Transposable Element insertions Repurpose Immune Endonucleases as Drivers of Reproductive Isolation in Mice

Rucker, T.; Vandormael-Pournin, S.; Mordier, J.; Lecompte, L.; Tessandier, A.; Navarro, P.; Bourc'his, D.; Molaro, a.; Cohen-Tannoudji, M.

doi:10.64898/2026.09.24.753999

bioRxiv · 10.64898/2026.09.24.753999

Transposable Element insertions Repurpose Immune Endonucleases as Drivers of Reproductive Isolation in Mice

Rucker, T.·Vandormael-Pournin, S.·Mordier, J.·Lecompte, L.·Tessandier, A.·Navarro, P.·Bourc'his, D.·Molaro, a.·Cohen-Tannoudji, M.

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Abstract

The emergence of reproductive barriers between closely related populations is a fundamental step in speciation, yet the underlying genetic mechanisms remain poorly understood in mammals. Here we resolve the DDK syndrome, a long-standing model of hybrid incompatibility in mice, by showing that two independent retrotransposon insertions rewire immune Schlafen endoribonuclease genes expression, causing hybrid embryo death. A DDK-private MERVL element drives ectopic oocyte expression of Slfn1, while an intragenic ETn/MusD insertion in incompatible strains is associated with zygotic Slfn15 expression. SLFN1-SLFN15 heterodimerization constitutively activates tRNA ribonuclease activity, leading to global translation inhibition, and integrated stress response activation. Abolishing SLFN1 catalytic activity or SLFN15 expression rescues syndromic embryo development. Our findings uncover a previously unrecognized speciation mechanism in which transposable elements repurpose immune effectors as drivers of postzygotic reproductive isolation.

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Rucker, T., Vandormael-Pournin, S., Mordier, J., Lecompte, L., Tessandier, A., Navarro, P., Bourc'his, D., Molaro, a., Cohen-Tannoudji, M.. 2026-09-24. Transposable Element insertions Repurpose Immune Endonucleases as Drivers of Reproductive Isolation in Mice. https://doi.org/10.64898/2026.09.24.753999

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