%0 Journal Article
%T Targeting mosquito X-chromosomes reveals complex transmission dynamics of sex ratio distorting gene drives.
%A Haber DA
%A Arien Y
%A Lamdan LB
%A Alcalay Y
%A Zecharia C
%A Krsticevic F
%A Yonah ES
%A Avraham RD
%A Krzywinska E
%A Krzywinski J
%A Marois E
%A Windbichler N
%A Papathanos PA
%J Nat Commun
%V 15
%N 1
%D 2024 Jun 11
%M 38862555
%F 17.694
%R 10.1038/s41467-024-49387-7
%X 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.