MadSci Network: Genetics

Re: Is sex determination considered to be discontinuous variation?

Date: Mon Mar 23 14:07:48 1998
Posted By: Louise Freeman, Post-doc/Fellow Biology
Area of science: Genetics
ID: 886501218.Ge

Actually, most of what we think of as sexual characteristics are determined by a single gene, which is carried on the Y chromosome. This is the testis determination factor (TDF). Males get a copy of this gene; females do not. This gene acts during fetal development. Both XX and XY fetuses start out with the same sort of gonads. In males, the TDF causes the embryotic gonads to become testes. Without the TDF gene, the gonads become ovaries in female mammals.

Hormones produced by the developing testes determine what phenotypic sex the individual becomes. Both male and female fetuses have 2 sets of precursors to the adult genitalia: Mullerian ducts, which would develop into the uterus and fallopian tubes, and Wolfian, which would become the seminal vesicles and vas deferens. The fetal testes produce a hormone called Mullerian regression factor (MRF), which causes the Mullerian ducts to regress, or disappear. Thus, males do not develop a uterus. In females, who produce no MRF, the Mullerian ducts continue to grow, eventually becoming the female internal reproductive structures.

The other major hormone produced by the testes during development is the steroid hormone testosterone. Human males experience a surge of testosterone about midway through gestation; no such surge occurs in females. In some other mammals, like rats, the surge occurs late in gestation and continues for a week or so after birth. This testosterone has a variety of effects and influences not only the body but the behavior of animals.

One effect is to cause the Wolfian ducts to develop into the male reproductive tissues. Without testosterone, these structures regress in females, which is why females don't have seminal vesicles. In addition, the testosterone causes the development of the external male genitals: the penis. In the absence of testosterone, females develop a vagina and clitoris.

For these reasons, some scientists distingish between three different types of sex:
1) genotypic sex: Males are XY, females XX
2) gonadal sex: Males have testes, females ovaries
3) phenotypic sex: Males have penis, scrotum, etc. females vagina, uterus etc.

In most cases, these three types of sex agree, but under some conditions (experimental and natural) anomalies occur. More on this below.Sex can also be defined as hormonal (whether the individual has high levels of testosterone or estrogen) or behavioral (does it act more like a male or a female?)

After the developmental surge of testosterone, hormone levels fall and remain low throughout much of childhood, until they rise again with puberty and cause the development of male secondary sexual characteristics such as facial hair. However, experiments with animals show us that the early testosterone surge influences later behavior.

In rats, if you stop the action of developmental testosterone by removing the testes or treating the young males with anti-androgen drugs, you can change the appearance of the genitals. A complete androgen block will result in an animal that looks entirely female on the outside. In addition, when that animal grows up, it will behave more like a female. For instance, it will be less aggressive and, if courted by a normal male rat, will show female-like sexual behavior.

Conversely, if you treat developing female rats with testosterone, you can cause her external genitalia to look more like a male's. Such treatment also masculinizes the female's behavior: she will fight off a male rat who attempts to mate with her, but if she meets another female rat who is in estrus (or "heat") she will attempt to mount her as a male rat would.

Interestingly, certain hormone treatments (depending on the exact steroid given and at what point in development) can masculinize the body but not the brain, and vice versa. So you can get a female-looking rat acting like a male, and a male-looking rat who acts female. But all of these type of manipulations can result in the phenotypic sex (physical or behavioral) being different from that determined by the genotype.

Such manipulations in human fetuses, of course, would be unethical. But some "experiments of nature" show us that these same sort of effects occur in humans. One example is androgen insensitivity syndrome or AIS. Testosterone acts in cells by binding to a partucular protein, called the androgen receptor. The gene for this receptor is on the X chromosome, so females have 2 copies, males one. In AIS there is a mutation in the gene, so that the androgen receptor is either defective or missing. An XY male can have this mutation on the X chromosome and wind up completely insensitive to testosterone. Thus, although the testes form and produce hormones, testosterone cannot have its effects, and the external genitalia develop as a females. Internally, there is no uterus or fallopian tubes, since Mullerian regression factor made them regress. Humans like this look and usually think of themselves as female, but are sterile. There are even people with this condition working as actresses and models! This is an example of a genotypic and gonadal male producing a female phenotype.

Another human condition is congenital adrenal hyperplasia or CAH. Here, because a a defect in a different gene, the adrenal glands produce abnormally high levels of testosterone. If an XX human has this condition, the genitals can be masculinized, sometimes to the point where the child is mistaken for a boy at birth. The degree of masculinization varies, but depending on how much it is (and sometimes, when the condition is discovered), the decision may be made to raise the individual as a male. In other cases, the masculinization is treated surgically, (size of penis reduced, and vagina created) and the child raised female. In any case, this is an example of a genotypic and gonadal female having at least a partial male phenotype.

Another interesting case occurs in a particular strain of mice. In these animals, the part of the Y chromosome carrying the TDF has broken off and become attached to an X. If an XX individual inherits this TDF-carrying chromosome, the testes will develop, and the phenotype will be male. So here you would have a genotypic female that is a male gonadally and phenotypically.

I hope this answers your question, and shows how one very important gene, the TDF, can have multiple effects. However, sex determination is also influenced by other genes, such as the gene for the androgen receptor, and the genes that cause CAH. As with most human traits, multiple genes act together to produce the final phenotype. It also matters how you define sexual phenotype. You can consider the physical condition, the gonadal condition, the hormonal condition or behavior as phenotypic traits.

If you are interested in knowing more about this topic, I recommend the books Eve's Rib, by Robert Poole or the first few chapters of Behavioral Endocrinology by Becker, Breedlove and Crews.

Thank you for your question.

Louise M. Freeman

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