Sex is Complicated!
From humble origins: the orchestration of a giant baby-shaped group of cells.Humans develop from two cells—a sperm and an egg—that divide and divide and divide until a baby-shaped animal begins to take shape. Early on in this process each cell is able to turn into ANY KIND OF CELL IT WANTS. These are called stem-cells. They're the shape-shifter-superheroes of development. All cells start off being omnipotent (WE CAN DO WHATEVER WE WANT!) but end up as brain or eyeball or toe or liver or heart or skin or tongue or.......you get it....specialized cells of all kinds that are locked into their fate. The function of these cells is determined by the pattern of genes they turn on and off. The process of stem-cells becoming Whatever-cells is basically what baby-making is all about. Internal remodeling of generic structures into more specific ones is common during development. Body parts form and dissolve and migrate until the process is finished —and a baby-shaped-baby results. For example: did you know that you used to have gills? True fact. Well, actually you had the beginnings of gills—the same cells that make a fish’s gills take a different path in human-babyblobs. Turns out humans have little use for gills so these develop into ears and jaws instead. Also—your fingers once were fused into little paddles but the selective destruction of the skin between your fingers liberated them (or maybe not? Anyone out there have fused toes??)
Gonads. Gonads. Gonads. Primary and Secondary Sex Determination.Gonads start out this way too—as undecided lumps of cells. It is the DNA code on the chromosomes that determine the fate—male (XY) or female (XX)—this is called primary sex determination. For both XX and XY individuals the first 7 weeks of fetal gonad development are identical. During the primary sex determination phase these generic cells are resolved into either testes or ovaries. At around four weeks two areas of cells called the genital ridges—located somewhere south of the developing kidneys—divide, grow and begin spreading out into the adjacent connective tissues. These new connections are called sex cords. Germ cells (future egg or sperm cells) migrate to the sex cords over the next three weeks. At seven weeks the developing gonads come to a ‘fork in the road’. Sex-specific genes now begin to influence the development of the sex cords. Whether the sex cords develop into testis is mainly determined by the presence of SRY—a gene located on the short arm of the Y chromosome. XX individuals with copies of SRY—which can happen if a portion of the Y chromosome is hitch-hiking on another chromosome or if SRY is injected into a developing fetus—develop testis and other male features. In contrast to this situation, a gene on the X chromosome inhibits testis formation (DAX1) when two copies are present. That means that XY individuals with an extra portion of an X chromosome may develop as female despite having a copy of SRY. These situations where the presence or absence of very small portions of genetic material can determine the fate of relatively large complex organ systems is possible because a majority of the genes drive sex differentiation are located on autosomal chromosomes—neither X nor Y but somewhere on one of the 22 other pairs of chromosomes.
Once the progress toward male or female gonads is set in motion, secondary sex determination begins. Secondary sex determination is the work of hormones. Testosterone and estrogen determine the fate of the nascent gonads during and direct the construction of sex organs during fetal development and later produce secondary sex characteristics that develop at puberty. For example, testosterone and another hormone (AMH) direct the degeneration of a structure called the Müllerian duct, which is identical to the rudimentary oviduct in female fetuses and orchestrates the construction of other typical male physical traits. Unlike genes—which are like the instruction book a cell uses to construct machinery and other cell-parts—hormones are molecules roaming around inside and between cells that act as signals that turn genes on and off.
Genes don't do anything. They delegate.DNA by itself is necessary but not sufficient for any biological processes. Genes are instructions for construction. Though every cell in your body has exactly the same instructions—yet they have obviously different functions. The reason cells can be specialized is because cells only turn on certain genes to make certain products. Look at these two rooms:
At the most basic level, they are the same: both have four walls and some chairs and some tools, but these are further specialized to determine the function. Now look at this room:
If genes are the book that tell a person how to build the game show set, then hormones are the keys to doors one, two, or three. Like in the game show where the right combination of door and key is necessary to unlock a life of glamour and adventure (cruise on the Mediterranean! House full of popcorn furniture! Goat dressed in a hula skirt!), the right combination of hormones (keys) and their receptors (locks) is necessary to produce sex organs (behind door number 1: GONADS!!). It’s not as simple as opening a door—but it is the combination of hormone plus receptor that signals the genes that code for male or female parts to be turned on or off. For example: in individuals with XY chromosomes—after their genes have already orchestrated the construction of testis and it’s time for hormones to signal the expression of the genes necessary for the construction of other sex characteristics. If the receptor for testosterone is not present the individual will develop typically female sex-traits. In this case the signal—testosterone—is present but is unable to activate the genes necessary to build male-parts. Hormones also influence brain development, bone growth and myriad other physical traits—not just genitals.
If hormones are the answer, then are hormones are the cause?Regulation and production sites of hormones are an obvious place to begin the investigation of the biological origin of transsexual identity. Hormones shape our fetal bodies and our grown-up bodies. It's no mystery that testosterone or estrogen are the foundation of many a transition. When looking for the mechanism of transsexual identity (if one exists) an obvious place to look is the genes that make hormones and their receptors. It is hypothesized that increased amounts of testosterone play a role in the development of a male-gender-identity in XX individuals (transmen)[1] and that the converse is also true--decreased amounts of testosterone may play a role in the formation of ‘female’ brains in XY individuals (transwomen) [2]. If this is true then a likely suspect is a gene that plays a role in the production of testosterone.
Here's one. Meet CYP17.
It's job is to make hormone-precursors (other genes encode machinery that turns the products of CYP17 into testosterone or estrogen). CYP17 has a sequence variation in the DNA code in the promoter region of the gene—the area that acts as the On/Off switch for the gene. This DNA variation is present in both cis and trans males and females, but at different frequencies—that means, more transmen have the DNA variant than cis-women, and this number is more similar to the number of cismen or transwomen who carry the DNA variant [3]. So, the promoter variation of this gene, CYP17, is associated with transmen—but it is not causal. An XX individual who carries the variant is more likely trans than an XX individual without it—but it’s not a certain fate. While the TC variant in CYP17 increases the production of testosterone it alone is not sufficient to explain MtF identity. Different cellular processes are the result of the expression of different patterns of genes in space and time. If CYP17 is involved in causing transmale XX individuals, it is not doing it alone.
1. MeyerBahlburg, H.F.L., et al., Gender change from female to male in classical congenital adrenal hyperplasia. Hormones and Behavior, 1996: p. 319-332.
2. Hare, L., et al., Androgen Receptor Repeat Length Polymorphism Associated with Male-to-Female Transsexualism. Biological Psychiatry, 2009: p. 93-96.
3. Bentz, E.K., et al., A polymorphism of the CYP17 gene related to sex steroid metabolism is associated with female-to-male but not male-to-female transsexualism. Fertility and Sterility, 2008: p. 56-59.
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Thanks go to Sam of TRUE for researching and writing this article.
