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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 not only among various species, but also 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 future 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 future males, tra splicing includes an exon containing several in-frame stop codons, resulting in an 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, 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, the 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 this bewildering diversity, M-factors are difficult to pinpoint. Nevertheless these last 2 years saw a few major breakthroughs in the field. In 2015, Hall et al. identified Nix in Aedes aegypti. Nix knockout resulted in largely feminized genetic males and the production of a dsx female isoform. Conversely, ectopic expression of Nix resulted in genetic females with nearly complete male genitalia. Nix is expressed only in males very early in embryonic development and contains 3 RNA recognition motifs. Not surprisingly, a Nix ortholog has been found in only one other mosquito species, namely the Asian tiger mosquito (Aedes albopictus). Searches in Culex and Anopheles genera were negative.

The identification of the M-factor in Anopheles gambiae followed quickly afterwards. The gene was called Yob. It encodes a short, 56 amino acid-long protein and does not share any homology with 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, ectopic delivery of Yob mRNA is lethal to genetically female embryos, but has no discernible effect on the sexual development of genetic males, while 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, nor Yob, but it has a paralog, namely the pre-mRNA-splicing factor Cwc22, from which it arose by gene duplication. 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 Mdmd gene have been found on chromosomes Y, II, III, or V. All 4 encoded proteins have been annotated. Along with 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)