Abstract
Only female insects transmit diseases such as malaria, dengue and Zika; therefore, control methods that bias the sex ratio of insect offspring have long been sought. Genetic elements such as sex-chromosome drives can distort sex ratios to produce unisex populations that eventually collapse, but the underlying molecular mechanisms are unknown. We report a male-biased sex-distorter gene drive (SDGD) in the human malaria vector Anopheles gambiae. We induced super-Mendelian inheritance of the X-chromosome-shredding I-PpoI nuclease by coupling this to a CRISPR-based gene drive inserted into a conserved sequence of the doublesex (dsx) gene. In modeling of invasion dynamics, SDGD was predicted to have a quicker impact on female mosquito populations than previously developed gene drives targeting female fertility. The SDGD at the dsx locus led to a male-only population from a 2.5% starting allelic frequency in 10–14 generations, with population collapse and no selection for resistance. Our results support the use of SDGD for malaria vector control.
Highlights
Female insects transmit diseases such as malaria, dengue and Zika; control methods that bias the sex ratio of insect offspring have long been sought
Y drives are attractive for mosquito vector control because they can progressively reduce the number of females and disease transmission as they spread
We used mathematical modeling to test the likely spread of this sex-distorter gene drive (SDGD) design
Summary
Female insects transmit diseases such as malaria, dengue and Zika; control methods that bias the sex ratio of insect offspring have long been sought. Synthetic sex distorters have been generated in A. gambiae mosquitoes by using site-specific nucleases such as I-PpoI or CRISPR– Cas[9], which cleave conserved repeated sequences in the mosquito ribosomal DNA gene cluster located exclusively on the X chromosome[13,14] These nucleases, when expressed during spermatozoa development, selectively cleave the X chromosome, thereby favoring the production of Y-bearing gametes and causing a 95% male bias in the progeny[13,14]. We hypothesized that it might be possible to circumvent meiotic sex-chromosome inactivation by developing an autosomal male-biased sex distorter and coupling sex-ratio distortion with drive This could result in a quicker impact on disease transmission and a synergistic effect (robustness) between the sex distorter and gene-drive components. We report the design and validation of an SDGD to spread the X-chromosome-shredding I-PpoI endonuclease and produce a male-only insect population
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