Is it easy to become a man
Why is a person's gender not always determined by a set of chromosomes
Daria Spasskaya, N+1
Last week, in the journal Science, a group of British biologists reported the discovery of a new "sex switch" in the mammalian genome. Removing a small piece of 500 base pairs in the genome of mouse embryos with the male genotype XY caused them to develop into females. This experiment reminds us that the boundary between the male and female sex is not at all as rigid and predetermined as we used to think. All that initially determines the difference between the sexes is the presence or absence of the Y chromosome in the embryo, but in the XX century doctors faced situations when its carriers turned out to be women. The editors of N+1 decided to figure out how men and women become and what can prevent this.
A woman who turned out to be a man
Since 1968, all women participating in major international sports competitions, such as, for example, the Olympic Games, had to undergo genetic testing to confirm their gender. According to the organizers, this was done to eliminate fraud and equalize the opportunities of all participants in women's competitions. In 1985, the Spanish champion hurdler Maria Jose Martinez-Patino came to the World University Games in the Japanese city of Kobe, where she was asked to take a sex test.
As Martinez-Patino herself tells in the Lancet magazine (Personal Account: A woman tried and tested), she grew up and looked like an ordinary girl, she had breasts and a vagina. Moreover, two years before the Universiade, she had already been tested at the International Athletics Championships in Helsinki and received a "certificate of femininity". However, according to the results of a chromosome test conducted in Kobe, doctors concluded that Maria is genetically a man with a karyotype (chromosome set) XY. She was suspended from the competition and stripped of all previously received awards.
The "Certificate of Femininity" of Maria Martinez-Patino, issued to her in Helsinki (María José Martínez-Patiño / The Lancet 2005).
The reason for the introduction of mandatory testing for belonging to the female sex for professional athletes was the story of Dora Ratjen, a German track and field athlete who participated in the 1936 Olympic Games. As it turned out after the games, Dora was a man who, consciously or not, deceived the organizing committee. A few years after that, doctors began to examine all the participants, and with the development of technology, visual examinations were replaced by a blood test with a karyotype check.
For sure, from 1968 to 1996, while mandatory gender testing was in effect for all competing women, genetic anomalies similar to the case of Maria Martinez-Patino were identified repeatedly. However, Martinez-Patino's story, at her own request, became public. Despite the fact that the decision on disqualification was soon canceled due to protests, in 1992 Maria finished her sports career and became a political scientist and a fighter for the rights of athletes. Largely thanks to her efforts, mandatory testing was canceled as a procedure degrading human dignity and capable of leading to severe psychological trauma.
Nevertheless, the sports committees reserved the right to conduct analyses in "suspicious" cases. In recent years, hyperandrogenism, which is characterized by a high level of testosterone in the blood of women, has been called a reason for the withdrawal of athletes from competitions. However, the Indian runner Duty Chand and the South African athlete Caster Semenya, who were disqualified for this reason, were able to prove through the court their right to compete at the Olympic Games for the women's national team. The main argument of the defense was the lack of a proven link between the concentration of testosterone in the blood and athletic performance. Currently, under pressure from activists, the International Olympic Committee has relaxed the requirements and even allows transgender people to play for the women's national team.
Woman "by default"
At the beginning of embryonic development in embryos, regardless of the chromosome set formed during fertilization of an egg by a sperm, the reproductive system is laid in the same way and provides opportunities for the development of both the female and male reproductive systems. In particular, in the embryo, the Wolf and Muller ducts are formed simultaneously, which then turn into a vas deferens in men and a uterus with fallopian tubes and a vagina in women. The germ glands (gonads) of the embryo are not differentiated and contain primary germ cells, which can turn into both ovarian cells and testicular cells.
In order to start the development of glands along the male pathway, a Y chromosome is needed, more precisely, its only gene called SRY (sex-determining region Y). This gene encodes a transcription factor, that is, a protein that controls the expression of other genes. The inclusion of the SRY gene at a certain stage of development leads to the differentiation of primary progenitor cells into Sertoli cells - auxiliary testicular cells. Sertoli cells produce an anti-Muller hormone that suppresses the development of the Muller duct into the female genital tract. In addition, they produce factors that contribute to the development of the testis, the appearance of sperm precursors in it and the maturation of Leydig cells that produce testosterone. With the participation of testosterone, the wolf channel is transformed into the vas deferens, and under the action of its derivative – dihydrotestosterone – the differentiation of the external genitalia according to the male type occurs.
If there is a Y chromosome, but SRY for some reason did not work, "by default" the activation of transcription factors WNT4 and RSPO1, which determine the development of the female reproductive system, occurs: differentiation of precursors into auxiliary ovarian cells (granulosa cells), the formation of oocytes and follicles. In the absence of anti-Muller hormone and testosterone, the internal and external genitalia are differentiated according to the female type, and the Wolf channel is reduced.
A diagram illustrating the embryonic development of the gonads and genital tract according to the female (XX) and male (XY) types. Wolf's duct and the structures formed from it are marked in red, and Muller's duct is purple. Flavio JW / Wilimedia commons
The dying sex
The sex determination system involving the Y chromosome appeared in mammals about 300 million years ago (according to other sources, about 160 million years ago) and is characteristic of most of them (but not all). Most likely, in the course of evolution, the sex chromosomes originated from a pair of identical somatic chromosomes as a result of the fact that one of them acquired the functions of determining the male sex. The X- and Y-chromosomes cannot exchange sites with each other in the same way as the other pairs of chromosomes do, so the DNA on the Y-chromosome cannot be repaired by recombination. This makes it vulnerable to the accumulation of mutations and degradation.
The XX/XY sex determination system is typical for mammals, but animals have other options. For example, some insects have a system similar to ours, except that they do not have a Y chromosome. They use the XX/XO system, where females carry two X chromosomes and males carry one. The development of gonads in this case is determined by the dose of genes located on the sex chromosome. In social insects, many individuals are haploid, that is, they carry a single set of chromosomes instead of a double one. They develop from unfertilized eggs and become males. Individuals with a double set of chromosomes become females.
In birds and many reptiles, sex is determined by a pair of chromosomes ZZ and ZW, and ZW corresponds to the female sex. It is not fully known how the launch of a male or female development program is determined - it is likely that the DMRT1 genes on the Z chromosome and FET1 and ASW on the female W chromosome are involved. However, in some reptile species, such as alligators, sex is determined not by a special chromosome, but by environmental conditions, in particular, the temperature at which the embryo develops.
As a result of degradation over the millions of years that have passed since the appearance of sex chromosomes, the Y chromosome has lost the vast majority of genes. Now it encodes only 50 proteins, while the X chromosome contains more than a thousand genes. Scientists have calculated that if the Y chromosome loses DNA at the same rate, it will disappear in 5-10 million years.
However, a comparison of the sequences of the human and chimpanzee Y chromosomes has shown that since the divergence of species (about six million years ago), some chimpanzee genes on this chromosome have acquired harmful mutations and "broke down", while in humans they are still functional. This allows us to hope that the human Y-chromosome has stopped decreasing, or at least it is doing so at a slow speed.
Evolution of the Y chromosome and degradation due to forbidden recombination with the X chromosome (Jennifer Graves /Cell 2006).
Not just sex chromosomes
If a single SRY gene is needed to switch gender, what did scientists discover in a recent article in Science? As we have already mentioned, SRY encodes a protein that triggers a cascade of downstream reactions. Its main target is the SOX9 gene. This gene also encodes a transcription factor and is necessary for the differentiation and functioning of Sertoli cells. In order to start the process, the amount of Sox9 in the embryonic sex glands must reach a certain critical value, but, as scientists have shown earlier, SRY alone is not enough for this. To enhance the expression of SOX9, remote regulatory sites called enhancers are needed (which means "amplifiers" in translation).
Researchers from the Francis Crick Institute in London have discovered an amplifier codenamed Enh13, which is connected to work before everyone else and without which Sox9 does not accumulate in the right amount. This site, measuring only 557 base pairs, is located on chromosome 17, at a considerable distance from the SOX9 gene controlled by it, and it turned out to be very difficult to identify it. According to scientists, transgenic mice with the male genotype XY and the deleted Enh13 developed according to the female type. This piece of DNA turned out to be conservative in mammals – it also seems to contribute to the determination of sex in humans. At least in some patients with genotype XY, but the "reversed" sex, the amplifier was absent due to the loss of a piece of the 17th chromosome.
Sequential expression of SRY and SOX9 genes in developing mouse testes (dpc – days post coitum, days after conception). Kenichi Kashimada and Peter Koopman / Development 2010.
Recently, scientists have come to the conclusion that it is the SOX9 gene, and not SRY, that is the key factor for the development of male-type sex glands. Perhaps in five million years, SRY will transfer its SOX9 activation functions to some other protein, and then the existence of the male sex will not depend on the preservation of the Y chromosome, which was discussed in the previous paragraph.
Probably, when the female program is activated, the expression of SOX9 is actively suppressed with the participation of its "female antagonist" – the FOXL2 gene, which is expressed in granulosa cells of the ovary. If the FOXL2 gene is broken, the embryo may develop testes instead of ovaries. Therefore, in fairness, it should be noted that it is also possible to "accidentally" become a man with a female genotype. However, if non-men with genotype XY are born with a frequency of 1 per 3000 newborns, non-women with genotype XX appear seven times less often. Sometimes this happens due to an accidental "jump" of the SRY gene on the X chromosome.
Who are all these people
Conditions when the phenotypic, gonadal (that is, determined by the presence of the corresponding sex glands) and chromosomal sex do not correspond to each other are called sex formation disorders (DSD – Disorders of sex development). They usually lead to infertility and often to a violation of the formation of the genitals, so it is difficult to determine the actual sex of such people and in the scientific literature they are called intersex. They determine their social and passport gender based on their worldview and environment.
In addition to mutations in the SRY and SOX9 genes, mutations of more than a dozen genes on somatic chromosomes have been identified, whose malfunctions during fetal development can lead to DSD. Many disorders occur due to a malfunction of the endocrine system. A common cause of DSD is androgen insensitivity syndrome. This was the diagnosis eventually made by Maria Jose Martinez-Patino, as well as jazz singer Eden Atwood. With complete insensitivity to testosterone, they are phenotypically "one hundred percent" women, despite the presence of a Y chromosome and formed testes. Partial resistance to male hormones leads to the formation of a mixed phenotype.
A more common syndrome is the excessive production of male sex hormones as a result of a violation of the adrenal cortex (adrenogenital syndrome). People with this syndrome look excessively masculine regardless of the genotype, and women have deformed genitals. Perhaps the victims of this syndrome – and the Olympic Committee – were athletes disqualified from international competitions for excessive testosterone levels.
American psychologist John Money, who dealt with the problems of sexual identity, suggested that the concept of gender is multi-step, and there is a whole abyss from chromosomal sex to social. Considering how many things can go wrong in the process of forming a man or a woman, it seems that the conventions associated with a set of sex chromosomes or the presence of an extra piece of flesh, it's high time to discard and allow people to be who they feel they are.
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