Abstract

Accurate transcription is required for the faithful expression of genetic information. To provide insight into the molecular mechanisms that control the fidelity of transcription, we analyzed the landscape of transcription errors in human embryonic stem cells. These measurements provide the first reasonable estimate of the fidelity of transcription in human cells and identify multiple genetic and epigenetic factors that control its accuracy. In addition, we developed a new reporter mouse to identify cell types and tissues that commit these errors the most. These experiments revealed that CA1 and dentate gyrus neurons are highly sensitive to transcriptional mutagenesis, lending new support to the hypothesis that transcription errors play a role in the progression of Alzheimers disease. Taken together, these experiments provide unprecedented insight into the fidelity of gene expression in human cells and the molecular mechanisms that govern the central dogma of life.