{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:03:18Z","timestamp":1782950598723,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011544","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T00:00:00Z","timestamp":1698019200000}}],"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T00:00:00Z","timestamp":1696982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CCF-2046488"],"award-info":[{"award-number":["CCF-2046488"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cancer Center at Illinois"},{"DOI":"10.13039\/501100003086","name":"Basque Government","doi-asserted-by":"crossref","award":["Gipuzkoa Fellows"],"award-info":[{"award-number":["Gipuzkoa Fellows"]}],"id":[{"id":"10.13039\/501100003086","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100011033","name":"Spanish State Research Agency","doi-asserted-by":"crossref","award":["Ramon y Cajal Grant"],"award-info":[{"award-number":["Ramon y Cajal Grant"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004837","name":"Spanish Ministry of Science and Innovation","doi-asserted-by":"crossref","award":["PID2021-126718OA-I00"],"award-info":[{"award-number":["PID2021-126718OA-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Greg Gulick Honorary Research Award Opportunity"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Emerging ultra-low coverage single-cell DNA sequencing (scDNA-seq) technologies have enabled high resolution evolutionary studies of copy number aberrations (CNAs) within tumors. While these sequencing technologies are well suited for identifying CNAs due to the uniformity of sequencing coverage, the sparsity of coverage poses challenges for the study of single-nucleotide variants (SNVs). In order to maximize the utility of increasingly available ultra-low coverage scDNA-seq data and obtain a comprehensive understanding of tumor evolution, it is important to also analyze the evolution of SNVs from the same set of tumor cells. We present\n                    <jats:sc>Phertilizer<\/jats:sc>\n                    , a method to infer a clonal tree from ultra-low coverage scDNA-seq data of a tumor. Based on a probabilistic model, our method recursively partitions the data by identifying key evolutionary events in the history of the tumor. We demonstrate the performance of\n                    <jats:sc>Phertilizer<\/jats:sc>\n                    on simulated data as well as on two real datasets, finding that\n                    <jats:sc>Phertilizer<\/jats:sc>\n                    effectively utilizes the copy-number signal inherent in the data to more accurately uncover clonal structure and genotypes compared to previous methods.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1011544","type":"journal-article","created":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T13:38:39Z","timestamp":1697031519000},"page":"e1011544","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Phertilizer: Growing a clonal tree from ultra-low coverage single-cell DNA sequencing of tumors"],"prefix":"10.1371","volume":"19","author":[{"given":"Leah L.","family":"Weber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idoia","family":"Ochoa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1468-2407","authenticated-orcid":true,"given":"Mohammed","family":"El-Kebir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,10,11]]},"reference":[{"issue":"4260","key":"pcbi.1011544.ref001","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1126\/science.959840","article-title":"The Clonal Evolution of Tumor Cell Populations: Acquired genetic lability permits stepwise selection of variant sublines and underlies tumor progression","volume":"194","author":"PC Nowell","year":"1976","journal-title":"Science"},{"issue":"1","key":"pcbi.1011544.ref002","first-page":"1","article-title":"Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics","volume":"11","author":"K Morita","year":"2020","journal-title":"Nature Communications"},{"key":"pcbi.1011544.ref003","doi-asserted-by":"crossref","first-page":"e51480","DOI":"10.7554\/eLife.51480","article-title":"Novel insights into breast cancer copy number genetic heterogeneity revealed by single-cell genome sequencing","volume":"9","author":"T Baslan","year":"2020","journal-title":"eLife"},{"issue":"4","key":"pcbi.1011544.ref004","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.cell.2018.03.041","article-title":"Chemoresistance evolution in triple-negative breast cancer delineated by single-cell sequencing","volume":"173","author":"C Kim","year":"2018","journal-title":"Cell"},{"issue":"7834","key":"pcbi.1011544.ref005","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41586-020-2864-x","article-title":"Single-cell mutation analysis of clonal evolution in myeloid malignancies","volume":"587","author":"LA Miles","year":"2020","journal-title":"Nature"},{"issue":"5","key":"pcbi.1011544.ref006","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.cell.2019.10.026","article-title":"Clonal decomposition and DNA replication states defined by scaled single-cell genome sequencing","volume":"179","author":"E Laks","year":"2019","journal-title":"Cell"},{"issue":"7853","key":"pcbi.1011544.ref007","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/s41586-021-03357-x","article-title":"Breast tumours maintain a reservoir of subclonal diversity during expansion","volume":"592","author":"DC Minussi","year":"2021","journal-title":"Nature"},{"issue":"2","key":"pcbi.1011544.ref008","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nmeth.4140","article-title":"Scalable whole-genome single-cell library preparation without preamplification","volume":"14","author":"H Zahn","year":"2017","journal-title":"Nature Methods"},{"issue":"9","key":"pcbi.1011544.ref009","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1101\/gr.232272.117","article-title":"High-throughput single-cell DNA sequencing of acute myeloid leukemia tumors with droplet microfluidics","volume":"28","author":"M Pellegrino","year":"2018","journal-title":"Genome Research"},{"issue":"Supplement_1","key":"pcbi.1011544.ref010","doi-asserted-by":"crossref","first-page":"i125","DOI":"10.1093\/bioinformatics\/btac253","article-title":"Reconstructing tumor clonal lineage trees incorporating single-nucleotide variants, copy number alterations and structural variations","volume":"38","author":"X Fu","year":"2022","journal-title":"Bioinformatics"},{"issue":"3","key":"pcbi.1011544.ref011","first-page":"1","article-title":"CAISC: A software to integrate copy number variations and single nucleotide mutations for genetic heterogeneity profiling and subclone detection by single-cell RNA sequencing","volume":"23","author":"J Kannan","year":"2022","journal-title":"BMC bioinformatics"},{"issue":"1","key":"pcbi.1011544.ref012","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-016-0936-x","article-title":"Tree inference for single-cell data","volume":"17","author":"K Jahn","year":"2016","journal-title":"Genome Biology"},{"issue":"11","key":"pcbi.1011544.ref013","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1101\/gr.234435.118","article-title":"PhISCS: a combinatorial approach for subperfect tumor phylogeny reconstruction via integrative use of single-cell and bulk sequencing data","volume":"29","author":"S Malikic","year":"2019","journal-title":"Genome Research"},{"issue":"17","key":"pcbi.1011544.ref014","doi-asserted-by":"crossref","first-page":"i671","DOI":"10.1093\/bioinformatics\/bty589","article-title":"SPhyR: tumor phylogeny estimation from single-cell sequencing data under loss and error","volume":"34","author":"M El-Kebir","year":"2018","journal-title":"Bioinformatics"},{"issue":"11","key":"pcbi.1011544.ref015","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1101\/gr.243121.118","article-title":"SiCloneFit: Bayesian inference of population structure, genotype, and phylogeny of tumor clones from single-cell genome sequencing data","volume":"29","author":"H Zafar","year":"2019","journal-title":"Genome Research"},{"issue":"7","key":"pcbi.1011544.ref016","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nmeth.3867","article-title":"Clonal genotype and population structure inference from single-cell tumor sequencing","volume":"13","author":"A Roth","year":"2016","journal-title":"Nature Methods"},{"issue":"2","key":"pcbi.1011544.ref017","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41587-020-0661-6","article-title":"Characterizing allele-and haplotype-specific copy numbers in single cells with CHISEL","volume":"39","author":"S Zaccaria","year":"2021","journal-title":"Nature Biotechnology"},{"issue":"1","key":"pcbi.1011544.ref018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-022-02693-z","article-title":"CONET: Copy number event tree model of evolutionary tumor history for single-cell data","volume":"23","author":"M Markowska","year":"2022","journal-title":"Genome Biology"},{"key":"pcbi.1011544.ref019","article-title":"NestedBD: Bayesian Inference of Phylogenetic Trees From Single-Cell DNA Copy Number Profile Data Under a Birth-Death Model","author":"Y Liu","year":"2022","journal-title":"bioRxiv"},{"issue":"1","key":"pcbi.1011544.ref020","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-021-02291-5","article-title":"MEDALT: single-cell copy number lineage tracing enabling gene discovery","volume":"22","author":"F Wang","year":"2021","journal-title":"Genome Biology"},{"issue":"1","key":"pcbi.1011544.ref021","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s13059-022-02794-9","article-title":"MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution","volume":"23","author":"TL Kaufmann","year":"2022","journal-title":"Genome biology"},{"issue":"1","key":"pcbi.1011544.ref022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-021-02583-w","article-title":"CellPhy: accurate and fast probabilistic inference of single-cell phylogenies from scDNA-seq data","volume":"23","author":"A Kozlov","year":"2022","journal-title":"Genome biology"},{"issue":"1","key":"pcbi.1011544.ref023","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1186\/s13059-022-02813-9","article-title":"SIEVE: joint inference of single-nucleotide variants and cell phylogeny from single-cell DNA sequencing data","volume":"23","author":"S Kang","year":"2022","journal-title":"Genome Biology"},{"issue":"8","key":"pcbi.1011544.ref024","doi-asserted-by":"crossref","first-page":"msac143","DOI":"10.1093\/molbev\/msac143","article-title":"Accounting for errors in data improves divergence time estimates in single-cell cancer evolution","volume":"39","author":"K Chen","year":"2022","journal-title":"Molecular biology and evolution"},{"issue":"9","key":"pcbi.1011544.ref025","doi-asserted-by":"crossref","first-page":"2512","DOI":"10.1093\/bioinformatics\/btac143","article-title":"A Bayesian method to cluster single-cell RNA sequencing data using copy number alterations","volume":"38","author":"S Milite","year":"2022","journal-title":"Bioinformatics"},{"issue":"1","key":"pcbi.1011544.ref026","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-019-1922-x","article-title":"DENDRO: genetic heterogeneity profiling and subclone detection by single-cell RNA sequencing","volume":"21","author":"Z Zhou","year":"2020","journal-title":"Genome biology"},{"issue":"4","key":"pcbi.1011544.ref027","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.cels.2020.04.001","article-title":"SCARLET: single-cell tumor phylogeny inference with copy-number constrained mutation losses","volume":"10","author":"G Satas","year":"2020","journal-title":"Cell Systems"},{"issue":"Supplement_1","key":"pcbi.1011544.ref028","doi-asserted-by":"crossref","first-page":"i186","DOI":"10.1093\/bioinformatics\/btaa449","article-title":"Identifying tumor clones in sparse single-cell mutation data","volume":"36","author":"MA Myers","year":"2020","journal-title":"Bioinformatics"},{"issue":"18","key":"pcbi.1011544.ref029","doi-asserted-by":"crossref","first-page":"4293","DOI":"10.1093\/bioinformatics\/btac510","article-title":"SECEDO: SNV-based subclone detection using ultra-low coverage single-cell DNA sequencing","volume":"38","author":"H Rozho\u0148ov\u00e1","year":"2022","journal-title":"Bioinformatics"},{"issue":"4","key":"pcbi.1011544.ref030","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1093\/genetics\/61.4.893","article-title":"The number of heterozygous nucleotide sites maintained in a finite population due to steady flux of mutations","volume":"61","author":"M Kimura","year":"1969","journal-title":"Genetics"},{"issue":"2","key":"pcbi.1011544.ref031","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.bbcan.2017.01.003","article-title":"Tumor evolution: Linear, branching, neutral or punctuated?","volume":"1867","author":"A Davis","year":"2017","journal-title":"Biochimica et Biophysica Acta (BBA)-Reviews on Cancer"},{"issue":"8","key":"pcbi.1011544.ref032","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1109\/34.868688","article-title":"Normalized cuts and image segmentation","volume":"22","author":"J Shi","year":"2000","journal-title":"IEEE Transactions on pattern analysis and machine intelligence"},{"issue":"12","key":"pcbi.1011544.ref033","doi-asserted-by":"crossref","first-page":"i62","DOI":"10.1093\/bioinformatics\/btv261","article-title":"Reconstruction of clonal trees and tumor composition from multi-sample sequencing data","volume":"31","author":"M El-Kebir","year":"2015","journal-title":"Bioinformatics"},{"key":"pcbi.1011544.ref034","first-page":"164","article-title":"Les lois de l\u2019\u00e9volution","volume":"7","author":"L Dollo","year":"1893","journal-title":"Bulletin de la Soci\u00e9t\u00e9 belge de g\u00e9ologie, de pal\u00e9ontologie et d\u2019hydrologie"},{"issue":"5","key":"pcbi.1011544.ref035","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data","volume":"2","author":"E Cerami","year":"2012","journal-title":"Cancer Discovery"},{"issue":"269","key":"pcbi.1011544.ref036","first-page":"pl1","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"J Gao","year":"2013","journal-title":"Science Signaling"},{"issue":"11","key":"pcbi.1011544.ref037","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s41568-018-0060-1","article-title":"The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers","volume":"18","author":"Z Sondka","year":"2018","journal-title":"Nature Reviews Cancer"},{"key":"pcbi.1011544.ref038","unstructured":"Van der Auwera GA, O\u2019Connor BD. Genomics in the cloud: using Docker, GATK, and WDL in Terra. O\u2019Reilly Media; 2020."},{"issue":"8","key":"pcbi.1011544.ref039","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1158\/2159-8290.CD-17-0151","article-title":"AACR Project GENIE: powering precision medicine through an international consortium","volume":"7","author":"APG Consortium","year":"2017","journal-title":"Cancer discovery"},{"issue":"3","key":"pcbi.1011544.ref040","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1056\/NEJMoa1102903","article-title":"Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers","volume":"366","author":"A Heravi-Moussavi","year":"2012","journal-title":"New England Journal of Medicine"},{"issue":"21","key":"pcbi.1011544.ref041","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1093\/hmg\/ddz207","article-title":"SNV identification from single-cell RNA sequencing data","volume":"28","author":"PM Schnepp","year":"2019","journal-title":"Human Molecular Genetics"},{"issue":"1","key":"pcbi.1011544.ref042","first-page":"1","article-title":"Systematic comparative analysis of single-nucleotide variant detection methods from single-cell RNA sequencing data","volume":"20","author":"F Liu","year":"2019","journal-title":"Genome biology"},{"key":"pcbi.1011544.ref043","first-page":"1","article-title":"Single-nucleotide variant calling in single-cell sequencing data with Monopogen","author":"J Dou","year":"2023","journal-title":"Nature Biotechnology"},{"key":"pcbi.1011544.ref044","first-page":"1","article-title":"De novo detection of somatic mutations in high-throughput single-cell profiling data sets","author":"F Muyas","year":"2023","journal-title":"Nature Biotechnology"},{"issue":"14","key":"pcbi.1011544.ref045","doi-asserted-by":"crossref","first-page":"7986","DOI":"10.1093\/nar\/gkab621","article-title":"Discovering single nucleotide variants and indels from bulk and single-cell ATAC-seq","volume":"49","author":"AR Massarat","year":"2021","journal-title":"Nucleic acids research"},{"issue":"35","key":"pcbi.1011544.ref046","doi-asserted-by":"crossref","first-page":"eabn6398","DOI":"10.1126\/sciadv.abn6398","article-title":"scAllele: A versatile tool for the detection and analysis of variants in scRNA-seq","volume":"8","author":"G Quinones-Valdez","year":"2022","journal-title":"Science Advances"},{"issue":"10","key":"pcbi.1011544.ref047","doi-asserted-by":"crossref","first-page":"e1010576","DOI":"10.1371\/journal.pcbi.1010576","article-title":"Variant calling enhances the identification of cancer cells in single-cell RNA sequencing data","volume":"18","author":"W Gasper","year":"2022","journal-title":"PLoS computational biology"},{"issue":"1","key":"pcbi.1011544.ref048","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1038\/s41467-022-30230-w","article-title":"Variant calling from scRNA-seq data allows the assessment of cellular identity in patient-derived cell lines","volume":"13","author":"D Ramazzotti","year":"2022","journal-title":"Nature communications"},{"key":"pcbi.1011544.ref049","doi-asserted-by":"crossref","unstructured":"El-Kebir M, Morris Q, Oesper L, Sahinalp SC. Emerging Topics in Cancer Evolution. In: PACIFIC SYMPOSIUM ON BIOCOMPUTING 2022. World Scientific; 2021. p. 397\u2013401.","DOI":"10.1142\/9789811250477_0036"},{"issue":"1","key":"pcbi.1011544.ref050","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13015-022-00209-9","article-title":"Parsimonious clone tree integration in cancer","volume":"17","author":"P Sashittal","year":"2022","journal-title":"Algorithms for Molecular Biology"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1011544","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T00:00:00Z","timestamp":1698019200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011544","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T13:38:12Z","timestamp":1698068292000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011544"}},"subtitle":[],"editor":[{"given":"Teresa M.","family":"Przytycka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,10,11]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011544","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.04.18.488655","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,11]]}}}