The fidelity of transcription in human cells

Claire Chung, Bert M. Verheijen, Xinmin Zhang, Biao Huang, Aeowynn Coakley, Eric McGann, Emily Wade, Olivia Dinep-Schneider, Jessica LaGosh, Maria Eleni Anagnostou, Stephen Simpson, Kelly Thomas, Mimi Ernst, Allison Rattray, Michael Lynch, Mikhail Kashlev, Berenice A. Benayoun, Zhongwei Li, Jeffrey Strathern, Jean Francois GoutMarc Vermulst

Research output: Contribution to journalArticlepeer-review


To determine the error rate of transcription in human cells, we analyzed the transcriptome of H1 human embryonic stem cells with a circle-sequencing approach that allows for high-fidelity sequencing of the transcriptome. These experiments identified approximately 100,000 errors distributed over every major RNA species in human cells. Our results indicate that different RNA species display different error rates, suggesting that human cells prioritize the fidelity of some RNAs over others. Cross-referencing the errors that we detected with various genetic and epigenetic features of the human genome revealed that the in vivo error rate in human cells changes along the length of a transcript and is further modified by genetic context, repetitive elements, epigenetic markers, and the speed of transcription. Our experiments further suggest that BRCA1, a DNA repair protein implicated in breast cancer, has a previously unknown role in the suppression of transcription errors. Finally, we analyzed the distribution of transcription errors in multiple tissues of a new mouse model and found that they occur preferentially in neurons, compared to other cell types. These observations lend additional weight to the idea that transcription errors play a key role in the progression of various neurological disorders, including Alzheimer’s disease.

Original languageEnglish (US)
Article numbere2210038120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
StatePublished - Jan 31 2023
Externally publishedYes


  • Alzheimer's disease
  • human embryonic stem cells
  • mutagenesis
  • transcription
  • transcription errors

ASJC Scopus subject areas

  • General


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