Sex-determination system

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The scientific understanding of sex determination has evolved significantly over the centuries through a series of landmark discoveries across plants, animals, and insects.

In 1694, German botanist Rudolf Jakob Camerarius conducted pioneering experiments on pollination, during which he identified the existence of distinct male and female reproductive structures in plants, including maize. His findings laid the groundwork for understanding plant reproduction and sexual differentiation .^[4]

In 1866, Gregor Mendel, an Austrian monk and scientist, published his seminal work on the inheritance of traits in pea plants. These findings—now known as Mendelian inheritance—introduced the concept of heritable units (genes) passed from two gametes. Mendel's principles eventually became the foundation of modern genetics.^[5]

In 1902, American zoologist C.E. McClung proposed that sex chromosomes played a central role in determining sex, based on cytological studies in insects. This was one of the earliest steps toward a chromosomal theory of sex determination.^[6]

In 1903, American geneticist Nettie Stevens made a groundbreaking discovery while studying the mealworm (Tenebrio molitor), demonstrating that sex is determined by specific chromosomes, now known as X and Y chromosomes. Her findings provided the first concrete evidence for chromosomal sex determination.^[7][8]

In 1917, botanist Charles Elmer Allen extended this understanding to the plant kingdom by discovering sex chromosomes in plants, confirming that the chromosomal mechanism is not exclusive to animals.^{[9][failed verification]}

In 1922, geneticist Calvin B. Bridges introduced the Genic Balance Theory, based on experiments with Drosophila melanogaster (fruit flies). He proposed that the ratio of X chromosomes to sets of autosomes determines sexual development, adding complexity to the previously accepted XX/XY system.^[10]

Finally, in 1928, Swiss biologist Fritz Baltzer was the first to describe environmental sex determination, showing that external environmental factors, such as temperature, could influence the development of sex in certain organisms. This discovery expanded the understanding of sex determination beyond purely genetic mechanisms.^[11]

Among animals, the most common chromosomal sex determination systems are XY, XO, ZW, ZO, but with numerous exceptions.

According to the Tree of Sex database^[12] (as of 2023), the known sex determination systems are:^[13]

^{1. complex sex chromosomes, homomorphic sex chromosomes, or others}

The XX/XY sex-determination system is perhaps the most familiar as it is found in humans and most other mammals, as well as in some insect species. In the XX/XY system, karyotypic females usually have two X chromosomes (XX), while karyotypic males usually have a single X and a single Y chromosome (XY). The X and Y sex chromosomes are different in shape and size from each other, unlike other chromosome pairs (autosomes), and are sometimes called allosomes. In some species, including humans, individuals remain phenotypically undifferentiated for some time during development (embryogenesis); in others, however, such as fruit flies, sexual differentiation occurs as soon fertilization occurs.^[14]

Some species (including humans) have a gene SRY on the Y chromosome that triggers development of the male phenotype. Members of SRY-reliant species can also have other chromosomal combinations such as XXY.^[14] In humans, karyotypic sex is generally determined by the presence or absence of a Y chromosome with a functional SRY gene. If the SRY gene is present and activated during fetal development, cells create testosterone and anti-müllerian hormone which typically leads to male phenotypic development.^[14] In embryos that lack a functioning SRY gene, such as most XX individuals, the individual develops phenotypically female.

In Y-centered sex determination, the SRY gene is the gene that triggers male phenotype development, however multiple genes are required for this process to complete. In XY mice, lack of the gene DAX1 on the X chromosome results in sterility, but in humans it causes adrenal hypoplasia congenita.^[15] However, when an extra DAX1 gene is placed on the X chromosome, the result is phenotypically female, despite the existence of SRY, since it overrides the effects of SRY.^[16] Even when there are functional X chromosomes in XX females, duplication or expression of SOX9 causes testes to develop.^[17][18] Gradual sex reversal in developed mice can also occur when the gene FOXL2 is removed from females.^[19] Even though the gene DMRT1 is used by birds as their sex locus, species who have XY chromosomes also rely upon DMRT1, contained on chromosome 9, for sexual differentiation at some point in their formation.^[14]

Some species, such as fruit flies, use the presence of two X chromosomes to determine femaleness.^[20] Species that use the number of Xs to determine sex are nonviable with an extra X chromosome.

Some fish have variants of the XY sex-determination system, as well as the regular system. For example, while having an XY format, Xiphophorus nezahualcoyotl and X. milleri also have a second Y chromosome, known as Y', that creates XY' females and YY' males.^[21]

At least one monotreme, the platypus, presents a particular sex determination scheme that in some ways resembles that of the ZW sex chromosomes of birds and lacks the SRY gene. The platypus has sex chromosomes ${\displaystyle X_{1},X_{2},X_{3},X_{4},X_{5},Y_{1},Y_{2},Y_{3},Y_{4},Y_{5}}$. The males have ${\displaystyle X_{1}Y_{1}/X_{2}Y_{2}/X_{3}Y_{3}/X_{4}Y_{4}/X_{5}Y_{5}}$, while females have ${\displaystyle X_{1}X_{1}/X_{2}X_{2}/X_{3}X_{3}/X_{4}X_{4}/X_{5}X_{5}}$. During meiosis, 5 of X form one chain, and 5 of Y form another chain. Thus, they behave effectively as a typical XY chromosomal system, except each of X and Y is broken into 5 parts, with the effect that recombinations occur very frequently at 4 particular points.^[22] One of the X chromosomes is homologous to the human X chromosome, and another is homologous to the bird Z chromosome.^[23]

Although it is an XY system, the platypus' sex chromosomes share no homologues with eutherian sex chromosomes.^[24] Instead, homologues with eutherian sex chromosomes lie on the platypus chromosome 6, which means that the eutherian sex chromosomes were autosomes at the time that the monotremes diverged from the therian mammals (marsupials and eutherian mammals). However, homologues to the avian DMRT1 gene on platypus sex chromosomes X3 and X5 suggest that it is possible the sex-determining gene for the platypus is the same one that is involved in bird sex-determination. More research must be conducted in order to determine the exact sex determining gene of the platypus.^[25]

In this variant of the XY system, females have two copies of the sex chromosome (XX) but males have only one (X0). The 0 denotes the absence of a second sex chromosome. Generally in this method, the sex is determined by amount of genes expressed across the two chromosomes. This system is observed in a number of insects, including the grasshoppers and crickets of order Orthoptera and in cockroaches (order Blattodea). A small number of mammals also lack a Y chromosome. These include the Amami spiny rat (Tokudaia osimensis) and the Tokunoshima spiny rat (Tokudaia tokunoshimensis) and Sorex araneus, a shrew species. Transcaucasian mole voles (Ellobius lutescens) also have a form of XO determination, in which both sexes lack a second sex chromosome.^[16] The mechanism of sex determination is not yet understood.^[26]

The nematode C. elegans is male with one sex chromosome (X0); with a pair of chromosomes (XX) it is a hermaphrodite.^[27] Its main sex gene is XOL, which encodes XOL-1 and also controls the expression of the genes TRA-2 and HER-1. These genes reduce male gene activation and increase it, respectively.^[28]

The ZW sex-determination system is found in birds, some reptiles, and some insects and other organisms. The ZW sex-determination system is reversed compared to the XY system: females have two different kinds of chromosomes (ZW), and males have two of the same kind of chromosomes (ZZ). In the chicken, this was found to be dependent on the expression of DMRT1.^[29] In birds, the genes FET1 and ASW are found on the W chromosome for females, similar to how the Y chromosome contains SRY.^[14] However, not all species depend upon the W for their sex. For example, there are moths and butterflies that are ZW, but some have been found female with ZO, as well as female with ZZW.^[27] Also, while mammals deactivate one of their extra X chromosomes when female, it appears that in the case of Lepidoptera, the males produce double the normal amount of enzymes, due to having two Z's.^[27] Because the use of ZW sex determination is varied, it is still unknown how exactly most species determine their sex.^[27] However, reportedly, the silkworm Bombyx mori uses a single female-specific piRNA as the primary determiner of sex.^[30] Despite the similarities between the ZW and XY systems, these sex chromosomes evolved separately. In the case of the chicken, their Z chromosome is more similar to humans' autosome 9.^[31] The chicken's Z chromosome also seems to be related to the X chromosome of the platypus.^[32] When a ZW species, such as the Komodo dragon, reproduces parthenogenetically, usually only males are produced. This is due to the fact that the haploid eggs double their chromosomes, resulting in ZZ or WW. The ZZ become males, but the WW are not viable and are not brought to term.^[33]

In both XY and ZW sex determination systems, the sex chromosome carrying the critical factors is often significantly smaller, carrying little more than the genes necessary for triggering the development of a given sex.^{[34][better source needed]}

The ZZ/Z0 sex-determination system is found in some moths. In these insects there is one sex chromosome, Z. Males have two Z chromosomes, whereas females have one Z. Males are ZZ, while females are Z0.^[35][36][37]

In some bryophyte and some algae species, the gametophyte stage of the life cycle, rather than being hermaphrodite, occurs as separate male or female individuals that produce male and female gametes respectively. When meiosis occurs in the sporophyte generation of the life cycle, the sex chromosomes known as U and V assort in spores that carry either the U chromosome and give rise to female gametophytes, or the V chromosome and give rise to male gametophytes.^[38][39]

The mating type in microorganisms is analogous to sex in multi-cellular organisms, and is sometimes described using those terms, though they are not necessarily correlated with physical body structures. Some species have more than two mating types. Tetrahymena, a type of ciliate, has 7 mating types

Mating types are extensively studied in fungi. Among fungi, mating type is determined by chromosomal regions called mating-type loci. Furthermore, it is not as simple as "two different mating types can mate", but rather, a matter of combinatorics. As a simple example, most basidiomycete have a "tetrapolar heterothallism" mating system: there are two loci, and mating between two individuals is possible if the alleles on both loci are different. For example, if there are 3 alleles per locus, then there would be 9 mating types, each of which can mate with 4 other mating types.^[40] By multiplicative combination, it generates a vast number of mating types. For example, Schizophyllum commune, a type of fungus, has ${\displaystyle 9\times 32\times 9\times 9=23328}$ mating types.

Haplodiploidy is found in insects belonging to Hymenoptera, such as ants and bees. Sex determination is controlled by the zygosity of a complementary sex determiner (csd) locus. Unfertilized eggs develop into haploid individuals which have a single, hemizygous copy of the csd locus and are therefore males. Fertilized eggs develop into diploid individuals which, due to high variability in the csd locus, are generally heterozygous females. In rare instances diploid individuals may be homozygous, these develop into sterile males. The gene acting as a csd locus has been identified in the honeybee and several candidate genes have been proposed as a csd locus for other Hymenopterans.^[41][42][43] Most females in the Hymenoptera order can decide the sex of their offspring by holding received sperm in their spermatheca and either releasing it into their oviduct or not. This allows them to create more workers, depending on the status of the colony.^[44]

Polygenic sex determination is when the sex is primarily determined by genes that occur on multiple non-homologous chromosomes. The environment may have a limited, minor influence on sex determination. Examples include African cichlid fish (Metriaclima spp.), lemmings (Myopus schisticolor), green swordtail,^[21] medaka,^[21] etc. In such systems, there is typically a dominance hierarchy, where one system is dominant over another if in conflict. For example, in some species of cichlid fish from Lake Malawi, if an individual has both the XY locus (on one chromosome pair) and the WZ locus (on another chromosome pair), then the W is dominant and the individual has a female phenotype.^[45]

The sex-determination system of zebrafish is polygenic. Juvenile zebrafishes (0–30 days after hatching) have both ovary-like tissue to testis tissue. They then develop into male or female adults, with the determination based on a complex interaction genes on multiple chromosomes, but not affected by environmental variations.^[46][47]

In systems with two sex chromosomes, they can be heteromorphic or homomorphic. Homomorphic sex chromosomes are almost identical in size and gene content. The two familiar kinds of sex chromosome pairs (XY and ZW) are heteromorphic. Homomorphic sex chromosomes exist among pufferfish, ratite birds, pythons, and European tree frogs. Some are quite old, meaning that there is some evolutionary force that resists their differentiation.^[48] For example, three species of European tree frogs have homologous, homomorphic sex chromosomes, and this homomorphism was maintained for at least 5.4 million years by occasional recombination.^[49]

The Nematocera, particularly the Simuliids and Chironomus, have sex determination regions that are labile, meaning that one species may have the sex determination region in one chromosome, but a closely related species might have the same region moved to a different non-homologous chromosome. Some species even have the sex determination region different among individuals within the same species (intraspecific variation).^[50][51][52] In some species, some populations have homomorphic sex chromosomes while other populations have heteromorphic sex chromosomes.

The New Zealand frog, Leiopelma hochstetteri, uses a supernumerary sex chromosome. With zero of that chromosome, the frog develops into a male. With one or more, the frog develops into a female. One female had as many as 16 of that chromosome.^[53]

Different populations of the Japanese frog Rana rugosa uses different systems. Two use homomorphic male heterogamety, one uses XX/XY, one uses ZZ/ZW. Remarkably, the X and Z chromosomes are homologous, and the Y and W as well. Dmrt1 is on autosome 1 and not sex-linked. This means that an XX female individual is genetically similar to a ZZ male individual, and an XY male individual is to a ZW female individual. The mechanism behind this is yet unclear, but it is hypothesized that during its recent evolution, the XY-to-ZW transition occurred twice.^[54][55]

Clarias gariepinus uses both XX/XY and ZW/ZZ system within the species, with some populations using homomorphic XX/XY while others using heteromorphic ZW/ZZ. A population in Thailand appears to use both systems simultaneously, possibly because C. gariepinus were not native to Thailand, and were introduced from different source populations which resulted in a mixture.^[56]

Multiple sex chromosomes like those of platypus also occurs in bony fish.^[57] Some moths and butterflies have ${\displaystyle W_{1}W_{2}Z{\text{♀}}/ZZ{\text{♂}}}$ or ${\displaystyle WZ_{1}Z_{2}{\text{♀}}/Z_{1}Z_{1}Z_{2}Z_{2}{\text{♂}}}$.^[58]

The Southern platyfish has a complex sex determination system involving 3 sex chromosomes and 4 autosomal alleles.^[59][60]

Gastrotheca pseustes has ${\displaystyle XY_{b}{\text{♀}}/XY_{a}{\text{♂}}}$ C-banding heteromorphism, meaning that both males and females have XY chromosomes, but their Y chromosomes are different on one or more C-bands. Eleutherodactylus maussi has a ${\displaystyle \mathrm {X} _{1}\mathrm {X} _{1}\mathrm {X} _{2}\mathrm {X} _{2}{\text{♀}}/\mathrm {X} _{1}\mathrm {X} _{2}\mathrm {Y} {\text{♂}}}$ system.^[61][62]

See ^[63] for a review.

Sexual chromosome pairs can arise from an autosomal pair that, for various reasons, stopped recombination, allowing for their divergence. The rate at which recombination is suppressed, and therefore the rate of sex chromosome divergence, is very different across clades.^[48]

In analogy with geological strata, historical events in the evolution of sex chromosomes are called evolutionary strata. The human Y-chromosome has had about 5 strata since the origin of the X and Y chromosomes about 300 Mya from a pair of autosomes. Each stratum was formed when a pseudoautosomal region (PAR) of the Y chromosome is inverted, stopping it from recombination with the X chromosome. Over time, each inverted region decays, possibly due to Muller's ratchet.^[64][65] Primate Y-chromosome evolution was rapid, with multiple inversions and shifts of the boundary of PAR.^[66]

Among many species of the salamanders, the two chromosomes are only distinguished by a pericentric inversion, so that the banding pattern of the X chromosome is the same as that of Y, but with a region near the centromere reversed. (fig 7 ^[67]) In some species, the X is pericentrically inverted and the Y is ancestral. In other species it is the opposite. (p. 15 ^[67])

The gene content of the X chromosome is almost identical among placental mammals. This is hypothesized to be because the X inactivation means any change would cause serious disruption, thus subjecting it to strong purifying selection. Similarly, birds have highly conserved Z chromosomes.^[55]

Neo-sex chromosomes are currently existing sex chromosomes that formed when an autosome pair fused to the previously existing sex chromosome pair. Following this fusion, the autosomal portion undergoes recombination suppression, allowing them to differentiate. Such systems have been observed in insects, reptiles, birds, and mammals. They are useful to the study of the evolution of Y chromosome degeneration and dosage compensation.^[68][69]

The sex-chromosome turnover is an evolutionary phenomenon where sex chromosomes disappear or become autosomal, and autosomal chromosomes become sexual, repeatedly over evolutionary time. Some lineages have extensive turnover, but others don't. Generally, in an XY system, if the Y chromosome is degenerate, mostly different from the X chromosome, and has X dosage compensation, then turnover is unlikely. In particular, this applies to humans.^[70][63][71]

The ZW and XY systems can evolve into to each other due to sexual conflict.^[72]

It is an evolutionary puzzle why certain sex chromosomes remain homomorphic over millions of years, especially among lineages of fishes, amphibians, and nonavian reptiles. The fountain-of-youth model states that heteromorphy results from recombination suppression, and recombination suppression results from the male phenotype, not the sex chromosomes themselves. Therefore, if some XY sex-reversed females are fertile and adaptive under some circumstances, then the X and Y chromosomes would recombine in these individuals, preventing Y chromosome decay and maintaining long-term homomorphism.^[73]

Sex reversal denotes a situation where the phenotypic sex is different from the genotypic sex. While in humans, sex reversal (such as the XX male syndrome) are often infertile, sex-reversed individuals of some species are fertile under some conditions. For example, some XY-individuals in population of Chinook salmon in the Columbia River became fertile females, producing YY sons. Since Chinook salmons have homomorphic sex chromosomes, such YY sons are healthy. When YY males mate with XX females, all their progeny would be XY male if grown under normal conditions.^[74]

Support for the hypothesis is found in the common frog, for which XX males and XY males both suppresses sex chromosome recombination, but XX and XY females both recombine at the same rate.^[75]

Many other sex-determination systems exist. In some species of reptiles, including alligators, some turtles, and the tuatara, sex is determined by the temperature at which the egg is incubated during a temperature-sensitive period. There are no examples of temperature-dependent sex determination (TSD) in birds. Megapodes had formerly been thought to exhibit this phenomenon, but were found to actually have different temperature-dependent embryo mortality rates for each sex.^[76] For some species with TSD, sex determination is achieved by exposure to hotter temperatures resulting in the offspring being one sex and cooler temperatures resulting in the other. This type of TSD is called Pattern I. For others species using TSD, it is exposure to temperatures on both extremes that results in offspring of one sex, and exposure to moderate temperatures that results in offspring of the opposite sex, called Pattern II TSD. The specific temperatures required to produce each sex are known as the female-promoting temperature and the male-promoting temperature.^[77] When the temperature stays near the threshold during the temperature sensitive period, the sex ratio is varied between the two sexes.^[78] Some species' temperature standards are based on when a particular enzyme is created. These species that rely upon temperature for their sex determination do not have the SRY gene, but have other genes such as DAX1, DMRT1, and SOX9 that are expressed or not expressed depending on the temperature.^[77] The sex of some species, such as the Nile tilapia, Australian skink lizard, and Australian dragon lizard, has an initial bias, set by chromosomes, but can later be changed by the temperature of incubation.^[21]

It is unknown how exactly temperature-dependent sex determination evolved.^[79] It could have evolved through certain sexes being more suited to certain areas that fit the temperature requirements. For example, a warmer area could be more suitable for nesting, so more females are produced to increase the amount that nest next season.^[79] In amniotes, environmental sex determination preceded the genetically determined systems of birds and mammals; it is thought that a temperature-dependent amniote was the common ancestor of amniotes with sex chromosomes.^[80]

There are other environmental sex determination systems including location-dependent determination systems as seen in the marine worm Bonellia viridis – larvae become males if they make physical contact with a female, and females if they end up on the bare sea floor. This is triggered by the presence of a chemical produced by the females, bonellin.^[81] Some species, such as some snails, practice sex change: adults start out male, then become female. In tropical clownfish, the dominant individual in a group becomes female while the other ones are male, and bluehead wrasses (Thalassoma bifasciatum) are the reverse.

Clownfish live in colonies of several small undifferentiated fish and two large fish (male and female). The male and female are the only sexually mature fish to reproduce. Clownfish are protandrous hermaphrodites, which means after they mature into males, they eventually can transform into females. They develop undifferentiated until they are needed to fill a certain role in their environment, i.e., if they receive the social and environmental cues to do so.^[82]

Some species, however, have no sex-determination system. Hermaphrodite species include the common earthworm and certain species of snails. A few species of fish, reptiles, and insects reproduce by parthenogenesis and are female altogether. There are some reptiles, such as the boa constrictor and Komodo dragon that can reproduce both sexually and asexually, depending on whether a mate is available.^[83]

There are exceptional sex-determination systems, neither genetic nor environmental.

The Wolbachia genus of parasitic bacteria lives inside the cytoplasm of its host, and is vertically transmitted from parents to children. They primarily infect arthropods and nematodes. Different Wolbachia can alter the reproductive abilities of its host by a variety of means, including cytoplasmic incompatibility, parthenogenesis, feminization and embryonic male killing.^[84]

Mitochondrial male sterility: In many flowering plants, the mitochondria can cause hermaphrodite individuals to be unable to father offspring, effectively turning them into exclusive females. This is a form of mother's curse. It is an evolutionarily adaptive strategy for mitochondria as mitochondria are inherited exclusively from mother to offspring.^[85] The first published case of mitochondrial male sterility among metazoans was reported in 2022 in the hermaphroditic snail Physa acuta.^[86]

In some species of insects, springtails and mites, male offspring lose their paternal genome (in whole or in part) during development or in the germline. Males can either be diploid, diploid with missing sex chromosome, functionally haploid or truly haploid, depending on the mechanism of elimination.^[87][85]

In some species of Hymenoptera (ants, bees and wasps), flies and crustaceans, all offspring of a particular individual female are either exclusively male or exclusively female.^[85] The underlying mechanisms are diverse and include maternally controlled paternal genome elimination and Mendelian inherited maternal sex-determining factors.^[88]

Sex determination systems may have evolved from mating type, which is a feature of microorganisms.

Chromosomal sex determination may have evolved early in the history of eukaryotes.^[89] But in plants it has been suggested to have evolved recently.^[90]

The accepted hypothesis of XY and ZW sex chromosome evolution in amniotes is that they evolved at the same time, in two different branches.^[91][92]

No genes are shared between the avian ZW and mammal XY chromosomes^[31] and the chicken Z chromosome is similar to the human autosomal chromosome 9, rather than X or Y. This suggests not that the ZW and XY sex-determination systems share an origin but that the sex chromosomes are derived from autosomal chromosomes of the common ancestor of birds and mammals. In the platypus, a monotreme, the X₁ chromosome shares homology with therian mammals, while the X₅ chromosome contains an avian sex-determination gene, further suggesting an evolutionary link.^[93]

However, there is some evidence to suggest that there could have been transitions between ZW and XY, such as in Xiphophorus maculatus, which have both ZW and XY systems in the same population, despite the fact that ZW and XY have different gene locations.^[94][95] A recent theoretical model raises the possibility of both transitions between the XY/XX and ZZ/ZW system and environmental sex determination^[96] The platypus' genes also back up the possible evolutionary link between XY and ZW, because they have the DMRT1 gene possessed by birds on their X chromosomes.^[97] Regardless, XY and ZW follow a similar route. All sex chromosomes started out as an original autosome of an original amniote that relied upon temperature to determine the sex of offspring. After the mammals separated, the reptile branch further split into Lepidosauria and Archosauromorpha. These two groups both evolved the ZW system separately, as evidenced by the existence of different sex chromosomal locations.^[92] In mammals, one of the autosome pair, now Y, mutated its SOX3 gene into the SRY gene, causing that chromosome to designate sex.^[92][97][98] After this mutation, the SRY-containing chromosome inverted and was no longer completely homologous with its partner. The regions of the X and Y chromosomes that are still homologous to one another are known as the pseudoautosomal region.^[99] Once it inverted, the Y chromosome became unable to remedy deleterious mutations, and thus degenerated.^[92] There is some concern that the Y chromosome will shrink further and stop functioning in ten million years: but the Y chromosome has been strictly conserved after its initial rapid gene loss.^[100][101]

There are some vertebrate species, such as the medaka fish, that evolved sex chromosomes separately; their Y chromosome never inverted and can still swap genes with the X. These species' sex chromosomes are relatively primitive and unspecialized. Because the Y does not have male-specific genes and can interact with the X, XY and YY females can be formed as well as XX males.^[21] Non-inverted Y chromosomes with long histories are found in pythons and emus, each system being more than 120 million years old, suggesting that inversions are not necessarily an eventuality.^[85] XO sex determination can evolve from XY sex determination with about 2 million years.^{[clarification needed][102]}

• Testis-determining factor
• Maternal influence on sex determination
• Sequential hermaphroditism
• Sex determination and differentiation (human)