{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T11:25:52Z","timestamp":1770895552675,"version":"3.50.1"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T00:00:00Z","timestamp":1593388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54HG007990"],"award-info":[{"award-number":["U54HG007990"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01HL137183"],"award-info":[{"award-number":["U01HL137183"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["2U41HG007234"],"award-info":[{"award-number":["2U41HG007234"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R01HG010053"],"award-info":[{"award-number":["5R01HG010053"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000888","name":"W.M. Keck Foundation","doi-asserted-by":"publisher","award":["DT06172015"],"award-info":[{"award-number":["DT06172015"]}],"id":[{"id":"10.13039\/100000888","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Nucleotide modification status can be decoded from the Oxford Nanopore Technologies nanopore-sequencing ionic current signals. Although various algorithms have been developed for nanopore-sequencing-based modification analysis, more detailed characterizations, such as modification numbers, corresponding signal levels and proportions are still lacking.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We present a framework for the unsupervised determination of the number of nucleotide modifications from nanopore-sequencing readouts. We demonstrate the approach can effectively recapitulate the number of modifications, the corresponding ionic current signal levels, as well as mixing proportions under both DNA and RNA contexts. We further show, by integrating information from multiple detected modification regions, that the modification status of DNA and RNA molecules can be inferred. This method forms a key step of de novo characterization of nucleotide modifications, shedding light on the interpretation of various biological questions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>Modified nanopolish: https:\/\/github.com\/adbailey4\/nanopolish\/tree\/cigar_output. All other codes used to reproduce the results: https:\/\/github.com\/hd2326\/ModificationNumber.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaa601","type":"journal-article","created":{"date-parts":[[2020,6,20]],"date-time":"2020-06-20T11:21:25Z","timestamp":1592652085000},"page":"4928-4934","source":"Crossref","is-referenced-by-count":27,"title":["Gaussian mixture model-based unsupervised nucleotide modification number detection using nanopore-sequencing readouts"],"prefix":"10.1093","volume":"36","author":[{"given":"Hongxu","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Biomolecular Engineering and Genomics Institute, University of California Santa Cruz , Santa Cruz, CA 95064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"IV","given":"Andrew D","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Engineering and Genomics Institute, University of California Santa Cruz , Santa Cruz, CA 95064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4571-3982","authenticated-orcid":false,"given":"Miten","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Engineering and Genomics Institute, University of California Santa Cruz , Santa Cruz, CA 95064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hugh","family":"Olsen","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Engineering and Genomics Institute, University of California Santa Cruz , Santa Cruz, CA 95064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedict","family":"Paten","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Engineering and Genomics Institute, University of California Santa Cruz , Santa Cruz, CA 95064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,6,29]]},"reference":[{"key":"2023062408051592300_btaa601-B1","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.cell.2011.08.042","article-title":"DNA demethylation dynamics","volume":"146","author":"Bhutani","year":"2011","journal-title":"Cell"},{"key":"2023062408051592300_btaa601-B2","doi-asserted-by":"crossref","first-page":"D303","DOI":"10.1093\/nar\/gkx1030","article-title":"MODOMICS: a database of RNA modification pathways. 2017 update","volume":"46","author":"Boccaletto","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2023062408051592300_btaa601-B3","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1214\/08-AOS651","article-title":"Hypothesis test for normal mixture models: the EM approach","volume":"37","author":"Chen","year":"2009","journal-title":"Ann. Stat"},{"key":"2023062408051592300_btaa601-B4","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1080\/01621459.2012.695668","article-title":"Inference on the order of a normal mixture","volume":"107","author":"Chen","year":"2012","journal-title":"J. Am. Stat. Assoc"},{"key":"2023062408051592300_btaa601-B5","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nbt.3423","article-title":"Three decades of nanopore sequencing","volume":"34","author":"Deamer","year":"2016","journal-title":"Nat. Biotechnol"},{"key":"2023062408051592300_btaa601-B6","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.sbi.2012.04.002","article-title":"Going beyond five bases in DNA sequencing","volume":"22","author":"Korlach","year":"2012","journal-title":"Curr. Opin. Struct. Biol"},{"key":"2023062408051592300_btaa601-B7","author":"Leger","year":"2019"},{"key":"2023062408051592300_btaa601-B8","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023062408051592300_btaa601-B9","doi-asserted-by":"crossref","first-page":"3094","DOI":"10.1093\/bioinformatics\/bty191","article-title":"Minimap2: pairwise alignment for nucleotide sequences","volume":"34","author":"Li","year":"2018","journal-title":"Bioinformatics"},{"key":"2023062408051592300_btaa601-B10","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1146\/annurev-genom-090413-025405","article-title":"The pivotal regulatory landscape of RNA modifications","volume":"15","author":"Li","year":"2014","journal-title":"Annu. Rev. Genomics Hum. Genet"},{"key":"2023062408051592300_btaa601-B11","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1038\/s41467-019-10168-2","article-title":"Detection of DNA base modifications by deep recurrent neural network on Oxford nanopore sequencing data","volume":"10","author":"Liu","year":"2019","journal-title":"Nat. Commun"},{"key":"2023062408051592300_btaa601-B12","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/nmeth.3444","article-title":"A complete bacterial genome assembled de novo using only nanopore sequencing data","volume":"12","author":"Loman","year":"2015","journal-title":"Nat. Methods"},{"key":"2023062408051592300_btaa601-B13","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrg.2017.80","article-title":"The DNA methyltransferase family: a versatile toolkit for epigenetic regulation","volume":"19","author":"Lyko","year":"2018","journal-title":"Nat. Rev. Genet"},{"key":"2023062408051592300_btaa601-B14","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1016\/j.csda.2011.01.005","article-title":"A flexible extreme value mixture model","volume":"55","author":"MacDonald","year":"2011","journal-title":"Comput. Stat. Data Anal"},{"key":"2023062408051592300_btaa601-B15","doi-asserted-by":"crossref","first-page":"4586","DOI":"10.1093\/bioinformatics\/btz276","article-title":"DeepSignal: detecting DNA methylation state from nanopore sequencing reads using deep-learning","volume":"35","author":"Ni","year":"2019","journal-title":"Bioinformatics"},{"key":"2023062408051592300_btaa601-B16","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41592-019-0394-y","article-title":"Capturing the dynamics of genome replication on individual ultra-long nanopore sequence reads","volume":"16","author":"Mueller","year":"2019","journal-title":"Nat. Methods"},{"key":"2023062408051592300_btaa601-B17","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nmeth.4189","article-title":"Mapping DNA methylation with high-throughput nanopore sequencing","volume":"14","author":"Rand","year":"2017","journal-title":"Nat. Methods"},{"key":"2023062408051592300_btaa601-B18","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nmeth.4184","article-title":"Detecting DNA cytosine methylation using nanopore sequencing","volume":"14","author":"Simpson","year":"2017","journal-title":"Nat. Methods"},{"key":"2023062408051592300_btaa601-B19","doi-asserted-by":"crossref","first-page":"e0216709","DOI":"10.1371\/journal.pone.0216709","article-title":"Reading canonical and modified nucleobases in 16S ribosomal RNA using nanopore native RNA sequencing","volume":"14","author":"Smith","year":"2019","journal-title":"PLoS One"},{"key":"2023062408051592300_btaa601-B20","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13321-019-0349-4","article-title":"DNAmod: the DNA modification database","volume":"11","author":"Sood","year":"2019","journal-title":"J. Cheminf"},{"key":"2023062408051592300_btaa601-B21","author":"Stoiber","year":"2016"},{"key":"2023062408051592300_btaa601-B22","doi-asserted-by":"crossref","DOI":"10.1099\/mgen.0.000132","article-title":"Completing bacterial genome assemblies with multiplex MinION sequencing","volume":"3","author":"Wick","year":"2017","journal-title":"Microbial Genomics"},{"key":"2023062408051592300_btaa601-B23","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1038\/s41592-019-0617-2","article-title":"Nanopore native RNA sequencing of a human poly (A) transcriptome","volume":"16","author":"Workman","year":"2019","journal-title":"Nat. Methods"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btaa601\/33675515\/btaa601.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/19\/4928\/50692460\/btaa601.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/19\/4928\/50692460\/btaa601.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T23:22:47Z","timestamp":1687648967000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/19\/4928\/5864718"}},"subtitle":[],"editor":[{"given":"Jonathan","family":"Wren","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2020,6,29]]},"references-count":23,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2020,12,8]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaa601","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,10,1]]},"published":{"date-parts":[[2020,6,29]]}}}