A synthetic sex ratio distortion system for the control of the human malaria mosquito.
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ABSTRACT:
SUBMITTER: Galizi R
PROVIDER: S-EPMC4057611 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Genetic control aims to reduce the ability of insect pest populations to cause harm via the release of modified insects. One strategy is to bias the reproductive sex ratio towards males so that a population decreases in size or is eliminated altogether due to a lack of females. We have shown previously that sex ratio distortion can be generated synthetically in the main human malaria vector Anopheles gambiae, by selectively destroying the X-chromosome during spermatogenesis, through the activity of a naturally-occurring endonuclease that targets a repetitive rDNA sequence highly-conserved in a wide range of organisms. Here we describe a CRISPR-Cas9 sex distortion system that targets ribosomal sequences restricted to the member species of the Anopheles gambiae complex. Expression of Cas9 during spermatogenesis resulted in RNA-guided shredding of the X-chromosome during male meiosis and produced extreme male bias among progeny in the absence of any significant reduction in fertility. The flexibility of CRISPR-Cas9 combined with the availability of genomic data for a range of insects renders this strategy broadly applicable for the species-specific control of any pest or vector species with an XY sex-determination system by targeting sequences exclusive to the female sex chromosome.
| S-EPMC4971495 | biostudies-literature
Project description:Genetic methods of manipulating or eradicating disease vector populations have long been discussed as an attractive alternative to existing control measures because of their potential advantages in terms of effectiveness and species specificity. The development of genetically engineered malaria-resistant mosquitoes has shown, as a proof of principle, the possibility of targeting the mosquito's ability to serve as a disease vector. The translation of these achievements into control measures requires an effective technology to spread a genetic modification from laboratory mosquitoes to field populations. We have suggested previously that homing endonuclease genes (HEGs), a class of simple selfish genetic elements, could be exploited for this purpose. Here we demonstrate that a synthetic genetic element, consisting of mosquito regulatory regions and the homing endonuclease gene I-SceI, can substantially increase its transmission to the progeny in transgenic mosquitoes of the human malaria vector Anopheles gambiae. We show that the I-SceI element is able to invade receptive mosquito cage populations rapidly, validating mathematical models for the transmission dynamics of HEGs. Molecular analyses confirm that expression of I-SceI in the male germline induces high rates of site-specific chromosomal cleavage and gene conversion, which results in the gain of the I-SceI gene, and underlies the observed genetic drive. These findings demonstrate a new mechanism by which genetic control measures can be implemented. Our results also show in principle how sequence-specific genetic drive elements like HEGs could be used to take the step from the genetic engineering of individuals to the genetic engineering of populations.
| S-EPMC3093433 | biostudies-literature
Project description:An endogenous meiotic driver in the dengue and yellow fever vector mosquito Aedes aegypti can cause highly male-biased sex ratio distortion in crosses from suitable genetic backgrounds. We previously selected a strain that carries a strong meiotic drive gene (D) linked with the male-determining allele (M) on chromosome 1 in A. aegypti. Here, we performed segregation analysis of the M(D) locus among backcross (BC(1)) progeny from a driver male and drive-sensitive females. Assessment of sex ratios among BC(2) progeny showed ?5.2% recombination between the M(D) locus and the sex determination locus. Multipoint linkage mapping across this region revealed consistent marker orders and recombination frequencies with the existing reference linkage map and placed the M(D) locus within a 6.5-cm interval defined by the LF159 locus and microsatellite marker 446GAA, which should facilitate future positional cloning efforts.
| S-EPMC3283506 | biostudies-literature
Project description: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.
| S-EPMC7580827 | biostudies-literature
Project description:Introgression of a synthetic sex ratio distortion transgene into local genetic backgrounds of Anopheles coluzzii
| PRJEB48699 | ENA
Project description:In virtually all multicellular eukaryotes, mitochondria are transmitted exclusively through one parent, usually the mother. In this short review, we discuss some of the major consequences of uniparental transmission of mitochondria, including deleterious effects in males and selection for increased transmission through females. Many of these consequences, particularly sex ratio distortion, have well-studied parallels in other maternally transmitted genetic elements, such as bacterial endosymbionts of arthropods. We also discuss the consequences of linkage between mitochondria and other maternally transmitted genetic elements, including the role of cytonuclear incompatibilities in maintaining polymorphism. Finally, as a case study, we discuss a recently discovered maternally transmitted sex ratio distortion in an insect that is associated with extraordinarily divergent mitochondria.
| S-EPMC4547267 | biostudies-literature
Project description:BackgroundAt the turn of the 19th century the first observations of a female-biased sex ratio in broods and populations of the head louse, Pediculus humanus capitis, had been reported. A study by Buxton in 1940 on the sex ratio of lice on prisoners in Ceylon is still today the subject of reanalyses. This sex ratio distortion had been detected in ten different countries. In the last sixty years no new data have been collected, especially on scalp infestations under economically and socially more developed conditions.ResultsHere we report a female bias of head lice in a survey of 480 school children in Argentina. This bias is independent of the intensity of the pediculosis, which makes local mate competition highly unlikely as the source of the aberrant sex ratio; however, other possible adaptive mechanisms cannot be discounted. These lice as well as lice from pupils in Britain were carrying several strains of the endosymbiotic bacterium Wolbachia pipientis, one of the most wide spread intracellular sex ratio distorters. Similar Wolbachia strains are also present in the pig louse, Haematopinus suis, suggesting that this endosymbiont might have a marked influence on the biology of the whole order. The presence of a related obligate nutritional bacterium in lice prevents the investigation of a causal link between sex ratio and endosymbionts.ConclusionsRegardless of its origin, this sex ratio distortion in head lice that has been reported world wide, is stable over time and is a remarkable deviation from the stability of frequency-dependent selection of Fisher's sex ratio. A female bias first reported in 1898 is still present over a hundred years and a thousand generations later.
| S-EPMC428572 | biostudies-literature
Project description:Escherichia coli AlkB is a 2-oxoglutarate- and iron-dependent dioxygenase that reverses alkylated DNA damage by oxidative demethylation. Mouse AlkB homolog 1 (Alkbh1) is one of eight members of the newly discovered family of mammalian dioxygenases.In the present study we show non-Mendelian inheritance of the Alkbh1 targeted allele in mice. Both Alkbh1(-/-) and heterozygous Alkbh1(+/-) offspring are born at a greatly reduced frequency. Additionally, the sex-ratio is considerably skewed against female offspring, with one female born for every three to four males. Most mechanisms that cause segregation distortion, act in the male gametes and affect male fertility. The skewing of the sexes appears to be of paternal origin, and might be set in the pachythene stage of meiosis during spermatogenesis, in which Alkbh1 is upregulated more than 10-fold. In testes, apoptotic spermatids were revealed in 5-10% of the tubules in Alkbh1(-/-) adults. The deficiency of Alkbh1 also causes misexpression of Bmp2, 4 and 7 at E11.5 during embryonic development. This is consistent with the incompletely penetrant phenotypes observed, particularly recurrent unilateral eye defects and craniofacial malformations.Genetic and phenotypic assessment suggests that Alkbh1 mediates gene regulation in spermatogenesis, and that Alkbh1 is essential for normal sex-ratio distribution and embryonic development in mice.
| S-EPMC2972218 | biostudies-literature
Project description:BackgroundMore effective mosquito control strategies are urgently required due to the increasing prevalence of insecticide resistance. The sterile insect technique (SIT) and the release of insects carrying a dominant lethal allele (RIDL) are two proposed methods for environmentally-friendly, species-targeted population control. These methods may be more suitable for developing countries if producers reduce the cost of rearing insects. The cost of control programs could be reduced by producing all-male mosquito populations to circumvent the isolation of females before release without reducing male mating competitiveness caused by transgenes.ResultsAn RNAi construct targeting the RNA recognition motif of the Aedes aegypti transformer-2 (tra-2) gene does not trigger female-to-male sex conversion as commonly observed among dipterous insects. Instead, homozygous insects show greater mortality among m-chromosome-bearing sperm and mm zygotes, yielding up to 100% males in the subsequent generations. The performance of transgenic males was not significantly different to wild-type males in narrow-cage competitive mating experiments.ConclusionOur data provide preliminary evidence that the knockdown of Ae. aegypti tra-2 gene expression causes segregation distortion acting at the level of gametic function, which is reinforced by sex-specific zygotic lethality. This finding could promote the development of new synthetic sex distorter systems for the production of genetic sexing mosquito strains.
| S-EPMC4730765 | biostudies-literature
Project description:The congenic HG.CAST-(D17Mit196-D17Mit190) (HQ17(hg/hg)) mouse strain showed a significant departure on the expected 50%/50% offspring sex ratio in more than 2400 progeny (55.7% females). The entire pedigree file included data from 13 nonoverlapping purebred generations and an F(2) cross with the C57BL/6J inbred strain. Offspring sex ratio data were analyzed on the basis of 40 purebred HQ17(hg)(/hg) sires and 29 F(1) HQ17(hg)(/hg) x B6 sires under a Bayesian Binomial segregation model accounting for 4 different autosomal inheritance models of gene action (i.e., additive, dominance, recessive, and overdominance) and X-linked and Y-linked loci. For each model, the segregation effect was evaluated as a single regression coefficient for all sires or assuming 2 independent regression coefficients accounting for offspring sex ratio departures in purebred and F(1) sires, respectively. The deviance information criterion clearly favored the autosomal dominance model with different regression coefficients for the 2 groups of sires. Under this model, the dominance effect increased the percentage of female offspring by 4.3% (HQ17(hg)(/hg) purebred sires) and 8.2% (F(1) sires) with the highest posterior density regions ranging from 0.5% to 10.6% and from 1.3% to 14.4%, respectively. This article provides significant evidence of genetic determinism for sex ratio distortion in the HQ17(hg)(/hg) strain and develops new analytical tools to perform segregation studies on dichotomous traits.
| S-EPMC2855675 | biostudies-literature