Mendel's first law of genetics stating that two alleles of a heterozygote are transmitted with an equal probability is not always observed in nature. Some alleles or chromosomes ensure their preferential transmission to the next generation by affecting meiosis or gamete maturation. By affecting the core process of gene transmission and usually lowering individual fitness, these selfish elements, referred to as meiotic drivers or segregation distorters, can trigger genetic conflicts with impact on genome and species evolution. The present project aims at identifying the genes involved in a case of sex chromosome meiotic drive, the Paris sex-ratio system, discovered in Drosophila simulans by one of the partner teams. The distorter elements are typically linked to the X chromosome and prevent the production of Y-bearing sperm. This results in strong female-bias among the progeny from affected males. When a distorter allele spreads in populations, this sets the stage for an arms race involving the whole nuclear genome to control the sexual proportion: alleles at X-linked genes are selected if they increase the drive (enhancers), whereas those on the Y and on the autosomes are selected to suppress it (suppressors). Meiotic drive is known in a variety of organisms, however very few distorter and suppressor genes have been identified so far. Indeed the gene interactions inherent to these multigenic systems promote their evolution in non-recombining regions, which prevent their genetic analysis. The Paris system represents an exception to this rule, which make its genetic dissection possible. The project proposes three complementary approaches: 1) Genetic mapping: To identify the major distorter elements on the X chromosome and the causal nucleotide variants (QTNs), we will exploit the molecular variation of natural populations by developing an association study targeting candidate regions already mapped by one of the partners (task 2). To characterize the autosomal suppressors, we shall develop QTL mapping using RIAILs (recombinant inbred lines derived from an advanced intercross); then, we will identify major QTL(s) by developing positional cloning (task 3). 2) Studying changes in gene expression: One of the primary genetic elements involved in drive is a segmental duplication that affects the testicular expression of a gene encoding a transcription factor. Therefore, we will exploit RNAseq data to identify the genes and gene networks showing change in testicular transcripts associated with the sex-ratio trait. We will then use real-time PCR targeting candidate genes (provided by task 2, 3 and RNAseq) to further document the relation between genotype, gene expression and drive strength. 3) Functional validation of candidate genes: A selection of significant candidate genes, provided by genetic mapping and expression studies, will be subjected to functional validation using appropriate transgenic tools developed in D. simulans. The final result will be a molecular model of Paris sex-ratio drive, helpful for understanding the molecular and cellular mechanisms underlying drive in general and bringing some light to its evolutionary significance. In addition, because sex chromosome drive is frequently observed within the order Diptera, our work should open new perspectives to control pest insects. First, because their spread gives rise to skewed population sex ratio, sex-linked distorters can cause population reduction and even extinction. Second, sex-linked distorters could be used in emerging strategies of population replacement, to introduce genes causing the desired phenotype into wild populations.