The advantage of heterozygotes

Dual-use mutations

Alexandra Bruter, <url>

Quite often, the cause of infertility in both men and women are mutations. Intuitively, it is not quite clear why they exist, and even in a noticeable amount. It would be logical to assume that the pressure of natural selection, especially strong in this area, should effectively deal with such mutations. But this is not happening. A study by scientists from the Israeli Weizmann Institute Shmuel Petrokovski and Moran Gershoni sheds light on the reasons for this. They proposed a mathematical model that demonstrated that if a mutation in a gene harms only representatives of one sex, then such a mutation will occur twice as often as a similar mutation that harms representatives of both sexes (Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men, Nature Communications, 2014).

Why do mutations that cause serious diseases that manifest themselves in childhood, but are in a hurry to completely disappear?

Let's say some of them have been circulating in small closed populations until recently. For example, a number of rare genetic diseases are relatively common among Ashkenazi Jews. But not all the same?

Sometimes it turns out that a mutation harmful to someone is useful to someone.

A group of such cases is united under the name "advantage of heterozygotes". In such cases, a recessive mutation in homozygotes (organisms with two copies of the mutant gene) causes disease, and heterozygotes (organisms with one copy of the mutant gene) allows better adaptation to living conditions. In humans, we are talking, as a rule, about the best tolerance of infectious diseases. Sickle cell anemia and beta-thalassemia are quite severe blood diseases caused by mutations in the gene encoding one of the subparticles of the hemoglobin molecule. Sickle cell anemia is common in Africa, where the incidence of malaria is still very high. The distribution areas of malaria and sickle cell anemia are quite exactly the same. It turned out that the presence of one copy of the sickle cell anemia gene protects the carrier from malaria, and such a person does not suffer from anemia either. Beta-thalassemia is less common, it is common in the Mediterranean, in areas that also used to suffer from malaria. Apparently, homozygotes were also resistant to malaria.

Normal and sickle-shaped red blood cells (Wellcome Images)

There is a theory according to which the mutation that causes cystic fibrosis in the homozygous state protected the carrier from some infectious disease in the heterozygous state. Hypotheses have been put forward regarding cholera, gastrointestinal infections, tuberculosis, typhoid fever.

And it also happens that genetic variations that reduce the fertility of one of the sexes contribute to the growth of the fertility of the other. A study by Italian scientists published in PLOS One on the genetic nature of homosexuality has received wide resonance. By the time of publication of this work, there was already a number of evidence in favor of the fact that homosexuality has a genetic nature, but specific genes have not been identified. At the same time, it was unclear why the corresponding gene did not leave the population under the pressure of selection. The authors noticed that the relatives of homosexuals are significantly more likely to have a larger number of children. They built a mathematical model that confirmed the suspicions: everything looks as if there is a variant of a gene (or genes) that causes men to be predisposed to homosexuality, but increases the fertility of women. Nothing is known about the nature of these genes yet.

The asymmetric effect on men and women of a variant of a gene leads to the fact that the mechanisms of evolution of such genes are somewhat different. The work of Gershoni and Petrokowski is devoted to these differences. They looked at mutations that lead to the complete shutdown of genes that work only in men, and work in both sexes. First, they built a mathematical model that showed that mutations affecting "male" genes should occur twice as often as mutations affecting "common" genes. When the owner of an unsuccessful variant of a gene is a woman, the selection pressure does not affect him, and the variant can be transmitted through the female line as much as necessary, remaining unnoticed. Then the scientists decided to test their guess experimentally. Based on data from publicly available genetic libraries, they selected 95 genes, especially active in the testicles. The correct operation of most of these genes is necessary for the appearance of offspring, and significant mutations in them lead to sterility. The frequency of mutations in these and in the control (common for men and women) genes was analyzed on the material "1000 genomes", The data of the theoretical model were confirmed. Despite the severe effects of the mutations under consideration, they were twice as common as mutations common to men and women.

Perhaps, thanks to this new understanding, it will eventually be possible to explain why the frequency of certain diseases differs significantly in men and women.

Portal "Eternal youth" http://vechnayamolodost.ru18.08.2014