Abstract
ABSTRACT Genetic control strategies aimed to bias the sex of progenies towards males present a promising new paradigm to eliminate malaria-transmitting mosquitoes. A synthetic sex-ratio distortion (SD) system was successfully engineered in Anopheles gambiae by exploiting the meiotic activity of the I-PpoI endonuclease targeting ribosomal DNA (rDNA) repeats, exclusively located on the X chromosome. Males carrying the SD construct produce highly male-biased progenies without evident reduction in fertility. In this study, we investigated the fate of X and Y chromosomes in these SD males and found that ratios of mature X:Y-bearing sperm were comparable to wild-type insects, indicating absence of selection mechanisms during sperm maturation. We therefore tested the effect of meiotic cleavage of both X and Y chromosomes in a lab-generated SD strain carrying rDNA on both sex chromosomes, showing fertility comparable to wild-type and a reduced male-bias compared to SD males in which only the X is targeted. Exposure of Y-linked rDNA to I-PpoI cleavage for consecutive generations rapidly restored the male-bias to typical high frequencies, indicating a correlation between the number of cleavable targets in each sex chromosome and the sex-ratios found in the progeny. Altogether our results indicate that meiotic cleavage of rDNA repeats, located in the sex chromosomes of A. gambiae SD males, affects the competitiveness of mature sperm to fertilize the female oocyte, thereby generating sex-biased progenies. We also show that the presence of rDNA copies on the Y chromosome does not impair the effectiveness of engineered synthetic SD systems for the control of human malaria mosquitoes.
Highlights
Malaria is one of the most severe global health pro blems
To investigate whether sperm carrying the shredded X chromosome were removed before reaching matura tion, fluorescence in situ hybridization (FISH), using X and Y-specific probes, was performed on dissected Ag(PMB)1 testes as well as the spermathecae of females mated with Ag(PMB)1 males
We studied the impact of meiotic cleavage on the preferential inheritance of the sex chromosomes in transgenic males carrying ribosomal DNA (rDNA) clus ters in both Y and X chromosomes
Summary
Malaria is one of the most severe global health pro blems. Caused by the Plasmodium parasite, malaria was responsible for an estimated 435,000 deaths in 2017, mostly in Africa [1]. The female mosqui toes take human blood meals to obtain essential nutri ents for the development of their eggs and transmit the malaria-causing parasites during an infective bite. One of the most powerful genetic control approaches proposed, known as sex ratio distortion (SD), requires the devel opment of fully fertile Anopheles male mosquitoes that are able to produce a normal number of progenies but mostly consisting of males. Their release in wild popu lations would cause a progressive reduction in the number of malaria-transmitting females and, at the same time, diminish their population size. Occurring male-biased SD systems ( defined as natural ‘meiotic drivers’), found in Aedes aegypti [2] and Culex pipiens [3] males, are associated with prefer ential breakage of sex chromosomes during the first meiotic division [2,3]
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