Genic Balance Theory of Sex Determination

Sex Determination in Drosophila

The fruit fly Drosophila melanogaster, has eight chromosomes: three pairs of autosomes and one pair of sex chromosomes

Females (XX) and Males

(XY).

Sex Determination in Drosophila

However, the presence of the Y chromosome does not

determine maleness in Drosophila

Instead, each flys sex is determined by a balance between genes on the autosomes and genes on the X chromosome. This type of sex determination is called the genic balance system. The X chromosome contains genes with female producing effects, whereas the autosomes contain genes with maleproducing effects.

Sex Determination in Drosophila

Consequently, a flys sex is determined by the X:A ratio, the number of X chromosomes divided by the number of haploid sets of autosomal chromosomes.

Sex Determination in Drosophila

An X:A ratio of 1.0 produces a female fly; an X:A ratio of 0.5 produces a

male.
If the X:A ratio is less than 0.5, a male phenotype is produced, but the fly is weak and sterile such flies are sometimes called metamales.

An X:A ratio between 1.0 and 0.50 produces an intersex fly, with a mixture
of male and female characteristics. If the X:A ratio is greater than 1.0, a female phenotype is produced, but

these flies (called metafemales) have serious developmental problems and

many never emerge from the pupal case.

Genic Balance Theory

According to genic balance theory the sex is determined

by the ratio between X chromosomes and autosomes.

This theory was formulated by C.B. Bridges.

According to this theory, sex is determined by the

relative number of X chromosomes and autosomes.

It is actually the ratio between the X chromosomes and

autosomes determines the sex.

Mechanism of sex determination

Mechanism of sex determination is unclear but: A sex-switch gene has been discovered that directs female development. This gene, Sex-lethal (Sxl), is located on the X chromosome. ( It was originally called female lethal

because mutations of this gene killed female

embryos but have no effect on male embryos.)

Sxl gene
Apparently, Sxl has two states of activity. When it is on, it directs female development; when it is off, maleness ensures.
Sxl is activated when X:A = 1.0, and results in female development.

If X:A = 0.5, Sxl is deactivated leading to male

development.

 Genes on the X chromosome that act to regulate Sxl into the on state (female development) are called numerator elements because they act on the

numerator of the X/A genic balance equation.

Genes on the autosomes that act to regulate Sxl into the off state (male development) are called denominator elements.

 In normal males (X/A = 1 : 2), there is too little Sxl protein and the
Sxl gene shuts down; in the absence of Sxl expression, sexual differentiation follows the male pathway, which is the "default"

pathway.
In normal females (X/A = 1 : 1), there is enough Sxl protein that the Sxl gene continues to be expressed. Continued expression of the Sxl

gene initiates a cascade of genetic events, each gene in the cascade

controlling one or more other genes downstream, and results in the expression of female-specific gene products and the repression of

male-specific gene products.

The Sxl protein is an RNA-binding protein that determines the type of mRNA produced by some of the sex determining genes.

There is another gene, known as tra (named for a mutant version, "transformer").

The SXL protein apparently can bind to the primary tra transcript, and only when
SXL is so bound, is an active form of the TRA protein formed. TRA is also an RNA binding protein (transcription factor). However, it has a specific attraction to the primary transcript of a third gene, dsx (named for a mutant form, "doublesex"). When TRA is bound to the dsx mRNA transcript, the resulting exon splicing encodes a protein transcription factor (DSX-F) that represses the expression of male-specific genes. Hence, the fly with this cascade intact becomes female. If SXL isn't present, no TRA is ever made, and hence, the dsx transcript is spliced in a different way, leading to the production of a different form of DSX protein (DSXM), which represses the expression of female-specific genes.

Sex Determination in Drosophila melanogaster

The determination of male or female sex in Drosophila melanogaster depends upon the expression of a series of genes which regulate the splicing of a cascade of genes in a male-specific manner or in a female-specific manner:
The sex-lethal gene is transcribed in early female embryos but not in male embryos. The Sex-lethal protein is an RNA-binding protein. In late male embryos as well as in late female embryos, the sex-lethal gene is transcribed.

The Sex-lethal protein in developing female embryos blocks a splice acceptor site when it binds to the premRNA. The resulting late Sex-lethal protein is functional. In male embryos, the transcript is spliced differently. However, the spliced transcript contains an in-frame stop codon. As a result, no functional protein is synthesized. Next, the transformer gene is expressed. Once again, splicing of the transformer pre-mRNA depends on the presence of the Sex-lethal protein. In male embryos, once again, the spliced transcript contains an in-frame stop codon so no Transformer protein is synthesized. In female embryos, the late Sex-lethal protein binds to the pre-mRNA and results in an alternative splicing that removes the exon containing the stop codon. A functional Transformer protein can be synthesized. Finally, the double-sex gene is transcribed. Its pattern of splicing is affected by the presence of the Transformer protein which functions in association with the Transformer-2 protein (another RNA-binding protein). In male embryos, a male-specific Double-sex protein is then synthesized. In female embryos, a female-specific Double-sex protein is synthesized. Ultimately, the Double-sex protein negatively regulates the expression of genes required for differentiation of the opposite sex.