[Variation of the parameters of natural reproduction and Crow's indices in the ethnic groups of Dagestan].

Using the 2002 All-Russian population census data, the parameters of differential fertility as a component of natural selection (Crow's indices) have been calculated for women of seven age cohorts of the seven most numerous ethnic groups of the Republic of Dagestan. It has been shown that in the population of Dagestan in the second half of the 20th century the intensities of two types of selection tended to decrease, viz., intragroup selection relaxed in each ethnic group due to considerable reduction of interfamily variance in fertility and intergroup selection relaxed due to reduction ofinterethnic differences in fertility. A reduction of the average number of offspring (kappa) was observed in all ethnic groups, suggesting the spread of birth regulation practices (abortion and contraception). Nevertheless, all Muslim groups (aboriginal Dagestan ethnic groups and Azerbaijanis) are still characterized by an extended pattern of reproduction (2.7 < kappa < 3.3); in Russians kappa = 2.1. Interethnic differentials in natural reproduction rates, along with migration processes, account for the dynamics of the ethnic composition and gene-pool structure of the population of the Republic of Dagestan.

[Mapping genes of major recurrent depression in genetic isolates].

We conducted a genome-wide linkage scan in two extended pedigrees ascertained from two Dagestan genetic isolates (N(o)6007 and 6008) with high aggregation of early onset major depressive disorders (MDD). The first pedigree included in total 22 cases of MDD (15 available) and 11 suicides; the second pedigree contained 29 MDD cases (23 available) and 12 suicides. Five linked regions in our study are consistent with previous findings in association and/or linkage studies with MDD: 11p15, 12q23-24, 13q11-32, 18q22 and 22q11-13. We found two novel for early onset MDD genomic regions with significant linkages in N(o)6007 with Lods = 3.1-3.4 at 2p13.2-p11.2 (and some weak signal in the same region for N(o)6008) and at 14q31.12-q32.13. We also obtained suggestive level linkages at 9q33.3-q34.2 (N(o)6008), 13q31.1-q31.2 (N(o)6007), 11p15 (N(o)6008), 17q25.3 (N(o)6007) and 19q13.31-q13.33 (N(o)6008). Six linked regions (1p36.1-p35.2, 2p13.2-p11.2,13q31, 17q25.3, 18q22 and 22q12.3) were consistent across the two isolates' pedigrees while all other linkage regions (5q14.1-q14.3, 9q33.3-q34.2, 13q31.1-q32.1, 14q31.12-q32.13, 20p13) demonstrated population-specific genetic heterogeneity of MDD. Our results suggest that genetic mapping of complex diseases, including MDD, across genetically homogeneous isolates can enrich the harvest of linkage signals and expedite the search for susceptibility genes.

[The effect of inbreeding on accumulation of complex diseases in genetic isolates].

We have studied the effect of genetic processes in ethnically and demographically diverse isolates on the epidemiology of complex diseases. Our long-term studies of five indigenous Dagestan ethnic groups have revealed ten genetic isolates with aggregation of schizophrenia-related diseases. According to Neel's classification (1992), these isolates belong to primary and secondary depending on the duration of demographic process. We have found that the average demographic ages of the examined primary and secondary isolates were about 4000 and 700 years, respectively. The inbreeding level F was studied using two methods: analysis of marriage structure in three generations, which is traditional in population-genetic studies, and analysis of the same structure in extensive pedigrees (up to 11-13 generations). We have shown that with the second method, the F value increases two- to three-fold in various isolates. The accumulated inbreeding in the primary isolates proved to be twofold higher than that in the secondary ones. Primary isolates have revealed relatively higher genetic and clinical homogeneity in combination with higher aggregation of population-specific complex disease pathology compared to secondary isolates. A decrease in observed recombinations and the number of genomic loci linked with the disease in primary isolates have been also demonstrated. Thus, our studies showed that complex diseases can be less expensive and mapping of genes for time-consuming if conducted in primary rather than in secondary isolates, in particular when dealing with genetically heterogeneous outbred human populations.

[STR polymorphism in populations of indigenous Daghestan ethnic groups]. / STR-polimorfizm v populiatsiiakh korennykh narodov Dagestana.

Genomic diversity of 21 STR loci has been studied in six ethnic populations of Daghestan (the Caucasus), namely, Avars, Dargins, Kubachians, Lezgins, and Nogais, and the results have been compared with these data for European, African, and East Asian ethnic groups. Daghestan is unique in its ethnic diversity, which is the greatest in the Caucasus: 26 out of approximately 50 autochthonous ethnic groups of the Caucasus live there. The genetic origin of this wide ethnic diversity of Daghestan and the Caucasus as a whole is still obscure. The genetic heterogeneity of Daghestan populations has been found to be lower than that of most other populations in the world. This is explained by a prolonged isolation and gene drift in their demographic history. Generalized genetic distances between ethnic groups calculated for the whole set of loci studied allow differentiating Asian populations from African ones, with European populations occupying intermediate positions. All Daghestan ethnic populations form a distinct common group together with some European populations (Finnish, Polish, and French). Nogais are genetically close to Southeast Asian populations. The genetic closeness and the apparently equal genetic diversity of Daghestan and European populations suggest that the ethnic differentiation of the ancestral populations of Daghestan and European ethnic groups occurred in the earliest populations of modern humans.

[Genetic and epidemiological studies in Dagestan highland isolates]. / Genetiko-épidemiologicheskie issledovaniia v gornykh izoliatakh Dagestana.

Interpopulation differences in the epidemiology and age of onset of complex diseases, as well as expression of some vital parameters, have been found. The relationship between these interpopulation differences and the genetic processes that have been occurring in the populations throughout their history has been demonstrated. The Daghestan genetic isolates studied are characterized by aggregation of certain complex diseases. In each genetic isolate, almost all affected subjects with homogeneous clinical phenotypes belong to the same large pedigree with a limited number of founders. There is evidence for a large variance of the population risk of schizophrenia (morbid risk) in Daghestan isolates (this parameter varies from 0 to 5%). Examination of 211 cases of schizophrenia earlier diagnosed in Daghestan psychiatric hospitals has shown that only 139 of them meet the DSM-IV criteria for schizophrenia. The remaining 72 subjects have, according to DSM-IV criteria, various schizoaffective and affective disorders; all of these subjects are close relatives of the schizophrenic patients. The age of onset of schizophrenia in the isolates studied varies from 14 to 40 years (20.84 +/- 0.568 years). Offspring of consanguineous marriages exhibit later age at onset and a higher risk of schizophrenia than offspring of exogamous marriages. The results of multivariate genetic analysis indicate that different gene complexes are involved in the pathogeneses of early-onset and late-onset forms of schizophrenia. An association of schizophrenia incidence, its age dependence, and reproductive parameters with polymorphisms of some microsatellite loci have been demonstrated.

[Genetic subdivision of Dagestan ethnic populations]. / Geneticheskaia podrazdelennost' étnicheskikh populiatsii Dagestana.

Relationships between ethnic and genetic differentiation with respect to 54 microsatellites have been analyzed in five Daghestan ethnic groups. To detect the microsatellites, human chromosomes 3, 17, and 18 were screened with a step of 10 cM (Weber/CHLC 9.0 markers) at the Mammalian Genotyping Service (National Institute of Health, United States). Comparison of the polymorphism of these loci in Daghestan populations with average worldwide data has revealed generally low heterozygosity in Daghestan populations, which is accounted for by traditional endogamous and consanguineous marriages throughout the history of these populations. The inbreeding coefficient in Daghestan ethnic groups varies from 0.005 to 0.0134 and is close to the worldwide maximum known to date. For some DNA loci, significant differences between the offsprings of consanguineous and exogamous marriages with respect to allele sizes and their variance have been found. The Daghestan ethnic populations studied differ from one another in both the frequencies of common alleles and the presence of rare alleles that are unique for each ethnic group of Daghestan and have not been found in any other population in the world.

[Mapping genes of complex diseases in genetic isolates of Dagestan]. / Kartirovanie genov kompleksnykh zabolevanii v geneticheskikh izoliatakh Dagestana.

Original results of the analysis of genetic linkage between some genomic markers and two complex clinical phenotypes, schizophrenia and mental retardation, in pedigrees from Dagestan genetic isolates are described. Interpopulation differences in the epidemiology of the complex phenotypes were studied and in their genetic linkage was demonstrated. These differences are evidently related to the genetic structure of the isolates determined by their genetic history. The MR epidemiological index characterizing the lifetime morbid risk of schizophrenia varies in the Dagestan isolates studied from 0 to 4.95%, which is almost five times higher than the average worldwide population rate, 1%. Comparative genetic mapping permitted determination of the most probable genetic linkages and associations of loci from chromosomal regions 17p11.1-12, 3q13.3, and a locus from 22q with schizophrenia and locus 12q23 with mental retardation. There is evidence that this approach is effective for detailed study of the relationship between the genetic (allele and locus) and clinical heterogeneity of complex diseases, which favors successful identification of the genes determining them. The study of linkage disequilibrium (LD) in genetic isolates of Daghestan populations (which have a common genetic background) may be an effective methodological approach for revealing the numerous contradictory results of mapping of the same genes of complex disease performed by different researchers in different regions of the world.

[Mapping of the gene for autosomal-recessive progressive muscular dystrophy in an isolate from a highland region of Dagestan to chromosome 2-13]. / Kartirovanie gena autosomno-retsessivnoi progressiruiushchei myshechnoi distrofii v izoliate gornogo Dagestana na khromosome 2p13.

A unique inbred Avar family from an isolate of the Dagestan highland was studied. Unusual phenotypic expression of autosomal recessive progressive muscular dystrophy was revealed in 12 members of this family from three generations. Limb-girdle (proximal) muscular dystrophy (LGMD) was detected in nine patients, while the other three patients displayed typical distal myopathy (DM). Genetic linkage analysis with several candidate loci determining various forms of muscular dystrophy allowed a gene for this polymorphic syndrome to be assigned to chromosome 2p13. In spite of the difference in clinical manifestation, all patients appeared to be homozygous for a unique haplotype. This implies the founder effect and proves the same genetic basis of LGMD and DM in the family. Recombination analysis showed that the centromeric and telomeric ends of the gene region are marked with D2S2111 and D2S327, respectively (genetic distance < 1 cM). This region is overlapped by two larger regions in which the genes for LGMD type 2B (LGMD2B) and Miyoshi myopathy were recently mapped. Complex analysis of clinical and genetic data indicated that LGMD2B, Miyoshi myopathy, and the revealed polymorphic syndrome may represent allelic variants of 2p13-linked autosomal recessive muscular dystrophy.

[Comparative study of genetic adaptation of the Caucasian highlanders to historic and to the new urban environments]. / Sravnitel'noe izuchenie geneticheskoi adaptatsii gortsev Kavkaza k istoricheskoi i k novoi gorodskoi srede.

Marriage structure and female reproductive characteristics in a highland isolate and an urban population from Dagestan were compared. The studied urban population could be divided into three groups according to ethnic, genetic, and demographic parameters. In the native, highland population, a steady selection occurred due to a high, uncontrolled birthrate and a high prereproductive mortality. The genetic structure of the urban population still remained at the stage of formation. Different ethnic groups of the female urban population differed both in the rate and directions of selection. The migration of highlanders to the city mainly affected their mortality and morbidity, but not fecundity. The subpopulation of migrants from the highlands who retained a traditional endogamous and inbred marriage structure exhibited a high infant mortality comparable to that in the highland population. The migrant subpopulation in which interpopulation and interethnic marriages were contracted exhibited an increased genetic load expressed as high pre- and perinatal mortalities. The results obtained are discussed in terms of the hypotheses on the adaptive gene complex and the genetic and physiological mechanisms of differential adaptation of highland isolates to environmental changes due to migration or environmental pollution.

[Genetic polymorphism in three indigenous ethnic populations of Dagestan]. / Geneticheskii polimorfizm v trekh populiatsiiakh korennykh narodov Dagestana.

Genetic, demographic, and biochemical studies of three isolated ethnic populations of Dagestan were performed. Two populations lived in their historical (highland and lowland) habitats, and one population migrated from highlands to lowlands, i.e., changed its environment. A substantial genetic differentiation with respect to eight biochemical systems and marital structure was found. Altitudinal variation was revealed in allelic frequencies of group-specific component (GC) and haptoglobin (HP). The frequency of allele GC * 1 decreased and that of allele HP * 1 increased as the altitude increased in the studied localities. The studied populations differed with respect to the average heterozygosity levels per locus. Both absolute heterozygosity levels and the pattern of interpopulation differences estimated for all of the eight biochemical markers considerably differed from those estimated for all markers except for GC and HP. These data indicate that the latter two biochemical systems are important for adaptation of the studied Dagestan populations. In surviving migrants from highlands to lowlands, the levels of inbreeding and genetic polymorphism were intermediate between these values for highlanders and native lowlanders. Earlier, the 30% selective mortality was revealed in migrants from highlands to lowlands during the first years of adaptation to new conditions. Those individuals who died had a higher inbreeding level, homozygosity, and physiological sensitivity. In this study, only surviving migrants were examined. Therefore, it may be suggested that the inadaptive (dying) part of migrants also differed from the adaptive (surviving) part in the higher HP * 1 and GC * 2 allelic frequencies.

[A genetic and demographic study of Dagestan highland populations and migrants to the lowlands. The relationship between levels of consanguinity, homozygosity and physiologic sensitivity]. / Genetiko-demograficheskoe issledovanie gorskikh populiatsii Dagestana i migrantov iz nikh na ravninu. Vzaimosviaz' urovnei inbridinga, homozigotnosti i fiziologicheskoi sensitivnosti.

This is a continuation of a series of papers devoted to studying the genetic mechanisms of adaptation in migrants from isolated highland populations of Dagestan to new ecological conditions (lowlands). This paper describes the main results of studying the relationship between levels of inbreeding, homozygosity, and physiological sensitivity. Earlier, we found that decreased resistance to changing environmental factors in migrants to lowlands from the Dagestan highlands was connected with their high level of homozygosity. The data obtained allow us to assume that missing links in this chain of events include, in addition to parameters of inbreeding level, parameters of neurophysiological sensitivity, including absolute and differential sensitivity of various analyzers sensory systems, which are from 65 to 75% genetically determined. Migrants from highland auls (villages) to lowlands exhibited a decreased rate of sensomotor reactions in response to light and sound of various intensities, as well as decreased differential color sensitivity in the long-, medium-, and short-wave ranges of the spectrum, compared to highlanders. The results suggest the selective mortality of migrants from highlands to lowlands during adaptation to new conditions. Those migrants who dies were characterized by specific gene complexes that determined the characteristic features of expression of a number of interrelated polymorphic and quantitative traits. Thus, the high levels of homozygosity and inbreeding were accompanied by a greater neurophysiological sensitivity and lower indices of body weight and height.

[A genetic epidemiological study of arterial hypertension in an isolated mountain area of Dagestan]. / Genetiko-épidemiologicheskoe issledovanie arterial'noi gipertonii v gornom izoliate Dagestana.

Hereditary factors of arterial hypertension were evaluated genetically and epidemiologically in the study of an isolated population of Dagestan with high inbreeding. High prevalence of arterial hypertension was found. Its highest morbidity was found in native population of Tukhums characterized also by the highest inbreeding.

[Genetic-demographic study of mountain populations from Dagestan and their migrants to the lowlands. Comparison of basic parameters of fitness]. / Genetiko-demograficheskoe issledovanie gorskikh populiatsii Dagestana i migrantov iz nikh na ravninu. Sravnenie osnovnykh prarametrov prisposoblennosti.

Results of a total genetic demography study of females of postreproductive age from both parts of "splits" highland isolates of Dagestan, highlanders, and migrants to lowlands are described. The components of natural selection that were related to differential mortality and differential fertility were estimated in the highlanders and the migrants using Crow indices. Offsprings of female migrants were characterized by a higher prenatal (spontaneous abortions and still-births) and a lower prereproductive mortality. These differences may be accounted for by two mechanisms: (1) the effects of changing marital structure (female migrants are more exogamous) and (2) better medical care for the children of migrants compared to those living in highland auls (settlements), which are still difficult to access. It was demonstrated that mortality of probands' children before reproductive age, as well as the proportion of their close genetic relatives that died within five years after resettling, increased with an increase in the level of individual inbreeding in women examined (probands). These data allow us to suggest that the drastic increase revealed in mortality of the highlanders during the first years after resettling may be partially attributed to high levels of inbreeding and heterozygosity; these, in turn, decrease the individual's nonspecific resistance to new ecological factors. Fertility and prenatal mortality appeared to increase and decrease, respectively, with an increase in the inbreeding level.

[Genetic-demographic study of mountain populations of Daghestan and migrants from it to the lowlands. Study of genetic and marital structure]. / Genetiko-demograficheskoe issledovanie gorskikh populiatsii Dagestana i migrantov iz nikh na ravninu. Izuchenie geneticheskoi i brachnoi struktury.

The results of a genetic and demographic study of two "split" isolates of small native ethnic groups of Daghestan are described. Parts of these populations were resettled from habitual highland ecological conditions to radically new lowland conditions in the 1940s. These split isolates were compared with a population of native inhabitants of the Daghestan lowland. It was found that, since resettling, separated populations originating from split isolates became significantly different in both marriage and genetic structures. This is manifested in different phenotypic and allelic frequencies of a number of physiological and biochemical markers and in levels of their heterozygosity. To explain the differences revealed, a hypothesis was proposed about the relationship between levels of inbreeding, heterozygosity, and physiologic sensitivity that account for the differential adaptability of members of the isolated populations to changing environmental conditions. This is the first report of a series of papers describing the experimental testing of this hypothesis. While testing the validity of the hypothesis in this study, a positive linear correlation was found between inbreeding and homozygosity levels.

Population-genetics approach to the genetics of human behaviour.

Invariant values of inheritance factors within and between different populations can show the existence of and measure the degree of genetic determination of behavioural characters. The absence of inbred depression of quantitative behavioural characters in isolated populations of highland inhabitants of Daghestan is demonstrated by means of comparative analysis of the mean population values of psychophysiological characters in outbred, moderately isolated, and extremely isolated (and inbred) populations. The absence of pronounced adverse effects of inbred marriages, known as the 'Daghestan phenomenon', is explained by the antiquity of the native populations and the severe ecological conditions under which these populations live which have led to elimination of carriers of hereditary diseases and other detrimental phenotypes.

[Phenotypic and genetic differentiation of human populations with respect to morphologic and psychophysiological traits]. / Fenotipicheskaia i geneticheskaia differentsiatsiia populiatsii cheloveka po morfologicheskim i pscikhofiziologicheskim priznakam.

Four groups of human characters (mendelian markers, anthropometry, neurodynamics and psychodynamics) were studied in eight human populations characterized by different degrees of isolation and different ethnic backgrounds, and located in different ecological conditions. The populations examined were proved to display phenotypic and genetic differentiation for the studied groups of characters which were compared with linguistic and geographical distances. The role of genetic factors and that of environmental factors was shown to diminish and to increase, respectively, as the degree of complexity of expression of the group of characters under study (from anthropometry to psychodynamics) goes up.

[Integral evaluation of phenotypic and genotypic variability of morphologic and psychophysiologic human traits]. / Integral'nye otsenki fenotipicheskoi i genotipicheskoi izmenchivosti morfologicheskikh i psikhofiziologicheskikh priznakov cheloveka.

The paper demonstrates the expedience of the developed populational-genetic approach to studying the genetic bases of a complex of quantitative characters pertaining to different levels of human organization: anthropometry, neurodynamics and psychodynamics. The studies were carried out in eight human populations of different degree of isolation and ethnical background. It is shown that correlation phenotypic variability is higher for these characters, as compared to genotypic variability, the number of general genes responsible for this variability being decreased, respectively.

[Phenotypical and genetic differentiation of human populations for morphological and psychophysiological traits. Factor analysis]. / Fenotipicheskaia i geneticheskaia differentsiiatsiia populiatsii cheloveka po morfologicheskim i psikhofizicheskim priznakam. Faktornyi analiz.

The multivariate genetic factor analysis is used, as first attempt, to study genetic bases of correlation variability of neurodynamic and psychodynamic levels of individual organization among isolates of Daghestan. Closer similarity between factors described in templates of phenotypic correlations is explained by lower heritability of the parameters under study. Interpopulation differences revealed by the multivariate genetic analysis are the result of differences in the genetic structure of the populations.

[Heritability of neurodynamics and psychodynamics in human populations]. / Nasleduemost' neirodinamiki i psikhodinamiki v populiatsiiakh cheloveka.

A component analysis of human neurodynamic and psychodynamic characters in the norm was carried out in 8 human populations characterized by different degrees of isolation and ethnic origin. An increase in phenotypic variability and a decrease in heritability with increasing complexity of organization of the characters under study were demonstrated for all these populations. The additive effect plays the major role in genetic determination of neurodynamic and psychodynamic characters studied. For a number of neurodynamic parameters the effect of intralocus dominance indicative of the oligogenic determination system was observed. Data in favour of real contribution of the factors linked to X-chromosome were obtained for simple sensomotor reactions.