-associated mutagenesis 
(TAM) and transcription-coupled repair, but the net impact of transcription on 
mutation rate remains unclear, especially at the genomic scale. Using 
comparative genomics of related species as well as mutation accumulation lines, 
we show in yeast that the rate of point mutation in a gene increases with the 
expression level of the gene. Transcription induces mutagenesis on both DNA 
strands, indicating simultaneous actions of several TAM mechanisms. A 
significant positive correlation is also detected between the human germline 
mutation rate and expression level. These results indicate that transcription is 
overall mutagenic.