A. V. Polyakov

Prevalences of hereditary diseases in different populations of Russia

The geographic distribution of hereditary diseases (HDs) in different populations and ethnic groups of Russia has been studied. The main patterns of the formation of the prevalence and spectrum of HDs in five ethnic groups (Russians from six regions, Mari, Chuvashes, Udmurts, and Adygeans) from a total of ten regions of Russia have been analyzed. Analysis of correlations suggests that genetic drift is the main factor of the genetic differentiation of populations with respect to the prevalence of HDs. Accumulation of HDs in individual populations and ethnic groups has been analyzed. Hereditary diseases characterized by locally high prevalence rates in individual populations or ethnic groups have been detected. The main patterns of the accumulation of individual diseases and differences between populations and ethnic groups in this respect have been studied with the use of principal component analysis, which describes these patterns more graphically. It has been demonstrated that the genes of HDs are a promising tool for characterizing ethnogenetic processes in populations.

Types of Y chromosome deletions and their frequency in infertile men

Y chromosome deletions in the AZF locus were analyzed during a large-scale andrological and genetic examination of 810 infertile men. The search for Yq microdeletions was carried out according to the standard EAA/EMQN guidelines. The breakpoints were mapped for the revealed AZF deletions. The Y chromosome macro-and microdeletions were detected in 61 (7.5%) infertile men. The frequencies of AZF deletions in patients with azoospermia and severe oligozoospermia amounted to 12.2 and 8.1%, respectively. On the whole, the frequencies of Yq microdeletions and the genophenotypic correlations characteristic of various AZF deletion types agree with the relevant published data. However, spermatozoa in the ejaculate sediment of men with completely deleted AZFa region or AZFb+c deletions (from solitary spermatozoa to several dozens) were detected for the first time. It was demonstrated that the breakpoints were localized between AZFa and AZFb regions proximally to AZFb+c microdeletions for the majority of cytogenetically detectable deletions of the Y chromosome long arm. This indicates that the mechanisms underlying Yq macro-and microdeletions are somewhat different. The issues related to the role of Y chromosome deletions in the origins of X chromosome monosomy and X/XY mosaicism are discussed.

The frequency and spectrum of mutations and the IVS8-T polymorphism of the CFTR gene in Russian infertile men

The frequency and spectrum of mutations and the IVS8-T polymorphism of the CFTR gene have been studied in a cohort of 963 in Russian infertile men. Mutations have been found in 48 out of 1926 analyzed chromosomes (2.5%) in the heterozygous state (n = 46) and in the compound heterozygote L138ins/N1303K (n = 1). A CFTR gene mutation was combined with the 5T allele (mutCFTR/5T) in 11 patients. The following mutations have been found: F508del (n = 18), CFTRdele2,3(21kb) (n = 9), W1282X (n = 7), 2143delT (n = 4), 3849 +10kbC>T (n = 2), L138ins (n = 2), 1677delTA (n = 1), 2184insA (n = 1), 3821delT (n = 1), G542X (n = 1), N1303K (n = 1), and R334W (n = 1). The F508del mutation is the most frequent; it has been detected in 37.5% of the affected chromosomes. The total proportion of four mutations (F508del, CFTRdele2,3(21kb), W1282X, and 2143delT) is about 79% of all mutations found. The 5T allele has been found in 10.9% infertile men and 4.8% of control men. Significant differences in the frequency of the IVS8-5T variant of the CFTR gene have been found between these groups (p = 0.005), as well as between infertile patients without mutations and control men (p = 0.019). In total, the mutations and /or 5T allele have been found in 14.6% of the patients examined. These data indicate increased frequencies of the mutations of the CFTR gene and its allele variant IVS8-5T in Russian infertile men.

Genetic structure of the Udmurt population

Integrated study of the genetic structure of the Udmurt population with respect to different genetic systems has been performed. Data on the genes of genetic diseases, abiotic parameters analyzed by population statistic methods, and DNA polymorphism are summarized. The populations of six raions (districts) of Udmurt Republic (the Mozhga, Malaya Purga, Sharkan, Debesy, Igra, and Glazov raions) have been studied. The total population studied was 267 655 people (an urban population of 150 119 people and a rural population of 117 536 people), including 155 346 Udmurts. The population structure has been studied in six districts on the basis of the vital statistics, Crow’s indices, Malecot’s isolation by distance parameters, ethnically assortative marriage parameters, endogamy indices, inbreeding-endogamy (ie) indices, and frequencies of the genotype and allele frequencies of four DNA markers (17 alleles). The prevalences of hereditary diseases have been calculated for different population groups: urban and rural populations, Udmurts and other ethnic groups. These groups, especially the urban and rural populations, substantially differed from one another in the prevalences of autosomal dominant (AD) and autosomal recessive (AR) diseases. The correlation between the prevalence of AD and AR diseases and the ie index is positive and significant. The spectrum of hereditary diseases detected in six districts of Udmurtia comprises 149 diseases (80, 57, and 12 AD, AR, and X-linked diseases, respectively). Accumulation of individual diseases in districts of Udmurtia and accumulation of diseases in Udmurtia as compared to regions studied earlier has been found. Cluster analysis of the frequencies of genes of AD and AR diseases and DNA markers has determined the gene geographic position of Udmurts.

Heterozygous carrier rate for type I–IV proximal spinal muscular atrophy in Chuvashes, Udmurts, and residents of the Moscow region

The first estimation of the heterozygous carrier rates for the SMN1 gene deletions and SMN2 gene duplications in populations of Russia has been performed. The numbers of SMN gene copies have been deter-mined in samples from Chuvash and Udmurt populations, as well the population of the Moscow region, by means of multiplex ligation-dependent probe amplification. The heterozygous carrier rates for the CMA gene were 2.7% (1: 37 people), 2.8% (1: 36 people), and 2.8% (1: 36 people) in Chuvashes, Udmurts, and residents of the Moscow region, respectively. The SMN2 duplication frequencies have been determined in the studied groups. It is 1.5, 4, and 2.5% in Chuvashes, Udmurts, and residents of the Moscow region, respectively. The high SMN2 duplication frequency in Udmurts may explain why the SMN1 heterozygous carriage frequency in this population was overestimated in earlier PCR-RFLP analyses.

Novel large deletion c.22-1320_633+1224del in the CYB5R3 gene from patients with hereditary methemoglobinemia

Hereditary types I and II methemoglobinemia is a rare autosomal recessive disease due to a deficiency of either soluble or soluble and membrane-bound forms of the enzyme NADH-cytochrome b5 reductase. The molecular genetic bases of both types of the disease consist in changes in the CYB5R3 gene. In this study, the novel and, to date, only large deletion in this gene is described, discovered in two unrelated families with types I and II methemoglobinemia. The common founder haplotype on the chromosomes carrying this mutation was identified. A universal approach for searching for the deletion boundaries was developed, and the c.22-1320_633+1224del deletion breakpoints were determined. In addition, a system for identifying the deletion in heterozygous and homozygous states was designed.

Mutation analysis of K-ras protooncogene in colorectal adenocarcinomas and polyps in Russian patients

To estimate diagnostic value of K-ras mutations during cancer risk group formation, they were studied in the samples of sporadic carcinomas (n = 58), benign (n = 33), and malignant (n = 13) polyps of large intestine obtained during surgery or polypectomy. Using PCR analysis, restriction analysis, SSCP analysis and automated sequencing, eight various point mutations were revealed. Six of them were located in codon 12 and two, in codon 13 of the K-ras gene. Mutation frequency in carcinomas, benign and malignant polyps was 43, 49, and 69%, respectively. In the normal tissue samples of colorectum, no changes in codons 12 and 13 in the K-ras gene were observed. Mutations in the groups of Russian patients examined partially overlapped. In patients with colorectal carcinoma the mutation frequency in the K-ras gene was not associated with disease onset age, location, and the extent of tumor differentiation while it was associated with the stage of tumor process. In polyps, the maximum mutation frequency was revealed among patients over 70 years of age as well as in the adenomas of villous histology and large size (≥1cm). No correlation between the K-ras mutation frequency and the extent of polyp dysplasia was observed.

Molecular analysis of the Y chromosome in XX sex-reversed patients

Molecular genetic analysis was performed for 26 phenotypically male patients lacking the Y chromosome in the karyotype. The sex-determining region Y (SRY) gene was found in 77% of the patients. PCR analysis of Y-specific loci in the 17 SRY-positive patients revealed Yp fragments varying in size in 16 cases and cryptic mosaicism (or chimerism) for the Y chromosome in one case. The frequencies of class I, II, and III (Yp+)XX sex reversals were 18.75, 25.25, and 56%, respectively. All of the class III (Yp+)XX sex-reversed patients had a 3.5-Mb paracentric inversion flanked by inverted repeats 3 (IR3) on the short arm of the Y chromosome.

Spectrum and frequency of mutations in the connexin 32 gene (GJB1) in hereditary and sensory neuropathy type 1X patients from Bashkortostan

Hereditary motor and sensory neuropathy type 1X (HMSN 1X) is the second most frequent form of demyelinating polyneuropathies and is caused by mutations in the gene for connexin 32 protein (Cx32, GJB1). The contribution of HMSN 1X to the structure of HMSN in the Republic of Bashkortostan was determined. The GJB1 mutations were detected in 18 out of 131 unrelated patients, which constituted 13.7%. The four missense mutations identified were represented by: p.Pro87Ala (c.259C > G) with the frequency of 10%; p.Arg22Gln (c.65G > A) (2.98%); p.Arg15Gln (c.44G > A); and p.Thr86Ile (c.257C > T) (0.8%). The latter mutation was never described before. The frequent mutation p.Pro87Ala was tested for linkage disequilibrium with the alleles of five polymorphic microsatellite DNA loci associated with the GJB1. It was demonstrated that 10 out of 13 chromosomes carrying the mutation mentioned had common DXS8111-DXS983-DXS8107-DXS8052 haplotype. This finding suggested the distribution of this mutation on the territory of the Republic of Bashkortostan as a result of the founder effect. The mutational spectrum of GJB1 and mutation frequencies observed in the HMSN 1X patients examined were characterized by ethnic heterogeneity. This finding will provide development of most optimal algorithm of the HMSN DNA diagnostics in the region.

Medical Genetic Study of Hereditary Diseases in Abazins of the Karachay-Cherkess Republic

This paper estimates the load and nosological spectrum of monogenic hereditary diseases (HDs) in Abazins of the Karachay-Cherkess Republic (KChR), identified in Cherkessk and ten districts, Abazinsky, Ust-Dzhegutinsky, Malokarachaevsky, Karachaevsky, Prikubansky, Khabezsky, Nogaysky, Adyge-Khablsky, Urupsky, and Zelenchuksky. The number of the investigated population was 387231 individuals (including 33264 Abazins). We detected 153 patients from 105 families with 45 nosological forms of HDs: 83 patients from 50 families with 23 AD diseases, 47 patients from 42 families with 15 AR diseases, and 23 patients from 13 families with 7 X-linked diseases. The total load of HDs in Abazins was 1: 218 individuals (in the rural population 1: 162, in the urban population 1: 305). Frequent and rare nosological forms of HDs and the accumulation of certain diseases in Abazins in comparison with the previously surveyed populations of Russia were determined. On the basis of the prevalence of AD and AR hereditary diseases, a principal component analysis was carried out, which determined the genogeographical position of Abazins among nine ethnic groups (13 populations) of Russian Federation: six Russian regions, Bashkirs of the Bashkortostan, Tatars of the Tatarstan, Chuvashes of the Chuvashia, Maris of the Mari El, Udmurts of the Udmurtia, Adygeans of the Adygea, and Circassians and Abazins of the KChR.