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However, a single clustering resolution may not yield groups of cells that represent both broad, well-defined populations and smaller subpopulations simultaneously. Therefore, when cell identities are not known prior to sequencing, robust comparison and annotation of inferred de novo clusters remains a challenge. Here, we introduce CANTAO, in which we propose the average overlap metric to define the distance between single-cell clusters by comparing ranked lists of differentially expressed genes in a top-weighted manner. We benchmark CANTAO in truth-known datasets comprised of similar yet distinct cell populations and show that evaluating clusters with average overlap results in a consistent, precise, and biologically meaningful recapitulation of true cell identities. We then analyze unsorted mouse thymocytes and characterize stages of T-cell development in the thymus, including minor populations of double-negative (CD4-CD8-) T cells that are difficult to confidently detect among unsorted single cells. We demonstrate that CANTAO enables robust, reproducible characterization of single-cell data and clarifies biological interpretation of underlying identities in homogeneous populations.<\/jats:p>","DOI":"10.1038\/s44320-025-00176-4","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T12:26:09Z","timestamp":1765196769000},"page":"461-475","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CANTAO: guiding clustering and annotation in single-cell RNA sequencing using average overlap"],"prefix":"10.1038","volume":"22","author":[{"given":"Christopher","family":"Thai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2422-3068","authenticated-orcid":false,"given":"Amartya","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1768-5969","authenticated-orcid":false,"given":"Daniel","family":"Herranz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1446-4394","authenticated-orcid":false,"given":"Hossein","family":"Khiabanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"176_CR1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","volume":"20","author":"D Aran","year":"2019","unstructured":"Aran D, Looney AP, Liu L, Wu E, Fong V, Hsu A, Chak S, Naikawadi RP, Wolters PJ, Abate AR et al (2019) Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. 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HK is a full-time employee of Regeneron Pharmaceuticals.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}]}}