Genetics and Molecular mechanisms of Sex determination in animals

By | April 27, 2021
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Humans have long been fascinated by aspects of human sex differences and theories put forward towards understanding this difference can be traced back to era of Aristotle (335BCE). Aristotle proposed that the heat of the male partner during intercourse determined sex of the organism. It took many years and study involving diverse model organisms to understand the finer aspects of sex determination in different animals. The decision to be a male or a female or in very few cases a hermaphrodites is taken early in the development.

The Males and females are different at the morphological, physiological, and behavioral levels. This sexual dimorphism results from the integration of two processes: sex determination and sexual differentiation. Sex determination refers to the developmental program that commits the embryo to either the male or the female pathway. In many cases, sex determination is genetic: males and females have different alleles on chromosomes or even different genes that specify their sexual morphology. In animals, this is usually identified by chromosomal differences. The mechanisms underlying sex determination vary significantly among different animals but usually involve a conserved transcription factor belonging to protein containing DM domain.

The Drosophila doublesex (dsx ) gene at the bottom of the sex-determination cascade is the best characterized candidate so far, and is conserved from worms ( mab3 of C.elegans) to mammals (Dmrt-1). Studies done in different labs show that dsx homologues are regulated by different upstream regulators but usually have dsx homolog as common factor in sex determination pathway.

Sex determination in Drosophila melanogaster

In Drosophila, sex determination is under the control of the gene Sex lethal (Sxl). The epistatic relationships between Sxl and the other sex determination genes transformer (tra), transformer-2 (tra-2) and doublesex (dsx) have revealed that a hierarchical interaction exists among them. Their characterization has shown that sex-specific splicing of their primary transcripts controls their expression during development, the product of one gene controlling the sex-specific splicing of the pre-mRNA of the downstream gene in the cascade.

The initial switch (activation of sxl) is determined by threshold of four important proteins: Scute, Xis A, Runt and unpaired, which is below the threshold level in males owing to heterozygous nature (XY) leading to non functional Sxl, TRA proteins and finally leads to male pathway.

The Sxl gene encodes a splicing inhibitor which binds to the splice junctions of its own primary transcript, preventing the use of the exon that contains a stop codon. The Sxl protein also binds to its downstream target, tra mRNA. In females, the second exon is skipped as a result of functional Sxl binding, allowing the female flies to produce the functional TRA. Since functional Sxl is absent in males, as the second exon with a stop codon is retained and hence contributes to the non functional male specific sxl . This non functional Sxl in males fails to perform its normal function of binding to downstream Tra transcripts, which eventually produces a non-functional TRA protein in males.

TRA is an RNA-binding protein , along with TRA-2 protein enhances splicing at the site it binds . A classic target of TRA is the doublesex (dsx) primary transcript, of which the fourth exon bears the binding sites for TRA. In the presence of a related protein, TRA-2, functional TRA induces the female-type splicing which connects the fourth exon to the third. In males due to non functional TRA, the fourth exon is spliced out and the fifth exon is connected to the third (the male-type splicing).

Sex Determination pathway in Drosophila

In insects, such as the lepidopterons (butterflies and moths), the male is the homomorphic sex (ZZ) and the female the heteromorphic sex (ZW) (the letters Z and W are used to distinguish this system from the XY system). Most of the studies related to sex determination have been carried on Drosophila melanogaster and hence served as a paradigm. Unlike Drosophila, mouse and humans, the chromosomal make-up of silkmoth is ZZ in males and ZW in females. The important players in Drosophila sex determination (Sxl, Tra-2) are present in silkworm but are not functionally conserved in determining sex of the organism, except for Dsx which also sex specifically spliced in silkworm and known to play important role in sex determination in all insects including Silkworm. Few years ago it was shown that a single female specific piRNA determines sex in silkworm.

The findings related to molecular mechanism involved in sex determination pathway has gained importance mainly because of its potential implication in SIT (Sterile Insect Technique) programs. SIT plays important role in controlling and eradication of harmful insect agricultural pests. dsx gene is one of the potential candidate genes proposed to be used in SIT programs.

Sex determination in Mammals :

The XX/XY sex-determination system is the most familiar sex-determination systems, as it is found in human beings, most other mammals ( also observed in Insects). Females have two X chromosomes and males have a one X and one Y chromosome. During conception, the sex of embryo is determined. If a Y bearing sperm fertilizes a egg ( which always has a X chromosome) results in genetically male embryo and female embryo in case of X chromosome bearing sperm fertilizes egg. In humans its the presence of SRY gene on Y chromosome leads in formation of testis in males . In human embryo, SRY codes for a transcription factor responsible for activating testis specific pathway at about 7 weeks of development. This implies that untill seven weeks of development , an embryo has the potential to be either a male or female and its only the presence or absence of SRY changes the scenario.

Sex determination in Birds :

Sex determination in Birds like mammals is chromosomally depended but sex chromosomes as well as mechanism is largely different. All males in Birds possess two Z chromosomes while females have one Z and one W chromosome. As mentioned above, in mammals: males have one X and one Y chromosome and females have two copies of X chromosomes. The Y chromosome of males carry the male-dominant testis-determining gene SRY. However there is no indication of a Bird SRY genes nor there is no clear idea of a candidate gene responsible for female determination on W chromosome ,which provides a rather fuzzy picture of mechanism involved in sex determination of birds. Andrew Sinclair’s group in Murdoch children research institute in Australia deciphered the mechanism involved in avian sex determination and showed that Z linked DMRT1 as Bird sex-determination gene. ( For more details please check detail blog post on Z chromosome linked DMRT1 determines sex in Birds.