They won't be allowed to go to the Olympics
Two genetic rearrangements have made female moles intersex
Sergey Kolenov, N+1
Scientists have solved the secret of intersexuality of female moles. They were able to identify two mutations that lead to the formation of ovotesticules – gonads containing both ovarian and testicular tissues. As noted in the article for the magazine Science (Real et al., , bizarre physiology allows female moles to produce more male hormones, making them stronger and more aggressive. These features seem to be an adaptation to an underground lifestyle and tunnel digging.
The sex of mammals is determined genetically. In most species, with two X chromosomes, embryos develop into females, and a set of one X and one Y chromosome gives rise to males. However, there are a number of exceptions to this rule. For example, at least eight species of moles (Talpidae), including the well-known European mole (Talpa europaea), have intersex females. There are two X chromosomes in their genome, but instead of the usual ovaries, so-called ovotesticules develop – gonads, which simultaneously contain ovarian and testicular tissues.
Only the "female" half of the organ produces germ cells, while the tissues of the testes are sterile and are used to produce large volumes of male androgen hormones, including testosterone. Under their influence, females develop powerful musculature and aggressive behavior, which may serve as an adaptation to an underground lifestyle, digging tunnels and developed territoriality. Another side effect of excessive hormone production is the transformation of female genitals, which in female moles resemble male ones. At the same time, the sexual system of male moles has the usual structure for mammals.
A team of researchers led by Stefan Mundlos from the Institute of Molecular Genetics of the Max Planck Society decided to figure out what genetic mechanisms underlie the bizarre physiology of female moles. To do this, they sequenced the genome of the Iberian mole (Talpa occidentalis), which lives in Spain and Portugal.
In addition, the authors studied ovotesticules of seven-day-old individuals at the epigenetic and transcriptomic levels. The male and female parts of these organs were studied separately.
Comparing the data obtained with information about the genome of starbucks (Condylura cristata), another species of moles with intersex females, the authors identified eight candidate genes that could be responsible for the development of ovotesticles. However, it soon became clear that in mice and humans, mutations in these genes cause only a decrease in fertility, but not a sex change. In the regulatory DNA sequences, the authors also failed to identify sites associated with intersexuality.
Having failed, the researchers applied a different approach. They drew attention to the three–dimensional organization of chromatin, a complex of DNA and proteins that underlies chromosomes. Comparing its structure in Iberian moles and starfish, as well as shrews, mice and humans, the authors identified 39 candidate genes related to sex in topologically associated domains (TADs). However, mutations in only ten of them affected regulatory sites, and most actively in the case of the CYP17A1 and FGF9 genes, the first of which is associated with the work of androgens, and the second regulates the growth of the testes.
The authors found out that in the process of evolution, moles acquired two additional copies of CYP17A1 (that is, there were three in total). They suggested that as a result, the production of male sex hormones increased significantly. However, RNA analysis forced the researchers to slightly correct this hypothesis. It turned out that additional copies of the gene itself make only a small contribution to the enhanced production of androgens. The main role was played by the doubling and merging of regulatory elements of enhancers, due to which the first copy of CYP17A1 began to be expressed more actively. The idea was confirmed by introducing a doubled mole enhancer into the genome of experimental mice. As a result of the experiment, the production of testosterone increased in rodents of both sexes and muscle mass increased significantly.
Interestingly, in the "female" part of ovotesticules, the action of CYP17A1 is neutralized by another gene, CYP19A1, which produces an aromatase enzyme that converts androgens into female hormones estrogens. This allows female moles to maintain reproductive function even with high levels of male hormones. At the same time, CYP19A1 is not expressed in the "male" half of ovotesticules.
The mutation identified by the authors in the FGF9 gene turned out to be unique for moles. Normally, this sequence directs the gonads along the path of testicular formation and inhibits their transformation into ovaries. At the same time, FGF9 is turned off in the ovaries of mice, which makes it possible to start egg meiosis.
As the analysis showed, in the ancestors of moles, this site was inverted and acquired a connection with new regulatory elements. The authors suggested that this may explain why in the females of these animals, the meiotic division of female germ cells begins only after birth. Perhaps this feature allows you to protect the "male" half of the ovotesticles from developing along the path of the ovaries. To test this hypothesis, the authors implanted artificial chromosomes in mouse embryos for overexpression of FGF9. The experiment confirmed that the high activity of this gene inhibits meiosis in the ovaries.
According to the authors, such genomic rearrangements have a huge evolutionary potential, since they can significantly change physiological and anatomical features due to a small number of mutations. Perhaps they are found in nature much more widely than we know.
In recent years, there have been many reports that the human Y chromosome is supposedly doomed to extinction. To find out what this idea is based on and whether it corresponds to reality, read the material "How males live without a Y chromosome".
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