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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.
摘要：
已提出工程性别比例扭曲器（SRD）作为旨在抑制有害害虫的遗传控制策略的强大组成部分。已经提出了两种类型的基于CRISPR的SRD机制：X-切碎，消除了携带X的精子，和X中毒，消除了女性遗传被破坏的X染色体。当与Y染色体相连时，这些差异会对SRD的种群动态产生深远的影响：X-碎纸机具有侵入性，构成了经典的减数分裂Y型驱动器，而X中毒是自我限制的，无法入侵，但也与选择隔绝。这里,我们在精子发生过程中针对三个X连锁基因的疟疾载体冈比亚按蚊中建立了X中毒菌株，导致男性偏见。我们发现性别扭曲主要是由携带X的精子丢失引起的，关于雌性后代合子后致死性的证据有限。通过利用果蝇模型，我们清楚地表明，工程SRD性状可以在这两种昆虫中不同地运作。不像X-切碎，X中毒理论上可以在精子发生的早期阶段起作用。因此，我们探索了减数分裂前Cas9表达以靶向蚊子X染色体。我们发现,通过预防减数分裂性染色体失活的发生，如果精子发生必需基因的诱变在功能上平衡，这种方法可能使Y连锁SRD的发展成为可能。
