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bioRxiv · 10.1101/2025.10.27.684751

Developing Y chromosome sex ratio distorters in the model insect Drosophila melanogaster

Arien, Y.·Zacharia, C.·Yonah, E.·Bonda, E.·Papathanos, P. A.
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Abstract

CRISPR-Cas9 sex ratio distortion (SRD) systems can suppress insect populations by biasing progeny toward males, but realizing such systems requires reliable Cas9 expression from insect Y chromosomes. Here, we tested whether the spermatocyte-specific {beta}Tub85D promoter can drive functional Cas9 expression when inserted on the Drosophila melanogaster Y chromosome. Using CRISPR-mediated homology-directed repair, we generated a Y-linked {beta}Tub85D-Cas9-T2A-eGFP construct and compared its activity with an autosomal counterpart. Whereas autosomal {beta}Tub85D-Cas9 induced strong male-biased sex ratios when paired with an X-poisoning gRNA, the Y-linked construct failed to distort sex ratios and exhibited approximately 2,000-fold reduction in Cas9 transcript abundance. Nonetheless, weak but detectable GFP fluorescence and Cas9 transcripts confirmed partial Y-linked promoter activity. These findings provide the first direct experimental evidence of meiotic sex chromosome inactivation (MSCI) acting on the Drosophila Y chromosome, revealing that meiotic promoters can remain weakly active despite strong repression. This work defines transcriptional limits of the Drosophila Y chromosome and informs the design of next-generation Y-linked gene drives for sustainable insect control.

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Arien, Y., Zacharia, C., Yonah, E., Bonda, E., Papathanos, P. A.. 2025-10-27. Developing Y chromosome sex ratio distorters in the model insect Drosophila melanogaster. https://doi.org/10.1101/2025.10.27.684751

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