Gender Spectrum (Part 2)

Alexandra Bruter, <url>The beginning of the article is here.

So far, we have talked about the fact that the genotype of a human cell can be either XX or XY, as something taken for granted. In fact, this is not quite true, and violation of this rule generates a whole range of diseases. For example, Shereshevsky-Turner syndrome or Klinefelter syndrome. Before dividing, the cell doubles its set of chromosomes. During division, a complex protein machinery controls the process of chromosome divergence – it is important that one of a pair of identical chromosomes gets into each of the daughter cells. Sometimes this process is disrupted and either two chromosomes or none enter the cell.

If we are talking about meiosis, during which germ cells are formed with a single set of chromosomes, then either a cell with two sex chromosomes or a cell without sex chromosomes at all can turn out. If such a cell takes part in fertilization, a zygote may form with a rather bizarre set of sex chromosomes: X0, XXY, XYY, XXX. Perhaps the most severe of this group of diseases is the Shereshevsky-Turner syndrome (X0). X-chromosome trisomy often goes unnoticed. Also, the condition associated with the XYY genotype often goes unnoticed, although such people may experience developmental delays and decreased fertility. Kleinfelder syndrome (XXY) is rarely diagnosed before puberty. It is not always diagnosed later, and patients are treated for any particular symptom. In general, they are characterized by a very mild degree of mental retardation, infertility and endocrine disorders. There can be no genotype Y0, because the X chromosome, unlike the Y chromosome, encodes a number of vital proteins.

All these disorders can develop not only during meiosis, but also during the fragmentation of zygote cells. For example, if a fertilized egg has the genotype XY, then after the division begins, part of the cells may lose the Y chromosome and become X0. The ratio of the number of cells with different genotypes will determine who the born child will look like: an ordinary man or a woman with Shereshevsky-Turner syndrome.

Recently, a case was described when heterosexual identical twins were born. Only a few such cases have been described, and all of them are associated with chromosomal abnormalities. Initially, the only embryo had the XXY genotype, but two events occurred: part of the embryo lost the Y chromosome, and the embryo split into two parts. As a result, two children were born: a girl, most of whose cells have genotype XX and a boy, most of whose cells have genotype XXY. Both children are not completely healthy, the boy has a slight degree of mental retardation. They are now five years old.

Until recently, it was believed that a person's sex is determined by the presence of the Y chromosome, or rather the SRY (sex-determining region Y) protein, whose gene is normally located on the Y chromosome. If there is no one, it will turn out to be a girl, if there is a boy. This turned out to be true even for those cases when the human genotype was XX, and the SRY gene turned out to be on some other chromosome due to recombination errors. This gene begins to work in the sixth week of intrauterine development. Before that, the embryo forms the beginnings of both female and male genitalia. The SRY protein triggers the formation of testicles, they synthesize testosterone, testosterone controls the further development of the rudiments of the male genitalia, and the rudiments of the female ones are absorbed under the influence of other hormones. In the absence of the SRY protein, the rudiments of the gonads turn into ovaries that produce estrogen, and everything happens the other way around.

The scheme of the development of the genitals in embryogenesis

The figure above shows an undifferentiated, bi–potent state of the human reproductive system, approximately at the 6th week of intrauterine development. There are rudiments of male genitalia (Wolf's canal) and female genitalia (Muller's canal). Gonads can take any path of development. The development of the reproductive system is closely related to the development of the urinary system, a rather complex multi-stage process, about which we wrote a little here. The Wolf canal develops as an outgrowth of the mesonephros, the precursor of the kidney in vertebrates. The mesonephros itself is then reduced, and metanephros turns into an adult kidney.

In the lower part of the picture there is a differentiated state, on the left there is a male version, on the right there is a female one. At the 6th week of embryonic development, the Sry gene is activated, and the development of gonads of the female or male type begins. If the gonads become ovaries (left), they begin to produce an anti-muller hormone, under the action of which the muller duct disappears. The mesonephros turns into an appendage of the testicle, and the Wolf canal turns into a vas deferens. In the absence of the SRY protein, the gonads become ovaries. In this case, the Wolf canal disappears, and the Muller duct gives rise to the uterus and oviducts. The oviduct, however, in mammals, even at the stage of embryonic development, turns into Fallopian tubes. The figure shows an earlier stage, but over time they will connect the ovaries and uterus. Reduction of unnecessary organs will mostly end by the 11th week of embryonic development.

Active genome research in recent decades has forced us to reconsider this concept and stop considering female-type development as a passive program that starts if another program is not started. For example, activation of the Wnt4 gene in embryos with genotype XY (for example, when an extra copy of it is present in the genome) leads to the formation of atypical gonads and rudimentary uterus and fallopian tubes. In embryos with genotype XX, mutations inactivating this gene lead to the fact that the uterus may not develop (this malformation, called Rokitansky syndrome, or Muller agenesis, and uterus transplantation for its treatment can be found in the essay "Mother and Uterus").

Another gene actively involved in the development of female genital organs is Rspo1, the product of which interacts with the WNT4 protein. Failures in its work lead to the fact that fragments of testicular tissue appear in the ovaries of a person with genotype XX.

However, the most painful thing about the binary theory of sex is the discoveries showing that the situation is not determined once and for all during intrauterine development, but must be supported all the time by the work of a large number of proteins, and can be replayed if the expression of any genes changes.

Artificial inactivation of the Foxl2 gene in mice led to the fact that granulosa cells (the outer layer of the follicle), normally helping egg maturation, turned into Sertoli cells involved in spermatogenesis. Inactivation of the Dmrt1 gene leads to the opposite consequences: adult testicular cells into ovarian cells.

Another source of errors in the formation of sex is the transmission of signals by hormones. A hormone is a small organic molecule. It is synthesized by an organ and released into the blood. The hormone affects the vital activity of cells that have a receptor for this hormone. Between the hormone and the receptor, when they meet, there is an interaction roughly like between two adjacent pieces of a puzzle. This interaction triggers a cascade of reactions that determine the behavior of the cell and, as a rule, changes the activity of some genes.

In order to move from the Y chromosome to the development of male organs, it is necessary that male sex hormones androgens (for example, testosterone) transmit signals. This requires the appropriate receptors. A mutation can occur in the gene encoding the receptor, just like in any other gene. Such mutations, depending on how much they harm the receptor, cause androgen insensitivity syndrome of varying severity. When the mutation only slightly affects the activity of the receptor, the XY genotype results in a completely ordinary man, possibly with mild disorders of spermatogenesis. If the receptor is significantly damaged by mutation, for example, the receptor is not synthesized in cells at all, despite the presence of testicles, the carrier of genotype XY looks like a woman, has female external genitalia. Such people do not have internal female genitalia, because their development is suppressed by an anti-muller hormone that is not related to androgens. Testicular development is also controlled not by hormones, but by the product of the SRY gene, so such people have them, although they do not descend from the body cavity and are not able to produce mature sperm. This syndrome usually does not manifest itself in any way until puberty, when menstruation does not appear. The syndrome does not manifest in any way in carriers of genotype XX.

Hyperplasia of the adrenal cortex is, on the contrary, a genetic disease that shifts the phenotype of the owners of genotype XX closer to the male. In the adrenal cortex, a number of enzymes convert cholesterol into steroid hormones. Steroid hormones include both male and female sex hormones, but the mechanism of their synthesis is such that first a group of enzymes converts cholesterol into male hormones, and other enzymes turn them into female ones. Mutations in the genes encoding these enzymes lead to a variety of consequences. Some are lethal. Some lead to the formation of genitals of both types. Some cause women to have male-type hair growth, irregular menstruation and fertility problems. Some do not cause anything at all.

Using the example of these two diseases, one can observe different gradations of the phenotype shift to the opposite genotype, that is, in practice, make sure that gender is really a continuous spectrum, and not two discrete values.

A separate difficult question is the influence of physiology on behavior and psyche. In the case of a child from South Carolina, the doctors chose the gender, but did not guess. There is still no clarity on the issues of where gender self-awareness comes from in general, and where self-awareness comes from, which does not correspond to either genotype, phenotype, or upbringing in people without visible developmental abnormalities. There is, for example, a sensational study indicating the hereditary nature of homosexuality (you can read about this work in the essay "They don't become gay"), but no candidate genes have been identified and the mechanism is not clear. Statistically significant differences between the features of higher nervous activity in men and women seem to exist, but they are so small, and the variability among representatives of both sexes is so great that no one tries to consider them secondary sexual characteristics. In fact, in the field of psychology, everything indicates even more strongly than in the field of physiology that there are no clearly separated sexes, but there is a continuous multidimensional spectrum.

As a result, we came to the conclusion that there is no one biological parameter "gender", that it consists of many parameters that may contradict each other. In this situation, it seems reasonable to abandon the use of the term "gender" altogether or to introduce a third meaning, primarily at the legal level. Although even the authors of the article in Nature admit that this is not possible in the United States in the near future. But in any case, society will have to somehow solve the issue of such people for itself - this is useful both to society and to people with developmental anomalies, who will find it much easier and more pleasant to live without stigmas.

Portal "Eternal youth" http://vechnayamolodost.ru02.03.2015