{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:24:51Z","timestamp":1772173491229,"version":"3.50.1"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NCI","award":["1R01CA245318"],"award-info":[{"award-number":["1R01CA245318"]}]},{"name":"NCI","award":["1R01CA258524"],"award-info":[{"award-number":["1R01CA258524"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Mitochondrial (MT) mutations serve as natural genetic markers for inferring clonal relationships using single cell sequencing data. However, the fundamental challenge of MT mutation-based lineage tracing is automated identification of informative MT mutations. Here, we introduced an open-source computational algorithm called \u201cMitoTracer\u201d, which accurately identified clonally informative MT mutations and inferred evolutionary lineage from scRNA-seq or scATAC-seq samples. We benchmarked MitoTracer using the ground-truth experimental lineage sequencing data and demonstrated its superior performance over the existing methods measured by high sensitivity and specificity. MitoTracer is compatible with multiple single cell sequencing platforms. Its application to a cancer evolution dataset revealed the genes related to primary BRAF-inhibitor resistance from scRNA-seq data of BRAF-mutated cancer cells. Overall, our work provided a valuable tool for capturing real informative MT mutations and tracing the lineages among cells.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013090","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T13:28:28Z","timestamp":1750685308000},"page":"e1013090","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["MitoTracer facilitates the identification of informative mitochondrial mutations for precise lineage reconstruction"],"prefix":"10.1371","volume":"21","author":[{"given":"Xuexin","family":"Yu","sequence":"first","affiliation":[]},{"given":"Jing","family":"Hu","sequence":"additional","affiliation":[]},{"given":"Yuhao","family":"Tan","sequence":"additional","affiliation":[]},{"given":"Mingyao","family":"Pan","sequence":"additional","affiliation":[]},{"given":"Hongyi","family":"Zhang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8617-900X","authenticated-orcid":true,"given":"Bo","family":"Li","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"pcbi.1013090.ref001","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.cell.2017.11.011","article-title":"Single-Cell Genomics: A Stepping Stone for Future Immunology Discoveries","volume":"172","author":"A Giladi","year":"2018","journal-title":"Cell"},{"issue":"1","key":"pcbi.1013090.ref002","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1038\/s41467-023-37353-8","article-title":"Pan-cancer classification of single cells in the tumour microenvironment","volume":"14","author":"I Nofech-Mozes","year":"2023","journal-title":"Nat Commun"},{"issue":"2","key":"pcbi.1013090.ref003","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.stem.2018.04.014","article-title":"Single-Cell Transcriptomics Meets Lineage Tracing","volume":"23","author":"L Kester","year":"2018","journal-title":"Cell Stem Cell"},{"key":"pcbi.1013090.ref004","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1146\/annurev.ge.29.120195.001055","article-title":"Molecular genetic aspects of human mitochondrial disorders","volume":"29","author":"NG Larsson","year":"1995","journal-title":"Annu Rev Genet"},{"issue":"1","key":"pcbi.1013090.ref005","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00294-013-0398-6","article-title":"Tissue-specific mitochondrial heteroplasmy at position 16,093 within the same individual","volume":"60","author":"K Krjut\u0161kov","year":"2014","journal-title":"Curr Genet"},{"issue":"11","key":"pcbi.1013090.ref006","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1101\/gr.202903.115","article-title":"A generic, cost-effective, and scalable cell lineage analysis platform","volume":"26","author":"T Biezuner","year":"2016","journal-title":"Genome Res"},{"issue":"7","key":"pcbi.1013090.ref007","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1038\/s41587-022-01210-8","article-title":"Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations","volume":"40","author":"TE Miller","year":"2022","journal-title":"Nat Biotechnol"},{"issue":"4","key":"pcbi.1013090.ref008","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41587-020-0645-6","article-title":"Massively parallel single-cell mitochondrial DNA genotyping and chromatin profiling","volume":"39","author":"CA Lareau","year":"2021","journal-title":"Nat Biotechnol"},{"issue":"6","key":"pcbi.1013090.ref009","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2019.01.022","article-title":"Lineage Tracing in Humans Enabled by Mitochondrial Mutations and Single-Cell Genomics","volume":"176","author":"LS Ludwig","year":"2019","journal-title":"Cell"},{"issue":"1","key":"pcbi.1013090.ref010","doi-asserted-by":"crossref","first-page":"108589","DOI":"10.1016\/j.celrep.2020.108589","article-title":"Overcoming Expressional Drop-outs in Lineage Reconstruction from Single-Cell RNA-Sequencing Data","volume":"34","author":"T Lu","year":"2021","journal-title":"Cell Rep"},{"issue":"1","key":"pcbi.1013090.ref011","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/s41467-022-28845-0","article-title":"MQuad enables clonal substructure discovery using single cell mitochondrial variants","volume":"13","author":"AWC Kwok","year":"2022","journal-title":"Nat Commun"},{"issue":"23","key":"pcbi.1013090.ref012","doi-asserted-by":"crossref","first-page":"4569","DOI":"10.1093\/bioinformatics\/btab358","article-title":"Cellsnp-lite: an efficient tool for genotyping single cells","volume":"37","author":"X Huang","year":"2021","journal-title":"Bioinformatics"},{"issue":"1","key":"pcbi.1013090.ref013","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1186\/s13059-019-1865-2","article-title":"Vireo: Bayesian demultiplexing of pooled single-cell RNA-seq data without genotype reference","volume":"20","author":"Y Huang","year":"2019","journal-title":"Genome Biol"},{"key":"pcbi.1013090.ref014","doi-asserted-by":"crossref","DOI":"10.1093\/bioinformatics\/btae231","article-title":"Joint inference of cell lineage and mitochondrial evolution from single-cell sequencing data","volume":"40","author":"P Sashittal","year":"2024","journal-title":"Bioinformatics"},{"issue":"10","key":"pcbi.1013090.ref015","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1016\/j.ccell.2023.09.003","article-title":"Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution","volume":"41","author":"H Zhang","year":"2023","journal-title":"Cancer Cell"},{"issue":"5","key":"pcbi.1013090.ref016","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nbt.2203","article-title":"Absolute quantification of somatic DNA alterations in human cancer","volume":"30","author":"SL Carter","year":"2012","journal-title":"Nat Biotechnol"},{"key":"pcbi.1013090.ref017","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jmp.2019.04.004","article-title":"A tutorial on Dirichlet Process mixture modeling","volume":"91","author":"Y Li","year":"2019","journal-title":"J Math Psychol"},{"issue":"7","key":"pcbi.1013090.ref018","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/s41591-018-0045-3","article-title":"Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing","volume":"24","author":"X Guo","year":"2018","journal-title":"Nat Med"},{"issue":"1","key":"pcbi.1013090.ref019","doi-asserted-by":"crossref","first-page":"5291","DOI":"10.1038\/s41467-021-25539-x","article-title":"Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis","volume":"12","author":"X Zhang","year":"2021","journal-title":"Nat Commun"},{"issue":"9","key":"pcbi.1013090.ref020","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1101\/gr.234062.117","article-title":"Single-cell RNA-seq analysis identifies markers of resistance to targeted BRAF inhibitors in melanoma cell populations","volume":"28","author":"Y-J Ho","year":"2018","journal-title":"Genome Res"},{"issue":"4","key":"pcbi.1013090.ref021","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3390\/ph11040101","article-title":"Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature","volume":"11","author":"A Pannunzio","year":"2018","journal-title":"Pharmaceuticals (Basel)"},{"issue":"1","key":"pcbi.1013090.ref022","doi-asserted-by":"crossref","first-page":"20","DOI":"10.20892\/j.issn.2095-3941.2019.0339","article-title":"COX-2 as a potential biomarker and therapeutic target in melanoma","volume":"17","author":"DV Tudor","year":"2020","journal-title":"Cancer Biol Med"},{"issue":"1","key":"pcbi.1013090.ref023","doi-asserted-by":"crossref","first-page":"12301","DOI":"10.1038\/s41598-019-48846-2","article-title":"MT2A is an early predictive biomarker of response to chemotherapy and a potential therapeutic target in osteosarcoma","volume":"9","author":"A Mangelinck","year":"2019","journal-title":"Sci Rep"},{"issue":"11","key":"pcbi.1013090.ref024","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1002\/2211-5463.13303","article-title":"Ferritin heavy chain (FTH1) exerts significant antigrowth effects in breast cancer cells by inhibiting the expression of c-MYC","volume":"11","author":"A Ali","year":"2021","journal-title":"FEBS Open Bio"},{"issue":"22","key":"pcbi.1013090.ref025","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1182\/blood.2020005795","article-title":"MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma","volume":"136","author":"Q Wang","year":"2020","journal-title":"Blood"},{"issue":"2","key":"pcbi.1013090.ref026","article-title":"MALAT1 Long Non-Coding RNA: Functional Implications","volume":"6","author":"G Arun","year":"2020","journal-title":"Noncoding RNA"},{"issue":"8","key":"pcbi.1013090.ref027","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1128\/AAC.46.8.2435-2441.2002","article-title":"Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum","volume":"46","author":"JM Peters","year":"2002","journal-title":"Antimicrob Agents Chemother"},{"issue":"6","key":"pcbi.1013090.ref028","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/S1535-6108(03)00310-6","article-title":"Targeting cyclooxygenase-2 in human neoplasia: rationale and promise","volume":"4","author":"AJ Dannenberg","year":"2003","journal-title":"Cancer Cell"},{"issue":"6","key":"pcbi.1013090.ref029","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/j.cell.2015.08.015","article-title":"Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity","volume":"162","author":"S Zelenay","year":"2015","journal-title":"Cell"},{"issue":"4","key":"pcbi.1013090.ref030","first-page":"655","article-title":"Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships","volume":"10","author":"A Zarghi","year":"2011","journal-title":"Iran J Pharm Res"},{"issue":"2","key":"pcbi.1013090.ref031","first-page":"240","article-title":"A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAF(V600E) colorectal tumors.","volume":"4","author":"A Ruiz-Saenz","year":"2023","journal-title":"Nat Cancer"},{"issue":"2","key":"pcbi.1013090.ref032","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S0165-6147(02)00043-3","article-title":"Cyclooxygenase 2: a molecular target for cancer prevention and treatment","volume":"24","author":"K Subbaramaiah","year":"2003","journal-title":"Trends Pharmacol Sci"},{"key":"pcbi.1013090.ref033","doi-asserted-by":"crossref","first-page":"268","DOI":"10.3389\/fonc.2019.00268","article-title":"Diverse Mechanisms of BRAF Inhibitor Resistance in Melanoma Identified in Clinical and Preclinical Studies","volume":"9","author":"SA Luebker","year":"2019","journal-title":"Front Oncol"},{"issue":"1","key":"pcbi.1013090.ref034","doi-asserted-by":"crossref","first-page":"19214","DOI":"10.1038\/s41598-020-76373-y","article-title":"Targeting PSMD14 inhibits melanoma growth through SMAD3 stabilization","volume":"10","author":"S Yokoyama","year":"2020","journal-title":"Sci Rep"},{"issue":"1","key":"pcbi.1013090.ref035","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1172\/JCI82534","article-title":"Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth","volume":"126","author":"M Dewaele","year":"2016","journal-title":"J Clin Invest"},{"issue":"1","key":"pcbi.1013090.ref036","doi-asserted-by":"crossref","first-page":"100882","DOI":"10.1016\/j.jbc.2021.100882","article-title":"PRPF19 regulates p53-dependent cellular senescence by modulating alternative splicing of MDM4 mRNA","volume":"297","author":"K Yano","year":"2021","journal-title":"J Biol Chem"},{"key":"pcbi.1013090.ref037","doi-asserted-by":"crossref","first-page":"598437","DOI":"10.3389\/fonc.2020.598437","article-title":"Elevated heterogeneous nuclear ribonucleoprotein C expression correlates with poor prognosis in patients with surgically resected lung adenocarcinoma","volume":"10","author":"W Guo","year":"2020","journal-title":"Front Oncol"},{"key":"pcbi.1013090.ref038","doi-asserted-by":"crossref","first-page":"580036","DOI":"10.3389\/fgene.2020.580036","article-title":"Effect of N6-Methyladenosine Regulators on Progression and Prognosis of Triple-Negative Breast Cancer","volume":"11","author":"S Wang","year":"2021","journal-title":"Front Genet"},{"issue":"5","key":"pcbi.1013090.ref039","doi-asserted-by":"crossref","first-page":"4804","DOI":"10.1002\/jcp.29357","article-title":"Identification of a prognostic alternative splicing signature in oral squamous cell carcinoma","volume":"235","author":"S Zhang","year":"2020","journal-title":"J Cell Physiol"},{"issue":"8","key":"pcbi.1013090.ref040","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1111\/jcmm.17254","article-title":"HNRNPC regulates RhoA to induce DNA damage repair and cancer-associated fibroblast activation causing radiation resistance in pancreatic cancer","volume":"26","author":"N Xia","year":"2022","journal-title":"J Cell Mol Med"},{"issue":"8","key":"pcbi.1013090.ref041","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/s41419-022-05157-1","article-title":"lncRNA CYTOR promotes aberrant glycolysis and mitochondrial respiration via HNRNPC-mediated ZEB1 stabilization in oral squamous cell carcinoma","volume":"13","author":"W Zhu","year":"2022","journal-title":"Cell Death Dis"},{"issue":"39","key":"pcbi.1013090.ref042","article-title":"mitoSplitter: A mitochondrial variants-based method for efficient demultiplexing of pooled single-cell RNA-seq","volume":"120","author":"X Lin","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pcbi.1013090.ref043","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2019.10.003","article-title":"Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma","volume":"179","author":"Q Zhang","year":"2019","journal-title":"Cell"},{"issue":"12","key":"pcbi.1013090.ref044","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1158\/2159-8290.CD-19-0329","article-title":"The Phenotypes of Proliferating Glioblastoma Cells Reside on a Single Axis of Variation","volume":"9","author":"L Wang","year":"2019","journal-title":"Cancer Discov"},{"issue":"3","key":"pcbi.1013090.ref045","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1086\/368264","article-title":"The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates","volume":"72","author":"N Howell","year":"2003","journal-title":"Am J Hum Genet"},{"issue":"3","key":"pcbi.1013090.ref046","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1073\/pnas.0912629107","article-title":"Rate, molecular spectrum, and consequences of human mutation","volume":"107","author":"M Lynch","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pcbi.1013090.ref047","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3390\/axioms12010012","article-title":"Numbers of Mutations within Multicellular Bodies: Why It Matters","volume":"12","author":"SA Frank","year":"2022","journal-title":"Axioms"},{"issue":"44","key":"pcbi.1013090.ref048","doi-asserted-by":"crossref","first-page":"18026","DOI":"10.1073\/pnas.1114759108","article-title":"Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants","volume":"108","author":"J-H Park","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pcbi.1013090.ref049","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.ajhg.2014.09.001","article-title":"Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants","volume":"95","author":"AE Shearer","year":"2014","journal-title":"Am J Hum Genet"},{"issue":"2","key":"pcbi.1013090.ref050","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1101\/gr.10.2.258","article-title":"High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR","volume":"10","author":"S Germer","year":"2000","journal-title":"Genome Res"},{"issue":"4","key":"pcbi.1013090.ref051","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"B Langmead","year":"2012","journal-title":"Nat Methods"},{"issue":"1","key":"pcbi.1013090.ref052","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"A Dobin","year":"2013","journal-title":"Bioinformatics"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013090","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T13:28:40Z","timestamp":1750685320000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013090"}},"subtitle":[],"editor":[{"given":"Simone","family":"Zaccaria","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2025,6,23]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1013090","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.11.22.568285","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,23]]}}}