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UniProt release 2017_11

Published November 22, 2017


Sex determination in insects: 50 ways to achieve sex-specific splicing

The primary signals triggering sex determination in insects are amazingly diverse among various species and sometimes even between strains of the same species. These various signals converge on a single downstream conserved transformer gene (tra) which undergoes sex-specific splicing. In developing females, splicing results in the production of an active tra protein. Tra in turn regulates sex-specific splicing of another highly conserved gene of this signaling cascade, namely double-sex (dsx) which ultimately decides the sexual fate of the embryo. In males, tra splicing includes an exon containing several in-frame stop codons, resulting in a truncated, inactive isoform, unable to affect dsx splicing, resulting in a male-specific dsx isoform.

The primary signals can be environmental and genetic. In some species, temperature, population density or nutritional status can trigger the sexual fate of the embryo. In the most studied organism, Drosophila (fruit fly), the number of X chromosomes in the embryo is crucial: 2 X chromosomes lead to female development, 1 X results in males. Counting X chromosomes is a mechanism common to drosophilids, but rarely observed outside this genus. In other species, such as wasps, ants and bees, sexual fate depends upon the fertilization process: unfertilized eggs (haploid) give rise to males and fertilized diploid eggs to females. Yet other insects involve dominant Mendelian cues, which can be either male-determining (usually referred to as M-factor) as in many dipterans, or female-determining (F-factor) as in butterflies. Due to their bewildering diversity, these cues are difficult to pinpoint. Nevertheless recent years have seen a few major breakthroughs in the identification of M-factors.

In 2015, Hall et al. identified the M-factor Nix in the yellow fever mosquito Aedes aegypti. Nix is expressed very early in male embryonic development. Knockout of Nix results in the production of the dsx female isoform and feminization, while ectopic expression of Nix in females leads to the formation of nearly complete male genitalia. The evolution of Nix appears confined to a subset of mosquitoes: only the Asian tiger mosquito (Aedes albopictus) has an orthologous gene, while other genera, such as Anopheles or Culex, are negative.

The M-factor of Anopheles gambiae, identified in 2016, is encoded by the Yob gene and consists of a short, 56 amino acid protein. It is not homologous to Nix. Yob is activated at the beginning of zygotic transcription and expressed throughout a male’s life. It controls male-specific splicing of dsx and several lines of evidence suggest that it is also involved in dosage compensation in this species in which females are XX and males XY. Indeed, the ectopic delivery of Yob mRNA is lethal to genetically female embryos, but has no discernible effect on the sexual development of genetic males. Its silencing in nonsexed embryos yields highly significant male deficiency in surviving mosquitoes.

Last, but not least, the third M-factor to be reported was that of the housefly. It was called Mdmd standing for Musca domestica male determiner. It encodes a 1,174 amino acid-long protein that is expressed very early in the zygote and maintained throughout male development until adulthood. In the absence of Mdmd, males turn into females capable of sexual reproduction. Here again, diversity is not an empty word: Mdmd is not conserved in all houseflies. It is absent in at least one strain for which the M-factor has been mapped onto a different chromosome. Mdmd does not share any similarity with Nix or Yob, but it has a paralog, namely the pre-mRNA-splicing factor Cwc22. Cwc22 is a spliceosome-associated protein that is indispensable for the assembly of the exon junction complex (EJC). Interestingly, it has been shown that changes in expression levels of EJC components also affect the splice site selection of alternatively spliced genes. The homology between Mdmd and Cwc22 brings us one step closer to alternative splicing and the mechanism of sex-specific tra production.

Multiple copies of the Mdmd gene have been found on chromosomes Y, II, III, or V. All 4 encoded proteins have been annotated and, along with the A. aegypti Nix and A. gambiae Yob products, they are now publicly available in UniProtKB/Swiss-Prot.

Changes to the controlled vocabulary of human diseases

New diseases:

Modified diseases:

Changes to the controlled vocabulary for PTMs

New terms for the feature key ‘Cross-link’ (‘CROSSLNK’ in the flat file):

  • Glycyl cysteine thioester (Gly-Cys) (interchain with C-...)

New term for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):

  • 2,3-didehydroalanine (Tyr)