Targeting mosquito X-chromosomes reveals complex transmission dynamics of sex ratio distorting gene drives

Daniella An Haber, Yael Arien, Lee Benjamin Lamdan, Yehonathan Alcalay, Chen Zecharia, Flavia Krsticevic, Elad Shmuel Yonah, Rotem Daniel Avraham, Elzbieta Krzywinska, Jaroslaw Krzywinski, Eric Marois, Nikolai Windbichler and Philippos Aris Papathanos ()
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Daniella An Haber: Hebrew University of Jerusalem
Yael Arien: Hebrew University of Jerusalem
Lee Benjamin Lamdan: Hebrew University of Jerusalem
Yehonathan Alcalay: Hebrew University of Jerusalem
Chen Zecharia: Hebrew University of Jerusalem
Flavia Krsticevic: Hebrew University of Jerusalem
Elad Shmuel Yonah: Hebrew University of Jerusalem
Rotem Daniel Avraham: Hebrew University of Jerusalem
Elzbieta Krzywinska: The Pirbright Institute
Jaroslaw Krzywinski: The Pirbright Institute
Eric Marois: Université de Strasbourg, INSERM, CNRS
Nikolai Windbichler: Imperial College London
Philippos Aris Papathanos: Hebrew University of Jerusalem

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Engineered sex ratio distorters (SRDs) have been proposed as a powerful component of genetic control strategies designed to suppress harmful insect pests. Two types of CRISPR-based SRD mechanisms have been proposed: X-shredding, which eliminates X-bearing sperm, and X-poisoning, which eliminates females inheriting disrupted X-chromosomes. These differences can have a profound impact on the population dynamics of SRDs when linked to the Y-chromosome: an X-shredder is invasive, constituting a classical meiotic Y-drive, whereas X-poisoning is self-limiting, unable to invade but also insulated from selection. Here, we establish X-poisoning strains in the malaria vector Anopheles gambiae targeting three X-linked genes during spermatogenesis, resulting in male bias. We find that sex distortion is primarily driven by a loss of X-bearing sperm, with limited evidence for postzygotic lethality of female progeny. By leveraging a Drosophila melanogaster model, we show unambiguously that engineered SRD traits can operate differently in these two insects. Unlike X-shredding, X-poisoning could theoretically operate at early stages of spermatogenesis. We therefore explore premeiotic Cas9 expression to target the mosquito X-chromosome. We find that, by pre-empting the onset of meiotic sex chromosome inactivation, this approach may enable the development of Y-linked SRDs if mutagenesis of spermatogenesis-essential genes is functionally balanced.

Date: 2024
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DOI: 10.1038/s41467-024-49387-7

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