Schizophrenia genes are searched in the mountains

1,000 years of loneliness to help geneticistsMarina Muravyeva, STRF.ru

Scientists from the Human Genetic Adaptation Group of the N.I. Vavilov Institute of General Genetics of the Russian Academy of Sciences have been trying to identify the genes responsible for chronic diseases by studying representatives of the indigenous peoples of Dagestan for decades. Currently, the attention of researchers is focused on the genes that determine the occurrence of schizophrenia.

Biological or social?In the 70-80-ies of the last century, heated discussions unfolded in the scientific community about which principle prevails in human development – biological or social.

The director of the Vavilov Institute of General Genetics of the Russian Academy of Sciences, Academician Nikolai Dubinin, was at the center of the controversy. Unlike philosophers and theoretical biologists, he understood the need for experimental studies of this problem. To this end, Dubinin in 1976 organized a group of human genetic adaptation, the leadership of which was entrusted to Kazima Bulayeva.

Existing studies at that time were traditionally based on twin and family methods, in which the heritability coefficient was estimated as an indicator of the degree of influence of the genotype on the phenotype (features of the structure and vital activity of the organism due to the interaction of its genotype with environmental conditions). At the same time, ethnocultural, ecological and demographic differences between different populations were not taken into account, on which the manifestation of the genotype in the phenotype also depends. The inconsistency of the data obtained using these methods prompted N. Dubinin to think about developing a new research scheme. This task was set for the group of human genetic adaptation.

"Then we proved the feasibility of a fundamentally new approach – population-based," says the head of the group, Doctor of Biological Sciences Kazima Bulaeva. – Among the populations of genetics, there are two types: outbred – with random marriages between members of the population and isolated – with intra-population and related marriages. We chose population isolates of the indigenous peoples of Dagestan as the object of research. What is the advantage of studying them? Judging by archaeological data, about 30 peoples have been living in this mountainous environment for more than 10 thousand years. Moreover, ethnologists and linguists assume the commonality of their origin from a single ancestral population. This hypothesis is supported by common features in the culture, traditions and moral values of the inhabitants of this mountainous area. The antiquity of demographic history and the mono-ethnicity of isolates reduces environmental "interference" and makes it possible in a relatively "pure" form to identify the role of genetic factors in the manifestation of complex human properties: psychophysiological features or chronic multifactorial diseases."

It's all about the ancestorExpeditionary research of the group of genetic Adaptation of the Institute of General Genetics of the Russian Academy of Sciences has been conducted in Dagestan since 1979.

During this time, scientists, having examined the populations of 15 indigenous peoples (including Laks, Avars, Dargins, Kumyks, Lezgins, Andians, etc.), have collected a unique database based on the following parameters:

• genetic structure of the population: a set of immunological, physiological, biochemical and DNA markers;
• environmental structure: the totality of ecological, historical, linguistic and ethnographic data;
• demographic structure: total and reproductive volume, endogamy-exogamy level, inbreeding coefficient;
• the main vital signs are: life expectancy, fertility, morbidity and mortality.

"The ancestor effect played a leading role in the historical formation of the gene pool of each isolate," Kazima Bagdadovna continues. – For example, if one of the founders of this isolate was a carrier of a chronic disease, and all marriages in the isolate were concluded between relatives, then the number of sick descendants with pathogenic factors of this ancestor grew in subsequent generations. This determined the aggregation of one specific chronic pathology specific to different isolates. Thus, oncological diseases are more common in some peoples, cardiovascular diseases in others, mental diseases in others, etc. Therefore, in small populations of ancient indigenous peoples, it is much easier to identify those genes that are responsible for a particular disease."

It is interesting to note that in the course of research, scientists have identified a considerable number of mountain isolates without signs of accumulation of any specific pathology, with a large number of centenarians, high fertility, low morbidity and mortality. This indicates that the ancestors of such isolates were not carriers of certain diseases, as a result of which the high frequency of related marriages did not affect the viability of representatives of these villages.

Kazima Bulayeva has developed a method for restoring deep pedigrees in isolates up to 13-14 generations. With its help, scientists can determine with a high degree of probability which of the founders of the genus was the carrier of pathology. Compiling in this way the pedigree of one of the smallest nationalities of Dagestan (at the moment it is represented by three thousand inhabitants), geneticists found out that the carrier of a certain mental pathology is one long-time ancestor. He was married to two women, and his descendants on both lines inherited the same mental illness. According to the research results of Kazima Bulayeva's group, in some isolates of Dagestan there is a high risk of schizophrenia – up to 5 percent (on average, this indicator ranges from one percent worldwide). The example of one highland village with 700 inhabitants is particularly illustrative: for five generations, marriages in it were concluded between cousins, as a result of which at the moment eight out of nine children living in this village suffer from a paranoid form of schizophrenia (the picture shows a fragment of the pedigree).

Joint effortsGenetic study of isolates is necessary for gene mapping (localization of a gene in the genome).

The first stage of mapping is to evaluate the heritability coefficient as an indicator of the proportion of genotype in phenotype. Next, the analysis of the coupling groups in the genome and the identification of genes in these groups is carried out.

To determine the linkage groups in the genome, powerful genetic and statistical methods of analyzing pedigrees have been developed, the results of which determine the degree of statistical reliability of the linkage of the studied diseases according to the LOD score. The higher this indicator, the more accurately scientists manage to localize the gene of the disease under study.

Since the mid-90s, Russian scientists have been conducting research in Dagestan together with American geneticists from the universities of Utah and California. Joint projects were funded from several prestigious American foundations – the National Institutes of Health (NIH), the National Institute of Mental Health (NIMH), the National Science Foundation (NSF).

"Thanks to this collaboration in the molecular genetic laboratory of J. Weber [editor's note: Laboratory of Human Molecular Genetics of the Department of Psychiatry at the University of Utah] scanned the entire genome of several hundred members of pedigrees living in 12 isolates of Dagestan, – says Kazima Bulaeva. – There are no such opportunities in Russia yet. As a result, we were able to identify the couplings that mark schizophrenia. We have established that one of the powerful pathogenic factors of the disease is localized in the 17th chromosome. This is the original result. Moreover, this linkage in the genome was confirmed in four of the twelve pedigrees analyzed by us. Similar data were obtained for the 1st and 22nd chromosomes. This is very important, because along with the differences in the genomic linkages of different isolates, genomic localization of pathogenic factors of the same disease that are common to them have been identified. These common genomic couplings are caused by genome regions with pathogenic factors preserved in the genetic memory of the inhabitants of isolates, inherited by them from the common ancestral population."

The next task that the researchers from K. Bulaeva's group set themselves is the identification of genes in linked genomic regions, in particular, in the 17th and 22nd chromosomes. This work will be carried out in one of the laboratories of Harvard University. The results of the new stage of research will allow scientists to determine which specific genes cause schizophrenia, as well as, possibly, some other mental illnesses.

By the way, it became known recently that the group of human genetic adaptation together with the laboratory of M. Hammer from Arizona State University (USA) won another grant from the National Science Foundation. These funds will be used to study the genetic differentiation of another 12 ethnic groups of Dagestan.

"Many foreign colleagues are interested in our research," Kazima Bulayeva shares. – I think that together we will be able to achieve even greater results in gene mapping. Of course, such interest is determined not by the fact that we study Dagestan ethnic populations, but by a new research scheme that we have developed to search for genes responsible for the manifestation of complex psychophysiological phenotypes or chronic diseases. For genetics, both are complex, i.e. dependent on both genetics and the environment. Therefore, isolates in this case are the optimal object for research and solving a promising and urgent task – determining the genes of diseases. Progress in the diagnosis and treatment of chronic diseases depends on the success of its solution."

Portal "Eternal youth" http://vechnayamolodost.ru/28.08.2007