Clonal Dynamics in the Male Germline from Development to Next Generation

Ikeda, T.; Langhinrichs, M.; Nizharadze, T.; Koike, C.; Kato, Y.; Yamaguchi, K.; Shigenobu, S.; Yoshido, K.; Suzuki, S.; Nakagawa, T.; Maruyama, A.; Mizuno, S.; Takahashi, S.; Rodewald, H.-R.; Höfer, T.; Yoshida, S.

doi:10.1101/2025.09.02.672339

bioRxiv · 10.1101/2025.09.02.672339

Clonal Dynamics in the Male Germline from Development to Next Generation

Ikeda, T.·Langhinrichs, M.·Nizharadze, T.·Koike, C.·Kato, Y.·Yamaguchi, K.·Shigenobu, S.·Yoshido, K.·Suzuki, S.·Nakagawa, T.·Maruyama, A.·Mizuno, S.·Takahashi, S.·Rodewald, H.-R.·Höfer, T.·Yoshida, S.

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Abstract

Germ cells secure the continuity and evolutionary potential of species. Yet how reproductive success is allocated among the founder cells of the mammalian male germline, the primordial germ cells (PGCs), remains unknown. Here, we quantitatively traced individual PGCs, non-invasively barcoded in mouse embryos, across their establishment, lifelong maintenance within the testis, spermatogenesis, and transmission to the next generation. We found that highly skewed clonal contributions arise from a very early stochastic bottleneck during migration to the developing testes and remain stable throughout adult reproductive life. Reproductive success during adulthood was proportional to the embryonically established PGC clone size. Mathematical modeling shows that the patchy compartmentalization of PGC clones within the extended thin seminiferous tubules maintain clonal diversity and safeguard against the expansion of clones that gain a selective advantage. These findings uncover fundamental principles governing the development, stability, and evolutionary transmission of the mammalian germline.

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Ikeda, T., Langhinrichs, M., Nizharadze, T., Koike, C., Kato, Y., Yamaguchi, K., Shigenobu, S., Yoshido, K., Suzuki, S., Nakagawa, T., Maruyama, A., Mizuno, S., Takahashi, S., Rodewald, H.-R., Höfer, T., Yoshida, S.. 2025-09-02. Clonal Dynamics in the Male Germline from Development to Next Generation. https://doi.org/10.1101/2025.09.02.672339

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