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Abstract Horizontal gene transfer drives rapid evolutionary innovation, yet well-substantiated cases are largely confined to prokaryotes. Eukaryote-to-eukaryote transfer remains exceptionally rare, and direct genome-scale demonstrations are absent. Here, inspired by endosymbiotic genome acquisition, we show that mammalian cells can initiate genome-scale horizontal gene transfer through phagocytic uptake of intact algal cells, albeit at a much lower frequency than cell fusion.
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