Long-read sequencing technology indicates genome-wide effects of non-B DNA on polymerization speed and error rate


DNA conformation may deviate from the classical B-form in ∼13% of the human genome. Non-B DNA regulates many cellular processes; however, its effects on DNA polymerization speed and accuracy have not been investigated genome-wide. Such an inquiry is critical for understanding neurological diseases and cancer genome instability. Here, we present the first simultaneous examination of DNA polymerization kinetics and errors in the human genome sequenced with Single-Molecule Real-Time (SMRT) technology. We show that polymerization speed differs between non-B and B-DNA – It decelerates at G-quadruplexes and fluctuates periodically at disease-causing tandem repeats. Analyzing polymerization kinetics profiles, we predict and validate experimentally non-B DNA formation for a novel motif. We demonstrate that several non-B motifs affect sequencing errors (e.g., G-quadruplexes increase error rates), and that sequencing errors are positively associated with polymerase slowdown. Finally, we show that highly divergent G4 motifs have pronounced polymerization slowdown and high sequencing error rates, suggesting similar mechanisms for sequencing errors and germline mutations.

Genome Research

#Click the Cite button above to demo the feature to enable visitors to import #publication metadata into their reference management software. #

#Click the Slides button above to demo Academic’s Markdown slides feature. #

#Supplementary notes can be added here, including code and #math.

Monika Cechova
Monika Cechova

My research interests include distributed robotics, mobile computing and programmable matter.