In the X/A ratio, X is the numerator and A is the denominator and there are genetic elements on both, described as 'numerator elements' and 'denominator elements' that contribute to this ratio. The elements interact with the target gene of X/A ratio signal. For instance, in Drosophila, the target gene of X/A ratio is the gene Sxl (sex lethal)and the two numerator elements which interact with this gene Sxl, are sis-a and sis-b (sisterless). In C. elegans, direct microinjection of cloned mnDp8 (a small X chromosome duplication) was able to shift the sexual phenotype of 2X : 3A male animals towards intersexes or hermaphrodites. Although,' all duplications for X-chromosome segments tested lead to increase in X/A ratio in 2X : 3A individuals from 0.67 to 0.70, but all these DNA clones were not effective. There is also some evidence that there may be abundant non-coding sequences on the nematode X chromosome that may correspond to numerator elements, which in Drosophila have been found to be involved in the synthesis of sex linked transcription factors.
X/A ratio, sex linked master control genes and autosomal regulatory genes Drosophila melanogaster
(a) Sex linked master control genes. As discussed above, the X/A ratio works as a signal and sets the master control genes into functional state. These master genes include Sxl (sex lethal)gene in Drosophila and xol-1, sdc-1 and sdc-2genes in C. elegans. In Drosophila, Sxl responds to the dosage of sis-a and sis-b genes and also to other genes like da (daughterless) and snf (sans-fille). It (Sxl)acts in early embryogenesis and becomes set in one of the two modes, either active (in females) or inactive (in males). Whenever Sxl mutates, losing function (lf)in female or gaining function (gf)in male, the mutants are lethal and hence the name sex lethal. Once set in female mode, Sxl acts as a regulator of four processes : (i) dosage compensation, (ii) somatic sex, (iii) germ line sex and (iv) regulation of its own activity. In male it has no function (Fig. 17.11).
The function of Sxl is achieved by differential control on splicing of its transcript (HnRNA), which has a stop codon (in frame) undergoing one of the following two fates : (i) in males, due to stop codon, full length protein is not obtained, and the truncated proteins produced are non-functional; (ii) in females during early phase, stop codon is removed by splicing (due to the activation by sis elements), so that a functional protein is obtained, which during later phase not only further promotes this productive splicing of transcripts leading to positive autoregulation, but also controls the splicing of target genes like tra. This autoregulation is necessary, so that stable response to X/A ratio is achieved, because the apparent X/A ratio may change due to dosage compensation (increased activity of X in XY males). The Sxl active protein also causes productive splicing of tra (transformer) transcript leading to an active feminizing product, so that in the absence of active Sxl protein, default splicing of tra transcript results in male soma. It is not clearly understood, how Sxl achieves gametogenesis in female and male fruit flies.
(b) Autosomal regulatory genes for somatic and germ line sexual phenotypes. There are also four major autosomal regulatory genes (tra, tra-2, dsx = double sex, ix = intersex), which interact in an orderly cascade to determine somatic sexual phenotype (this set of genes in Drosophila has no effect in germ lines, but in C. elegans corresponding genes determine both soma and the germ line). We already mentioned that active Sxl protein causes productive splicing of tra (Fig. 17.12). Following this, tra and tra-2 gene products jointly act on the target gene dsx, which, due to female splicing in XX flies represses male development, thus permitting female development, and in XY flies, due to default splicing, represses female development, permitting male development. The gene ix is needed only for the female development and not for the male development.
For gametogenesis, many genes have been studied, but it is not known if any of these genes can exercise a choice between tra-2 and ovo, which in mutant state leads to abortive oogenesis, but not to spermatogenesis. The gene tra-2 has a male specific role in the germ line, in addition to female specific role in the soma, but the details are not yet known with certainty.
(b) Autosomal regulatory genes for somatic and germ line sexual phenotypes.A cascade of regulatory genes located on autosomes are found in the nematode C. elegans. Relative to corresponding genes in fruitfly these genes in the nematode, are many more in number and involve many more steps. They also have a dual effect in soma and germ line, unlike in Drosophila, where separate genes control the soma and the germ line. The activity of the last gene of the cascade i.e. tra-1 (transformer-1) is essential for female somatic development, so that dominant gain of function (gf)mutation leads to XO female, absence or low activity of tra-1 leads to male, and nul1 mutation (loss of function = lf) leads t0 masculinization of XX individuals (Table 17.4).
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