The sex determination of an organism is the developmental phenomenon in which a particular sex type of a bipotential embryo is fixed and regulated by both internal and environmental mechanisms. The internal mechanism includes the role of chromosomes and environmental mechanism involves the influence of abiotic factors.

15.1.      Chromosomal Sex Determination in Drosophila

It is achieved in Drosophila, by a balance of female determinants on the X chromosome and male determinants on the autosomal chromosomes or it is determined by the ratio of X chromosomes to the autosomal chromosomes. Generally, fruit flies carrying either one or two X chromosomes with two sets of autosomes but some other combination of ratios and their resulting sex phenotype are listed below

When an X chromosome is lost from the nucleus of an embryonic cell, then its descended cells will be XO (male) on the place of XX (female). In Drosophila and other insects the gynadomorphic phenotype is frequently seen, that having both male and female specific structures because the insects don’t possess sex hormone so each cell decides their own sex.

The major genes enrolled in sex determination of Drosophila are Sex-lethal (Sxl), transformer (tra), transformer-2 (tra2), intersex (ix), doublesex (dsx).  The figure is shown below illustrating the signal cascade of Drosophila sex determination that is determined by X: A. The development of pre-specific sex in Drosophila is illustrated.

The sxl gene is the central basis of Drosophila sex determination and this feminizing gene expresses in individuals with high values of X: A ratio. The feminizing gene expression is stimulated by the proteins encoded from the X chromosome like sisterless-a and sisterless-b. Deadpan and Extramacrochaetae are the denominator proteins that may able to form inactive heterodimers with the numerator proteins. It seems that the X: A ratio is probably measured by the competition between X-chromosomal activators and autosomal derived repressors of the Sex-lethal gene promoter.

The Sex-lethal protein itself acts as an activator and binds to the late promoter and increase own production in the female. The Sex-lethal protein itself act as a splicing factor and remove male exon from the transcript. The sex-lethal transcript from 354 amino acid long sex-lethal protein in the female. However, in male individuals, the default splicing incorporates a stop codon (UGA) after 48 amino acids. The differential splicing and its subsequent results are revealed by the figure shown below

The Sex-lethal gene regulates sex determination by controlling the processing of the transformer (tra) mRNA. The female-specific Sxl protein activates a female-specific 3´ splice site in the transformer pre mRNA, by blocking the binding of splicing factor U2AF. This reduces the affinity (female-specific) of U2AF to bind to 3´ splice site and form a female-specific mRNA and then protein.

The transformer (tra) protein and a similar protein transformer-2 (tra2) are critical to generating the female phenotype by activating the expression of female-specific doublesex (dsx) gene. The male-specific doublesex gene is also expressed in the male individuals, but the transcripts are sex-specific and determine the particular phenotype.

The dsx proteins are helpful in the differentiation of sex-specific genital organs in Drosophila melanogaster.      

15.2.      Sex Determination in Humans

Chromosomal Sex Determination in humans

The chromosomal sex determination in human is further categorised into primary and secondary sex determination to make it easier. Primary sex determination is the term generally illustrates the chromosomal role in the determination of sex-specific gonads. Usually, in humans, the female is XX and the male is XY means the individuals of both sexes carries at least one X chromosome. Since the female is XX, each of her eggs has a single X chromosome. The male generates two types of gametes, either bearing the X chromosome or Y chromosome while the females bear only a single type of egg having X chromosome. When the egg receives another X chromosome from the sperm, the resulting individual is female or if the egg receives a Y chromosome from the sperm then the individual is male.

The mammalian Y chromosome is a crucial factor for sex determination; it carries a gene that encodes a factor that organizes the gonad into a testis rather than an ovary. For example, if an individual having a X chromosome and no second X or Y (i.e. XO)  then it will develop female gonads and if an individual carrying more than one X chromosomes with a single Y chromosome (i.e. XXXXXY) then it will develop male gonads.

The formation of ovaries and testes diverge from a common precursor (bipotential gonad) on the basis of Y chromosome. The sex-determining region, SRY gene of the Y chromosome causes the indifferent gonad to develop as a testis with the help of other genes found on the autosomes.

Secondary sex determination predicts the phenotypic characteristics of the body other than gonad. These characters include the specific assisted organs, glands, body size, voice pitch and musculature. These sex-specific characteristics are usually determined by gonadal hormones. However, the default female phenotype is generated even in the absence of both gonads.

The general cascade of mammalian sex determination is that the early embryo has two internal duct systems. One is Wolffian (male) and second is Müllerian (female), collectively known as bipotential gonad. But after 6 weeks a developmental pathway activates the different sets of genes that develop undifferentiated gonads as testis or ovaries and fix the gonadal sex of the embryo. The key elements in the mechanism of sex determination are described here

Sex-determining region of the Y chromosome (SRY) : 

It is the region of sex determination factors that resides on the short arm of the Y chromosome.  This region has a male-specific DNA sequence that encodes a peptide of 223 amino acids and acts as a transcription factor. This gene is termed as SRY (sex determining the region of the Y chromosome) that encodes the human testis determining factor.


It is an autosomal gene that plays a critical role in sex determination. When a human with XX chromosomes bears an extra copy of SOX9 then it will develop as males, even if they lack the SRY gene. Individuals with a single functional copy of sox9, have a disease with numerous skeletal and organ systems that are known as campomelic dysplasia and approximately its 75% XY patients develop as phenotypic females or hermaphrodites. Sox9 is found through all the vertebrates but the SRY doesn’t. So the Sox9 may be the older and more critical for sex determination, although in mammals it is activated by its relative, SRY gene.

Steroidogenic factor1 (SF1) :

It acts as the link between sry and the male developmental pathways. It is activated by SRY.  SF1 (steroidogenic factor1) is compulsory to develop bipotential gonad, but while Sf1 levels get down in the genital ridge it helps to the developing testis. It also appears to be active in masculinizing the Sertoli cells with Sox9 to elevate the levels of AMH transcription and also in the Leydig cells to activate the genes that encoding the enzymes to make testosterone.


It is a potential ovary-determining gene on the X chromosome, if an organism has two copies of DAX1 on an active X chromosome, the SRY signal would be reversed. It encodes a protein that competes with SRY factor and significant for the ovary development. It antagonises the function of SRY, and down-regulates SF1expression to assist the ovarian development.


It is a potential ovary-determining autosomal gene. Its expression becomes undetectable in XY gonads but maintained in XX.

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