{"doi":"10.1093/nar/gkaa1269","title":"Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome","abstract":"Approximately 13% of the human genome can fold into non-canonical (non-B) DNA structures (e.g. G-quadruplexes, Z-DNA, etc.), which have been implicated in vital cellular processes. Non-B DNA also hinders replication, increasing errors and facilitating mutagenesis, yet its contribution to genome-wide variation in mutation rates remains unexplored. Here, we conducted a comprehensive analysis of nucleotide substitution frequencies at non-B DNA loci within noncoding, non-repetitive genome regions, their ±2 kb flanking regions, and 1-Megabase windows, using human-orangutan divergence and human single-nucleotide polymorphisms. Functional data analysis at single-base resolution demonstrated that substitution frequencies are usually elevated at non-B DNA, with patterns specific to each non-B DNA type. Mirror, direct and inverted repeats have higher substitution frequencies in spacers than in repeat arms, whereas G-quadruplexes, particularly stable ones, have higher substitution frequencies in loops than in stems. Several non-B DNA types also affect substitution frequencies in their flanking regions. Finally, non-B DNA explains more variation than any other predictor in multiple regression models for diversity or divergence at 1-Megabase scale. Thus, non-B DNA substantially contributes to variation in substitution frequencies at small and large scales. Our results highlight the role of non-B DNA in germline mutagenesis with implications to evolution and genetic diseases.","journal":"Nucleic Acids Research","year":2021,"id":148581,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":123,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9454,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":258882,"name":"Marzia A. Cremona","orcid":"0000-0001-8899-7316","position":1,"is_corresponding":false},{"id":19563,"name":"Robert S. Harris","orcid":"0000-0001-5464-6892","position":2,"is_corresponding":false},{"id":45502,"name":"Di Chen","orcid":"0000-0001-6546-3389","position":3,"is_corresponding":false},{"id":582647,"name":"Kristin A. Eckert","orcid":"0000-0002-8659-5062","position":4,"is_corresponding":false},{"id":19593,"name":"Francesca Chiaromonte","orcid":"0000-0001-5605-9886","position":5,"is_corresponding":false},{"id":405086,"name":"Yi-Fei Huang","orcid":"0000-0001-5594-6731","position":6,"is_corresponding":false},{"id":19591,"name":"Kateryna D. Makova","orcid":"0000-0002-6212-9526","position":7,"is_corresponding":false},{"id":632274,"name":"Wilfried M. Guiblet","orcid":"0000-0001-6319-3418","position":0,"is_corresponding":true}],"reference_count":154,"raw_metadata":null,"created_at":"2026-07-18T23:42:46.224799Z","pmid":"33450015","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}