Vertebrate sex determination: evolutionary plasticity of a fundamental switch

Key Points

  • Sex determination in vertebrates is a highly plastic process that centres on the decision within the gonad to develop as a testis or ovary.

  • Regulation of this process has been co-opted by a diverse array of genetic and environmental upstream signals in mammals, birds, reptiles and fish.

  • Although many of the same genes are involved, their order in the cascade is not conserved.

  • Multiple upstream and downstream elements may feed into a threshold decision process driving a bistable outcome.

  • A common theme is the existence of antagonistic signals that ensure canalization of one pathway or the other once a threshold bias for testis or ovary fate exists.


The discovery of the Sry gene in 1990 triggered a revolution in our understanding of sex determination. More recently, advances in non-model organisms have been fuelled by the rapid evolution of affordable genome and transcriptome technologies. This Review considers the unusual plasticity in the bipotential system of sex determination and some of the diverse mechanisms that have evolved to control this critical developmental decision, including strong genetic pathways, environmental influences and epigenetic regulation. Ideas emerging from model and non-model organisms that suggest that sex determination operates as an antagonistic network with the emergent property of bistability are discussed.

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Figure 1: Opposing signals control the fate of the mouse gonad.
Figure 2: Transitions between sex-determining mechanisms are common.
Figure 3: Many fish use visual cues for sex determination.
Figure 4: Many factors of different magnitudes may contribute to a 'parliamentary decision' in the gonad.
Figure 5: Old and new models for sex-determination mechanisms.


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I am grateful to my colleagues, Corey Bunce, Stefano Di Talia, Brigid Hogan, Jennifer McKey and Ceri Weber, for their comments on the manuscript and to Ceri for redrawing Fig. 4b. I also thank the many colleagues in the field whose figures I have adapted for this review.

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Correspondence to Blanche Capel.

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PowerPoint slides


Bipotential primordia

Primordial tissue that can take one of two fates.


Animals having two distinct sexes.

Primary sex determination

Based on the Jost paradigm: the decision within the gonad to initiate differentiation as a testis or an ovary.

Psychological sex

'Brain sex', inclusive of the gender with which an individual identifies and partner preference.

Gonadal sex determination

The decision to differentiate as a testis or ovary, referred to as 'primary sex determination' based on the Jost paradigm. However, evidence for sexual dimorphism before gonadal sex determination in many species suggests this term is more appropriate.

Genetic sex determination

(GSD). Sex determination that is driven by a gene or chromosomal difference between the sexes.

Environmental sex determination

(ESD). Sex determination driven by effects of the environment, which can include temperature, toxicants, population density, nutrients, hormones and behavioural cues.

Heteromorphic sex chromosomes

Sex chromosomes that are morphologically distinguishable.


To channel development along a narrow path.

Heterogametic sex

The sex that produces two genetically different gametes.


Animals with both male and female phenotypic characteristics, often distributed bilaterally. Gynandromorphs occur in many species but are more common in arthropods and birds.


Animals composed of two or more genetically different cell types (often arising from fusion of two fertilized eggs).

Eutherian mammals

Placental mammals that complete fetal development within the uterus.

Metatherian mammals

(Also known as marsupials). Placental mammals, such as kangaroos, that are born in mid-gestation and complete fetal development after birth.

Secondary sex characteristics

Characteristics that usually follow primary sex determination of the testis or ovary, for example, colouration, musculature, genitalia and sex ducts.

Temperature-dependent sex determination

(TSD). One class of environmental sex determination in which sex determination is driven by temperature effects during a window of development.

Restriction site-associated DNA sequencing

(RAD-seq). Random sequencing of genomes anchored at restriction sites. The method is designed to screen the genome to uncover variations that show a high association with specific groups (for example, phenotypic males or females).

Dimorphic expression

Expressed differently between the two sexes.

Homomorphic sex chromosomes

Sex chromosomes that are not morphologically distinguishable but nonetheless influence sex determination.

Multigenic sex determination

Sex determination that depends on multiple alleles segregating in the population.

Transient hermaphrodites

Animals that initially produce gametes of one sex, followed by full differentiation as male or female. Zebrafish all hatch producing oocytes, followed by maturation as functional males or females.

Sequential hermaphroditism

Functioning as one sex followed by a functional switch to the other sex.


Among species that change sex as adults, those that are first female, then male.


Among species that change sex as adults, those that are first male, then female.

Inter-renal gland

In fish, the functional equivalent of the mammalian adrenal cortex, producing corticosteroids and regulating water metabolism and stress.


(CCCTC-binding factor). A chromatin-binding factor that mediates repressive chromatin domains.


Expressed in a different sequence in development.

Parliamentary decision

A decision resulting from the contribution of many factors.

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Capel, B. Vertebrate sex determination: evolutionary plasticity of a fundamental switch. Nat Rev Genet 18, 675–689 (2017).

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