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15 reviewsThomas O’Leary3, David Lee3, Sacha Krieg3, Diana Wu3, Elizabeth Rubin3,1234567890():,;1234567890():,;Check for updatesPaula Amato1,3 & Shoukhrat Mitalipov 1Somatic cell nuclear transfer (SCNT) enables the direct reprogramming ofsomatic cells into functional oocytes, albeit with a diploid genome. To addressploidy reduction, we investigated an experimental reductive cell divisionprocess, termed mitomeiosis, wherein non-replicated (2n2c) somatic genomesare prematurely forced to divide following transplantation into the metaphasecytoplasm of enucleated human oocytes. However, despite fertilization withsperm, SCNT oocytes remained arrested at the metaphase stage, indicatingactivation failure. Artificial activation using a selective cyclin-dependent kinaseinhibitor successfully bypassed this arrest, inducing the segregation ofsomatic chromosomes into a zygotic pronucleus and a polar body. Comprehensive chromosome tracing via sequencing revealed that homologouschromosome segregation occurred randomly and without crossover recombination. Nonetheless, an average of 23 somatic chromosomes were retainedwithin the zygote, demonstrating the feasibility of experimentally halving thediploid chromosome set. Fertilized human SCNT oocytes progressed throughnormal embryonic cell divisions, ultimately developing into embryos withintegrated somatic and sperm-derived chromosomes. While our studydemonstrates the potential of mitomeiosis for in vitro gametogenesis, at thisstage it remains just a proof of concept and further research is required toensure efficacy and safety before future clinical applications.