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Mosaic integration, the most general integration task, poses a greater challenge regarding disparity in modality abundance across datasets. Here, we present Align and CompletE (ACE), a mosaic integration framework that assembles two types of strategies to handle this problem: modality alignment-based strategy (ACE-align) and regression-based strategy (ACE-spec). ACE-align utilizes a novel contrastive learning objective for explicit modality alignment to uncover the shared latent representations behind modalities. ACE-spec combines the modality alignment results and modality-specific representations to construct complete multi-omics representations for all datasets. Extensive experiments across various mosaic integration scenarios demonstrate the superiority of ACE\u2019s two strategies over existing methods. Application of ACE-spec to bi-modal and tri-modal integration scenarios showcases that ACE-spec is able to enhance the representation of cellular heterogeneities for datasets with incomplete modalities. The source code of ACE can be accessed at https:\/\/github.com\/CSUBioGroup\/ACE-main.<\/jats:p>","DOI":"10.1093\/gpbjnl\/qzaf062","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T13:19:00Z","timestamp":1754313540000},"source":"Crossref","is-referenced-by-count":0,"title":["ACE: A Versatile Contrastive Learning Framework for Single-cell Mosaic Integration"],"prefix":"10.1093","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3183-3342","authenticated-orcid":false,"given":"Xuhua","family":"Yan","sequence":"first","affiliation":[{"name":"School of Computer Science and Engineering, Central South University , Changsha 410083,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7547-6423","authenticated-orcid":false,"given":"Jinmiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Computational Biology and Program in Cancer and Stem Cell Biology, Duke-NUS Medical School , Singapore 169857,","place":["Singapore"]},{"name":"Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR) , Singapore 138671,","place":["Singapore"]},{"name":"Immunology Translational Research Program, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore (NUS) , Singapore 117545,","place":["Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6372-6798","authenticated-orcid":false,"given":"Ruiqing","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Central South University , Changsha 410083,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0188-1394","authenticated-orcid":false,"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, 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