Hymenoptera
One such interesting mechanism is the haplodiploid genetic system we encounter in the insect order of Hymenoptera. More than 200,000 species of ants, bees and wasps are capable of laying both unfertilized eggs, that typically develop into uniparental (originating from one single female parent) haploid males, and fertilized eggs that can give us biparental (originating from two parents, male and female) diploid females (see Figure 1).
That can be accomplished with several strategies. One of the best understood seems to be single-locus complementary sex determination (sl-CSD), in which sex is determined by multiple alleles at a single locus. Heterozygotes at that sex locus develop as females whereas hemizygotes, and the odd case of homozygous diploids (i.e. through matched matings or faulty meiosis), develop as males (see Figure 2) thus providing us with the pattern presented above (see Figure 1).
In honeybees, for example, the sex locus has recently been identified as the csd (complementary sex determiner) gene that encodes an SR protein (Arginine-Serine rich protein) [6]. The initial observation that csd function was required only in females and that its product is nonfunctional when derived from only one allele [7] was followed by the suggestion of three possible models. First, that different allelic CSD proteins form active heterodimers. Second, that CSD proteins derived from the same allele form homomers, with two homomer species in females and one in males. And third, that merely the existence of different alleles is required in females for csd to complete its function [8].
However, it should be noted that sl-CSD has been known to exhibit an evolutionary pressure against species with higher rates of inbreeding, due to one of its major faults. In most cases, mating leads to the creation of offspring with two different alleles at the sex locus (diploid females). However, a mating in such populations has higher probability of a union between a male and a female that share the same allele, a condition also known as a matched mating[9]. In matched matings half the diploid offspring are predicted to turn out homozygous at the sex locus and develop as males rather than females, whereas diploid males in species with sl-CSD are generally sterile, unable to mate or not viable (see Figure 3) [10]. Such is the example of the honeybee, where homozygous diploid males created from inbreeding are eaten by the workers [7].
Dipterans (Drosophila melanogaster)
Taking things a step further, we enter the realm of Dipterans and Drosophila melanogaster, one of the model organisms in which the sex determination pathway has been elucidated in the greatest detail. Here the choice between male and female development is made by one single switch gene by the name of sex-lethal (sxl) in response to the ratio of X chromosomes to autosomes (X:A ratio) [11]. The latter is communicated early in development through the delicate balance between the dose-sensitive X chromosome numerator elements (those include genes such as sis-a, sis-b, runt and less so sis-c) and the autosomal denominators (such as dpn) in conjunction with the maternally derived products of the da gene and the more recently studied emc, groucho, her and snf (see Figure 4) [12]. We are not yet completely certain of the logistics of it, but it seems that the feminizing effect of the numerator elements is measured against the masculinising denominators, with the maternally derived products of the rest of the genes acting as point of reference.
All this takes place early in development, leading to the activation of the sxl gene through an "early" promoter in females. This early form of the SXL protein, absent in males, then orchestrates a specific splicing of the mRNA produced through the activation of the "mature" promoter in females. In males, standard splicing of the sxl mRNA leads to a non-functional protein. It is only in females, through an autoregulatory feedback loop, that sxl manages to keep itself in an active state through this sex-specific splicing [11,13] (see Figure 5).
Once the SXL active state has been established, it then goes on to regulate a series of other proteins that control female development, once again through the process of alternative splicing, leading finally to the two alternative products of the doublesex gene (dsx), DSXF and DSXM [14,15] (see Figure 6). The end-result? A series of intricate gene interactions that can take it from there and establish the development of the appropriate sex. Still, it is interesting to note, that the Y chromosome, present in males, takes no part in this entire process, and that its sole use is to help in the successful completion of the process of spermatogenesis later on in the differentiation of the male germline.
Nematodes (Caenorhabditis elegans)
Another model organism that uses a single gene switch and the subsequent hierarchy of gene pathways to determine sex is the nematode C.elegans. Here again the animal's sexual fate depends on the X:A ratio, and there isn't even a Y chromosome present in males to later on interfere with the germline. However, C.elegans worms are special in that the choice lies between males with one X chromosome and hermaphrodites with two.
As before, the X:A ratio is communicated with the help of several "X-signal elements", such as the SEX-1 (signal element on X) protein that acts on the level of transcription and the FOX-1 (feminizing locus on X) protein that acts post-transcriptionally [16]. These two, among others that have yet to be deciphered, manage to suppress the levels of the XOL-1 (XO lethal) key protein, or what we could call the C.elegans sex switching gene [17] (see Figure 7). From there on, it is a matter of tracking down a pathway of inhibitory genes, to result at the TRA-1 (transformer) protein, free to act in hermaphrodites and regulate several other genes [18,19]. This pathway in fact involves several groups of gene products, some of which retain their active state in males and others in hermaphrodites (see Figure 8). One possible model incorporating these interactions is depicted in Figure 9, and includes the interaction between HER-1 and the TRA-2 receptor in males, which allows the FEM proteins to inhibit TRA-1 from acting as a transcription factor (see Figure 9).
However, the C.elegans hermaphrodites pose an interesting issue. These are specialized females which in the fourth and final larval stage (L4) produce around 300 sperm, to use for self-fertilization when there are no males available [20]. This requires a careful regulation of the switching between the male and female differentiation of the same germ cells without the benefit of the usual sex determination pathway, since the "male" genes that normally regulate spermatogenesis are inactive anyway. Instead, a new series of genes take over in a specific stage of development and act in place of the HER-1 protein to inhibit tra-2 and allow spermatogenesis to take place till the end of the L4 stage (see Figure 10). Once this is over and at the onset of adult life, a new series of genes take their place, tra-2 is once again active, and the adult hermaphrodite is free to continue with oogenesis for the rest of its life [19,21] (see Figure 10).
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