Genes of schizophrenia and depression: the answer is close
About genetic isolates and Japanese science
Marina Muravyeva, STRF.ruScientists from the Institute of General Genetics named after
Vavilova RAS are close to identifying the genes responsible for the development of schizophrenia and depression. During the last year, the research was conducted in Japan: the project manager Kazima Bulayeva worked as a visiting professor.
(Bulaeva Kazima Bagdadovna, Head of the Human Genetic Adaptation Group of the N.I. Vavilov Institute of General Genetics of the Russian Academy of Sciences, Doctor of Biological Sciences, member of the International Committee on Social, Legal and Ethical Problems of Genetic and Epidemiological Research (ELSI, IGES), elected member of the Dagestan National Academy of Sciences.)
By 2020, depression will come out on top among the most common diseases in the world, overtaking today's leaders – infectious and cardiovascular diseases. WHO makes such disappointing forecasts. Already, more than half of all suicides on the planet are committed by people who are depressed. How to deal with the disease of the XXI century, many experts, including geneticists, think.
The problem is that mental, as well as other complex diseases (oncological, somatic, etc.) develop not only as a result of genetic disorders, but also under the influence of external factors. For example, depression is only 40-45 percent determined by heredity. In order to eliminate the influence of the environment as much as possible in determining the nature of the disease, in the group of human genetic adaptation of the IOGEN RAS under the leadership of Kazima Bulayeva, back in the mid-1970s, a fundamentally new approach was proposed – a population approach.
For its implementation, the so-called isolates of Dagestan were chosen as the object of research: about 30 indigenous peoples have been living in this mountainous area for more than 10 thousand years. The antiquity of demographic history and the mono-ethnicity of isolates reduces environmental "interference" and allows us to identify the role of genetic factors in the development of multifactorial diseases, in particular, schizophrenia and depression in a relatively "pure" form (see the article "1000 years of loneliness to help geneticists").
Foreign colleagues have been showing interest in the approach developed in Kazima Bulayeva's group in the search for disease genes for a long time. For example, since the mid-1990s, joint research has been conducted with American scientists. The idea is universal, the methodological approach can be applied in different countries where there are isolates. The prospects of these studies were also appreciated by Japanese scientists from the University of Hiroshima, so last year they offered Kazima Bulayeva cooperation.
Isolates of the Caucasus brought to Japan"There is an open door policy in Japanese science," says Kazima Bulayeva.
– For many years, the country has been isolated, so now much attention is being paid to strengthening international relations, various programs are being implemented, including exchange with foreign scientists and joint research. I think that's right. As Louis Pasteur said, science has no borders, "does not know the country."
In Japan, they select the most worthy, accomplished scientists in their field who are interesting for the development of a particular scientific direction. Kazima Bulayeva participated in biomedical research at the International Center for Radiation Information and at the Institute of Radiation Biology and Medicine at Hiroshima University.
(The International Radiation Information Center at the University of Hiroshima – International Radiation Information Center, University of Hiroshima – was reorganized in 1994 and together with the Institute of Radiation Biology and Medicine of the University began to collect and analyze information about the consequences of radiation damage to the population. The results of these studies are publicly available and available to scientists around the world. In addition, the university is doing a lot of work to expand joint international research projects with Japan, holding general conferences and symposiums.)
She was the second Russian researcher there. And although the main direction of research in research centers is related to oncology, however, the Japanese do not focus on one problem. Much attention, especially in recent years, has been paid to other diseases, including mental ones. Cancer patients often have severe depressive states, which negatively affects the course of treatment. In addition, the Japanese understand that it is necessary to use new methods of scientific research, new approaches in the study of the genetics of complex diseases. The genes that are responsible for the development of many of these diseases are still unknown.
"Japanese medical geneticists were interested in our population approach, implemented in isolates using the same clinical and genetic methods," says Kazima Bulayeva. – Isolates are small populations (communities, settlements) of a person who live in remote mountainous areas or remote northern areas, deserts, etc. Geographical barriers, as a rule, lead to marital isolation. Such intra-population marriages become related after several generations. This allows us to study different isolates with the accumulation of certain diseases. As a result, due to the fact that the ancestors may have only a part of the genes involved in the development of a complex disease, the same genes "walk" in modern patients from such isolates. Comparison of different isolates with aggregation of the same disease makes it possible to determine the entire spectrum of genes involved in the determination of the disease. This approach allowed us to establish a number of important facts in the identification of schizophrenia and depression genes, which are covered in joint articles with American colleagues in American J. Med.Genet/Neuropsychiatric Genetics (US), J.Genomics (UK), Psychiatric Genetics (US) and other journals".
The Japanese have their own isolates, and related marriages were until recently traditional, especially in remote mountain villages. But it's not just that. Isolates can be considered as a model that makes it quite easy and economical to map, that is, identify (localize) disease genes.
Good conditions in exchange for knowledgeFor visiting professors, the Japanese create excellent conditions: starting from household – they provide comfortable apartments, offices at the institute, a social package with medical insurance for treatment and purchase of medicines, and ending with excellent organization of scientific work, including payment of all travel expenses and the costs of equipment necessary for research.
By the way, management in Japanese institutions, according to Kazima Bulayeva, deserves individual compliments. His task, ultimately, is to provide for all the needs of the scientist and to create a favorable and friendly atmosphere. (So, in the first week after the arrival of invited scientists from Russia, China, New Zealand and India, the administration arranged a banquet for them. And before leaving, they were invited to a meeting of the Academic Council of the University and asked to tell about the scientific results obtained and their general impression of working in Japan.)
Japanese scientists have no "headache" about repairs, equipment delivery, or other current problems. The laboratory rooms are well equipped, dazzlingly clean. All organizational issues are promptly resolved by the administration. The administration of the Institute performs the functions of patenting and promoting scientific developments as fully as possible. In addition, it provides timely dissemination of information about new grants and conditions for their receipt, foreign and inter-institute internships for advanced training of researchers. In addition to the convenience of work, the material side is also a serious incentive for scientists. Salaries are quite high and comparable to the income level of American scientists. Therefore, in Japan, researchers are interested in work, in obtaining scientific results, publications in prestigious journals. And work "to the fullest".
"For me, as a workaholic, such working conditions were familiar, but the instant solution of various scientific, organizational and technical problems was clearly an unusual and unlike the Russian scientific reality phenomenon," says Kazima Bulaeva. – All invited foreign professors adapt very quickly to such conditions, and the Japanese try to make the most of their knowledge. I was invited to make presentations at the Brain Institute in Osaka, at meetings of two councils of the University of Hiroshima. At the request of researchers at this university, I taught them methods for analyzing genomic linkages with complex diseases."
In many ways, Japan's education and science system resembles the American one, Bulayeva notes. The United States played a huge role in the post-war reconstruction of Hiroshima. You can feel it. Although few people know English there. Because of the language barrier, it was difficult to establish communication. "If something needed to be discussed, I wrote a letter in English (I know the language well: I worked in the USA for five years), they translated this text into Japanese, then wrote an answer, translated it into English on the Internet and sent it to me," Kazima Bulayeva says. – Often these translations turned out to be so strange and even funny that it was difficult to understand what they really wanted to say. But fortunately, there are a lot of English terms in genetics, and mathematical formulas for genetic analysis are understandable to specialists from all countries. Therefore, in general, somehow managed to understand each other."
At the intragenic levelKazima Bulayeva continued her research at the Japanese scientific center: it was possible to fully verify two pedigrees of Dagestan isolates for depression and three for schizophrenia out of five genetic isolates with the accumulation of these diseases.
Using the pedigrees that Bulayeva learned to make up up to the 13th-14th generation, it is possible to establish genomic sites linked to the diseases under study.
"Japan has great technical capabilities, the most powerful computers, so we managed to make significant progress in the study of disease genes," Kazima Bulayeva notes. "In the first months of my stay there, about 500,000 single nucleotides (SNPs) were typed in each member of the pedigrees."
Typing of SNPs in modern human genomic research is a dominant technology. The human genome contains about 10 million SNPs, which opens up an incredible opportunity to penetrate deep into the human genome. Most of them do not affect human health and changes in the DNA strand occur outside the genes. Therefore, they can be used as genomic markers when searching for disease genes. If the change in nucleotides occurs inside or close to the regulatory region of the gene, then the SNP may be directly related to the functioning of the susceptibility gene to the disease under study.
When searching for disease genes, 300-400 microsatellites scanned throughout the genome are usually used. In the analysis, researchers try to find their associations with specific diseases in pedigrees or in groups of patients, in comparison with healthy ones. This is done with the help of a special computer program for calculating such genomic couplings. In the analysis, each pedigree is "scrolled" for each of the 23 human chromosomes.
"Given the vastness of our pedigrees – 300-700 people of 13-14 generations collected in 15 genetic isolates of Dagestan, one can imagine the volume of scientific research," says Kazima Bulayeva. – At the same time, the analysis of one such pedigree by one of the largest in size – the first chromosome (30 DNA markers) according to the genomic linkage search program takes more than three weeks of continuous computer operation in the IOGen RAS group. And in Japan, I could do the same analysis on their powerful computer systems for 3-4 hours!".
For example, 22 chromosomes were analyzed for the presence of genomic coupling with depression in pedigrees restored in two high-altitude isolates of the Caucasus with a high frequency of patients with depression (11-12 suicides occurred in these isolates over 20 years). Interestingly, not a single suicide has occurred in neighboring villages and patients with depression have not been registered. Genomic regions linked to these states were identified in these two isolates. Within the linked regions, violations of the number of copies were found – deletions (losses) or duplications (doubling) of DNA sections. 3 genomic regions with loss of heterozygosity characteristic only for these patients and absent in all healthy ones were identified. Now, together with foreign colleagues, it will be possible to determine which genes are responsible for the development of the disease under study.
From psychiatry to neurology"The data obtained during the typing of SNPs in members of pedigrees make it possible to identify molecular mutations in the linked genomic region or to determine the loss of heterozygosity," says Kazima Bulayeva.
– It is possible that in the structure of this gene there are alleles that are in a recessive state, therefore they cause a loss of heterozygosity and a person gets sick. And in another, heterozygosity is not lost, but he is a carrier courier of this disease without external manifestations of pathologies. We are practically already identifying the genes of these diseases. And in ethnically subdivided populations. This is very impressive: different isolates show the same picture of genomic linkages with microsatellites, more "coarse" genomic markers scanned by 10 cM. And then, when deepening into the genome study of SNPs, these inter–population differences or similarities are confirmed or other features are revealed. This approach allows us to identify the entire spectrum of genes involved in the determination of a particular complex disease that we are studying."
This methodology can be used not only to identify the genes of schizophrenia or depression. For example, the Japanese want to use it in the study of neurological diseases. According to Kazima Bulayeva, it is extremely important to establish how the same diseases manifest themselves in different racial and ethnic groups, which common and different genes in these groups are involved in the determination of diseases. This is a task of another level, but very interesting.
Following the results of the annual work in Japan, Kazima Bulayeva and her colleagues have prepared three articles, now they are working on the fourth. It is planned that they will be published in prestigious foreign magazines.
In addition, Kazima Bulayeva is going to continue work on typing SNPs in pedigrees from all examined Dagestan isolates. Of the 15 extensive pedigrees, 4 have been typed so far. The remaining pedigrees are at the stage of preparation for such typing as part of joint research with American colleagues. By autumn, scientists hope to get up to 640,000 SNPs from each person. After that, it will be necessary to analyze the material obtained, which is colossal in scale and scientific significance.
Portal "Eternal youth" http://vechnayamolodost.ru/16.06.2009