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Here, we developed a Targeted chromosome Elimination And Microcell-mediated chromosome transfer platform (TEAM) for chromosome replacement combining CRISPR\/Cas9-mediated chromosome elimination with microcell-mediated chromosome transfer (MMCT). Using this approach, we substituted the endogenous mouse Y chromosome (chrY) with either the mouse or human Y chromosome. Intraspecies substitutions yielded karyotypically stable embryonic stem cells that supported development into adult males. By contrast, in interspecies CSS, human chrY displayed severe instability and progressive DNA damage. Despite partial transcription of human chrY genes, recipient animals exhibited systemic inflammation, high rates of neonatal death, and poor growth. Reduced CENP-A levels were observed at human chrY centromeres, leading to segregation errors, micronuclei formation, and widespread chromosome rearrangements. This technology enables programmable construction of chromosome substitution models for investigating chromosomal function, genome evolution, and synthetic karyotype design in mammals.<\/jats:p>","DOI":"10.1093\/procel\/pwag010","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T12:38:32Z","timestamp":1772541512000},"page":"528-542","source":"Crossref","is-referenced-by-count":1,"title":["A programmable platform enabling targeted chromosome substitution and cross-species stability profiling"],"prefix":"10.1093","volume":"17","author":[{"given":"Lei","family":"Shi","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genome and Multi-omics Technologies, Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Gene Editing Technologies (Hainan), Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences , Shenzhen 518120,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiali","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genome and Multi-omics Technologies, Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Gene Editing Technologies (Hainan), Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences , Shenzhen 518120,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingdi","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genome and Multi-omics Technologies, Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Gene Editing Technologies (Hainan), Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences , Shenzhen 518120,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengye","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genome and Multi-omics Technologies, Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Gene Editing Technologies (Hainan), Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences , Shenzhen 518120,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9863-1668","authenticated-orcid":false,"given":"Jun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Texas Southwestern Medical Center , Dallas, TX 75235,","place":["United States"]},{"name":"Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center , Dallas, TX 75235,","place":["United States"]},{"name":"Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center , Dallas, TX 75235,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwei","family":"Zuo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genome and Multi-omics Technologies, Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Gene Editing Technologies (Hainan), Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences , Shenzhen 518120,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"2026060117172084100_pwag010-B1","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.3390\/plants10061158","article-title":"Effects of interspecific chromosome substitution in upland cotton on 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