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While it may contribute to pathogen virulence and drug resistance, hybridization remains poorly characterized, particularly how genetic distance between parental cells influences genomic compatibility and which compensatory mechanisms ensure hybrid viability. Here, we report the in vitro generation of an unusual sexual hybrid between Leishmania species infecting mammals (L. infantum) and reptiles (the Sauroleishmania L. tarentolae), and used this unique genetic model system to address these open questions. Our data provide evidence of genomic compatibility between even highly divergent Leishmania species, offering new insights into the evolutionary potential of Leishmania and related pathogens. We demonstrate that the genomic shock caused by the fusion of distinct genomes can be mitigated by two key mechanisms: (i) at the genomic level, chromosome loss allows the establishment of mosaic aneuploidy in the newly formed hybrid, and (ii) at the post-transcriptional level, preferential mono-parental allelic expression acts as a secondary compensatory mechanism. Our findings establish genome instability and post-transcriptional regulation as central processes in Leishmania hybridization, which may be of broad relevance to other biological systems undergoing genetic exchange.<\/jats:p>","DOI":"10.1093\/narmme\/ugag015","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T13:06:05Z","timestamp":1773234365000},"source":"Crossref","is-referenced-by-count":0,"title":["Genomic instability and mono-parental expression mitigate genomic shock in a cross-subgenus\n                    <i>Leishmania<\/i>\n                    hybrid"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5046-5557","authenticated-orcid":false,"given":"Viviane Noll","family":"Louzada-Flores","sequence":"first","affiliation":[{"name":"Department of Veterinary Medicine, University of Bari , 70010 Valenzano ,","place":["Italy"]},{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, INSERM U1347, Unit\u00e9 de Parasitologie mol\u00e9culaire et Signalisation , F-75015 Paris ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6286-1138","authenticated-orcid":false,"given":"Thomas","family":"Cokelaer","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, INSERM U1347, Unit\u00e9 de Parasitologie mol\u00e9culaire et Signalisation , F-75015 Paris ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9751-6753","authenticated-orcid":false,"given":"Marcela","family":"Fuentes-Carias","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, INSERM U1347, Unit\u00e9 de Parasitologie mol\u00e9culaire et Signalisation , F-75015 Paris ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2796-7855","authenticated-orcid":false,"given":"Pascale","family":"Pescher","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, INSERM U1347, Unit\u00e9 de Parasitologie mol\u00e9culaire et Signalisation , F-75015 Paris ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4894-1515","authenticated-orcid":false,"given":"Tiago Rodrigues","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9061-437X","authenticated-orcid":false,"given":"Maria Stefania","family":"Latrofa","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, University of Bari , 70010 Valenzano ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9787-932X","authenticated-orcid":false,"given":"Jairo Alfonso","family":"Mendoza-Roldan","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, University of Bari , 70010 Valenzano ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7518-476X","authenticated-orcid":false,"given":"Domenico","family":"Otranto","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, University of Bari , 70010 Valenzano ,","place":["Italy"]},{"name":"Department of Veterinary Clinical Sciences, City University of Hong Kong , Hong Kong 999077 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0256-2029","authenticated-orcid":false,"given":"Gerald F","family":"Sp\u00e4th","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, INSERM U1347, Unit\u00e9 de Parasitologie mol\u00e9culaire et Signalisation , F-75015 Paris ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2940-8539","authenticated-orcid":false,"given":"Isabelle","family":"Louradour","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, INSERM U1347, Unit\u00e9 de Parasitologie mol\u00e9culaire et Signalisation , F-75015 Paris 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