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 fly’s 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 male-

producing effects.

Sex Determination in Drosophila• Consequently, a fly’s 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 (DSX-

M), 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 pre-

mRNA. 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.