ABSTRACT
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 study of DNA polymerization kinetics in the human genome sequenced with Single-Molecule-Real-Time 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. We demonstrate that non-B DNA affects sequencing errors and human germline (1,000 Genomes Project, human-orangutan divergence, re-sequenced trios) and somatic (The Cancer Genome Atlas) mutations. Thus, non-B DNA has a large impact on genome evolution and human diseases.