Detection of Two Polymorphic Sites in the Human c-fms Gene: Allele Frequencies in Several Russian Populations

Two polymorphic sites were found in the human c-fms gene: one (G A) was in position 34047 in the last intron, and the other (dinucleotide TC CA) was in positions 34 293 and 34 294 in the 3"-untranslated gene region, 34 bp downstream of the translation stop codon. The polymorphic dinucleotide appeared to be immediately upstream of an octamer showing 100% homology to cis element –CAAACTTC–, which is responsible for controlled instability of mRNAs of several genes. Based on these data, functional significance was assumed for this polymorphism of the c-fms gene. Allele frequencies were established for several populations. The mutant allele of the polymorphism located in the intron were detected only in one family of ethnic Germans from the Altaiskii krai. Polymorphism of the second site, which is in the 3"-untranslated region of the c-fms gene, was observed in all Caucasoid and Mongoloid populations examined. Frequency of the rare allele varied from 19.7–25% in Arctic Mongoloids to 31–42.6% in Central Asian Mongoloids and was similar in two Caucasoid populations (22.6% in ethnic Russians and 26.5% in ethnic Germans). The wide distribution of the mutant allele in human populations of the two races was considered indicative of an adaptive role of the polymorphism in providing a certain level of the gene product, a receptor, in certain cell processes.     

Insertion-deletion polymorphism of the angiotensin-converting enzyme gene in populations of the Volga-Ural region

Insertion-deletion polymorphism at the angiotensin I-converting enzyme (ACE) gene in populations of the Volga-Ural region was examined by means of polymerase chain reaction. The populations studied belong to the Finno-Ugric (Komis, Maris, Mordovians, and Udmurts), Turkic (Chuvashes, Tatars, and Bashkirs), and Eastern-Slavic (Russians) ethnic groups. Distribution patterns of allele and genotype frequencies of this polymorphic system in the examined region were characterized. Comparison of the obtained results with the literature data on the ACE gene polymorphism in other Caucasoid and Mongoloid populations revealed some trends in the ACE genotype frequency dynamics depending on the ethnicity of the populations.     

Molecular genetic analysis of polymorphism of the HindII and (CA)-repeat of the factor VIII gene loci in people of the Volgo-Ural region

Molecular genetic analysis of polymorphism of the factor VIII gene at loci HindIII (intron 19) and (CA)-repeats (intron 13) was performed in seven ethnic groups of the Volga-Ural region (Bashkirs, Tatars, Chuvashes, Maris, Mordovians, Udmurts, and Komis). The allelic frequency of the HindIII locus was shown to be similar in these ethnic groups. The ethnic groups were more heterogeneous with regard to the genotype and allele frequencies of (CA)-repeats, which indicates that this polymorphic system can be used to characterize the genetic structure of the Volga-Ural human populations.     

Analysis of the allele polymorphism of (CTG)n and (GAG)n triplet repeats in DM,DRPLA, and SCA1 genes in various populations of Russia

Polymorphism of highly polymorphic triplet repeats CTG of the 3'-untranslated region of the myotonin protein kinase gene and CAG of the genes associated with dentatorobral-pallidoluysian atrophy (DRPLA, or Hew River syndrome) and spinocerebellar ataxia type 1 (SCA1) was analyzed in several ethnic populations of Russia. A difference in allele spectra of the three genes was demonstrated for populations differing in ethnic origin.     

Investigation of Gene Insertion–Deletion Polymorphism of the Gene for Angiotensin-Converting Enzyme in Populations of the Volga–Ural Region

Insertion–deletion polymorphism at the angiotensin I-converting enzyme (ACE) gene in populations of the Volga–Ural region was examined by means of polymerase chain reaction. The populations studied belong to the Finno-Ugric (Komis, Maris, Mordovians, and Udmurts), Turkic (Chuvashes, Tatars, and Bashkirs), and Eastern-Slavic (Russians) ethnic groups. Distribution patterns of allele and genotype frequencies of this polymorphic system in the examined region were characterized. Comparison of the obtained results with the literature data on the ACE gene polymorphism in other Caucasoid and Mongoloid populations revealed some trends in the ACE genotype frequency dynamics depending on the ethnicity of the populations.     

Polymorphism of the HFE gene associated with hereditary hemochromatosis in populations of Russia

Expression of hereditary hemochromatosis as well as predisposition to iron overload syndrome and sporadic porphyria cutanea tarda are currently believed to be associated with the inheritance of certain allelic variants of the HFE gene. Allele frequencies of the C282Y (845A) and H63D (187G) mutations in the HFE gene in human populations of different races are remarkably different, and the prevalence of the S65C (193T) mutation is still poorly studied. In the present study we estimated allele frequencies of HFE mutations in Russians and in a number of Siberian ethnic indigenous populations. In Russians, allele frequencies of the C282Y, H63D and S65C mutations were 3.7, 13.3 and 1.7%, respectively. These values were similar to those observed in populations of Europe. The C282Y mutation was not detected in the population samples of Siberian ethnic groups, including Mansis, Khantys (Finno-Ugric group), Altaians, and Nivkhs (Mongoloids), suggesting that the frequency of this allele in the populations examined was lower than 1%. The frequency of the C282Y allele in the Tuvinian and Chukchi samples (Mongoloids) constituted 0.45 and 0.8%, respectively. Furthermore, pedigree analysis of both Chukchi carriers discovered showed that some of their ancestors were from other ethnic groups. Low frequencies of this allelic variant is typical of many Eastern Asian populations, which are also characterized by rather low frequencies of the H63D variant. In contrast, in some ethnic groups of Western Siberia allelic frequency of the H63D mutation is rather high, constituting 8.7% in Altaians, 15.5% in Mansis, and 11.3% in Khantys. The frequency of this allele in Tuvinians, Nivkhs, and Chukchis constituted 5, 4.7, and 0.8%, respectively. These findings make it possible to estimate the proportion of individuals predisposed to iron overload syndrome in different Russian ethnic groups. The HFE allele frequency distribution patterns observed in the populations examined pointed to pre-Celtic appearance of the CY82 allele. It also provides elucidation of the evolutionary genetic relationships between Siberian ethnic groups and the contemporary populations of Eastern and Western Europe.     

Principal component analysis of gene frequencies of Chinese populations

Principal components (PCs) were calculated based on gene frequencies of 130 alleles at 38 loci in Chinese populations, and geographic PC maps were constructed. The first PC map of the Han shows the genetic difference between Southern and Northern Mongoloids, while the second PC indicates the gene flow between Caucasoid and Mongoloids. The first PC map of the Chinese ethnic minorities is similar to that of the second PC map of the Han, while their second PC map is similar to the first PC map of the Han. When calculating PC with the gene frequency data from both the Han and ethnic minorities, the first and second PC maps most resemble those of the ethnic minorities alone. The third and fourth PC maps of Chinese populations may reflect historical events that allowed the expansion of the populations in the highly civilized regions. A clear-cut boundary between Southern and Northern Mongoloids in the synthetic map of the Chinese populations was observed in the zone of the Yangtze River. We suggest that the ancestors of Southern and Northern Mongoloids had already separated before reaching Asia. The ancestors of the Southern Mongoloids may result from the initial expansion from Africa or the Middle East, via the south coast of Asia, toward Southeast Asia, and ultimately South China. Upon reaching the Yangtze River, they might even have crossed the river to occupy the nearby regions for a period of time. The ancestors of the Northern Mongoloids probably expanded from Africa via the Northern Pamirs, first went eastward, then towards the south to reach the Yangtze River. The expansion of the Northern Mongoloids toward the south of the Yangtze River happened only in the last 2 or 3 thousand years.     

Polymorphism of <Emphasis Type="Italic">CD209</Emphasis> and <Emphasis Type="Italic">TLR3</Emphasis> genes in populations of North Eurasia

The DC-SIGN (dendritic cell-specific intercellular adhesion molecule (ICAM)-3-grabbing non-integrin) and TLR3 (toll-like receptor 3) proteins are key effectors of the innate immunity and particularly play an important role in the organism’s antiviral defense as pattern-recognition receptors. Previously, we demonstrated that certain genotypes and alleles of single nucleotide polymorphisms (SNPs) rs2287886 (G/A) in the promoter region of the CD209 gene (encoding DC-SIGN) and rs3775291 (G/A, Leu412Phe) in the exon 4 of the TLR3 gene are associated with human predisposition to tick-borne encephalitis in the Russian population. In the present work, the distribution of genotype and allele frequencies for these SNPs was studied in seven populations of North Eurasia, including Caucasians (Russians and Germans (from Altai region)), Central Asian Mongoloids (Altaians, Khakass, Tuvinians, and Shorians), and Arctic Mongoloids (Chukchi). It was found that the CD209 gene rs2287886 SNP A/A genotype and A allele, as well as the TLR3 gene rs3775291 SNP G/G genotype and G allele (the frequencies of which in our previous studies were increased in tick-borne encephalitis patients as compared with the population control (Russian citizens of Novosibirsk)), are preserved with a high frequency in Central Asian Mongoloids (who for a long time regularly came in contact with tick-borne encephalitis virus in places of their habitation). We suggested that predisposition to tick-borne encephalitis in Central Asian Mongoloid populations can be predetermined by a different set of genes and their polymorphisms than in the Russian population.     

Principal component analysis of gene frequencies of Chinese populations

Principal components (PCs) were calculated based on gene frequencies of 130 alleles at 38 loci in Chinese populations, and geographic PC maps were constructed. The first PC map of the Han shows the genetic difference between Southern and Northern Mongoloids, while the second PC indicates the gene flow between Caucasoid and Mongoloids. The first PC map of the Chinese ethnic minorities is similar to that of the second PC map of the Han, while their second PC map is similar to the first PC map of the Han. When calculating PC with the gene frequency data from both the Han and ethnic minorities, the first and second PC maps most resemble those of the ethnic minorities alone. The third and fourth PC maps of Chinese populations may reflect historical events that allowed the expansion of the populations in the highly civilized regions. A clear-cut boundary between Southern and Northern Mongoloids in the synthetic map of the Chinese populations was observed in the zone of the Yangtze River. We suggest that the a     

Origin of caucasoid-specific mitochondrial DNA lineages in the ethnic populations of the Altai-Sayan region

The data on sequence variation in the first hypervariable segment (HVSI) of human mitochondrial DNA (mtDNA) representing Caucasoid mtDNA lineages in the gene pools of Altaians and Khakassians are presented. Identification of the subgroups of Caucasoid mtDNA lineages found in the gene pools of the ethnic populations of the Altai-Sayan region and the adjacent territories, Altaians, Khakassians, Tuvinians, Buryats, and Yakuts was carried out. All Caucasoid mtDNA lineages belonged to groups H, HV1, J*, J1, J1b1, T1, T4, U1a, U2, U3, U4, U5a1, I, X and N1a. Taking into consideration possible contribution of southern Caucasoid and eastern European components to the formation of the anthropological type of Altai-Sayan ethnic populations, distribution of the revealed Caucasoid mtDNA lineages among the ethnic populations of the Central Asia, Western Asia, Caucasus, and Eastern Europe was examined. The applied approach permitted identification of 60% of mtDNA types the majority of which had southern Caucasoid origin. Less than 10% of mtDNA types were of eastern European origin. The gene pools of Altaians and Khakassians displayed the presence of autochthonous components represented by mtDNA types from subgroups U2 and U4.     

Carrier detection and prenatal diagnosis in Duchenne and Becker muscular dystrophy families, using dinucleotide repeat polymorphisms.

To improve carrier detection and prenatal diagnosis for Duchenne and Becker muscular dystrophy families, we determined allele frequencies and measures of variation for four (dC-dA)n.(dG-dT)n loci identified within a deletion-prone region of the human dystrophin gene. The loci are highly polymorphic, with predicted heterozygosities of 71.6%-93.3%. Direct DNA sequence analysis of the (dC-dA)n.(dG-dT)n locus in intron 49 revealed an additional length polymorphism which varies by single-basepair increments, is adjacent to the dinucleotide repeat block, and enhances the polymorphic content of this marker. The four (dC-dA)n.(dG-dT)n loci are each easily amplified by PCR in two diplex reactions. The variability of allele lengths at these loci makes them ideal for carrier detection and prenatal diagnosis, often providing diagnostic information when RFLP analysis is uninformative. These markers have aided in identification of deletion mutations, exclusion of maternal cell contamination of chorionic villus samples, confirmation of paternity, and mapping of gene recombinations. The allele identification of these loci can be performed either with a radiolabel or with an automated, nonradioactive, fluorescent gel detection system.     

A further polymorphism of the Gd locus for glucose-6-phosphate dehydrogenase present among blacks (Nigerians) and apparently absent among Caucasoids: the quantitative isoelectrophoretic variation of the Gd+ allele.

A structural but isoelectrophoretic moderate variation of glucose-6-phosphate dehydrogenase (G6PD) activity is common among Nigerians (a black population exposed to a long-lasting intense Plasmodium falciparum malarial endemia). It had never even been searched for among Caucasoids and Mongoloids. In the present work, we attempted to ascertain whether this polymorphism exists among Caucasoids. With this purpose, two Caucasoid male populations were studied: Sardinians and Romans, who respectively did and did not experience an evolutionarily effective exposure to P. falciparum. The approach adopted here consisted in comparing the variations of G6PD activity observed between brothers who certainly received their Gd gene from the same grandparent (hence Gd genes identical by descent) with those between brothers who received it (in the Roman series) or may have received it (in the Sardinian series) from different grandparents. No evidence for common moderate G6PD activity variations segregating with the Gd gene was found either in Romans or Sardinians, who have both been studied with much larger samples and more sensitive approaches than those which detected such type of polymorphism among Nigerians. The upper 95% confidence limit of such zero estimates for the frequency of the isoelectrophoretic quantitative Gd variant alleles were about 0.04 and 0.025 for Romans and Sardinians, respectively. This is the first example of a genetic region (the Gd gene with its flanking sequences) apparently monomorphic in a major race and with several (four) polymorphic sites in another major race.     

Analysis of the Allele Polymorphism of (CTG)nand (CAG)n Triplet Repeats in Loci DM, DRPLA, and SCA1 in Several Populations of Russia

Polymorphism of highly polymorphic triplet repeats CTG of the 3"-untranslated region of the myotonin protein kinase gene and CAG of the genes associated with dentatorubral-pallidoluysian atrophy (DRPLA, or Hew River syndrome) and spinocerebellar ataxia type 1 (SCA1) was analyzed in several ethnic populations of Russia. A difference in allele spectra of the three genes was demonstrated for populations differing in ethnic origin.     

Genetic diversity and relationships of populations of northern Eurasia by polymorphic Alu insertions

Autosomal gene pools of 27 populations representing 12 ethnic groups of Siberia, Central Asia, and the Far East have been characterized for the first time using a set of eight polymorphic Alu insertions. The results of our analysis indicate a significant level of genetic diversity in populations of northern Eurasian and the considerable differentiation of their gene pool. It was shown that the frequency of the Alu (?) allele at the CD4 locus was inversely related to the magnitude of the Mongoloid component of the gene pool: the lowest and highest frequencies of the CD4 Alu deletion were recorded in Eskimos (0.012) and in Russians and Ukrainians (0.35), respectively. A gene flow analysis showed that Caucasoid populations (Russians, Tajiks, and Uzbeks), as well as Turkic ethnic groups of southern Siberia (Altaians and Tuvans), Khanty, and Mansi populations, in contrast to ethnic groups of eastern Siberia and the Far East, have been recipients of a considerable gene flow. A correlation analysis showed that genetic distances determined using polymorphic Alu insertions were correlated with the anthropological characteristics of the populations studied.     

A microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene: functional implications and racial differences

The human Toll-like receptor 2 (TLR2) mediates responses of both innate and adaptive immunity to Gram-positive bacteria, including mycobacteria. We sought functional polymorphisms in the 5'-untranslated region (UTR) of TLR2. We found a highly polymorphic (GT)n dinucleotide repeat 100 bp upstream of the TLR2 translational start site in intron 2. The numbers of GT repeats varied from 12 to 28. There were significant differences in allele distribution between African Americans and Caucasians (P=0.008) and between African Americans and Koreans (P=0.0003). The promoter activities of recombinant promoter-intron2/reporter constructs including the shortest [GT)n=12] or longest [(GT)n=28] alleles were significantly more stimulated when exposed to 200 IU ml(-1) of interferon-gamma than when exposed to 100 IU ml(-1) of GM-CSF (P<==0.03). Since TLR2 plays a critical role in the human innate immune response, this functional microsatellite polymorphism may be important in the pathogenesis of infectious and inflammatory diseases.     

Normal polymorphism of the (CTG)n repeat in the myotonin protein kinase (DM) gene on chromosome 19q13.3 in Western European populations

Polymorphism of a highly polymorphic CTG repeat in the 3'-untranslated region of the myotonin protein kinase gene was analyzed in healthy people from several Eastern European populations (Russians, Moldovans, Belarussians, Komis, Chuvashes, Udmurts, Bashkirs, Tatars, Maris, and Mordovians). In total, 26 alleles of the CTG repeat were found, the repeat number ranging from 5 to 33 (alleles with six and seven repeats were not detected). The heterozygosity of individual populations varied from 61 to 91%. In the total sample combining all populations, the observed and expected heterozygosities did not differ (fixation index -0.0022) suggesting selective neutrality of the normal polymorphism of the CTG repeat in the myotonin protein kinase gene.     

The blood groups of the Timuri and related tribes in Afghanistan

The present investigation is a study of the blood groups of the Timuri and related tribes in Afghanistan. There is little historical documentation for the origin of the Timuri. Their name is probably a misnomer, however, since they are apparently not descended from the armies of Timur, or Tamerlane, which invaded Afghanistan during the fourteenth century. Relatively few blood group studies have been carried out on the inhabitants of Afghanistan, so detailed comparisons with other populations can be made only for the ABO system. (Certain populations in Iran to the west and a few rather widely separated populations, such as the Baltis and Nepalis to the east, have been more thoroughly investigated, and comparisons can be made with them on at least seven genetical systems.) The presence of the A₂ allele suggests gene flow from the West, but the high frequency of B is consistent with other populations tested in Afghanistan. The Rh frequencies give little critical information but the low level of cde is suggestive of Mongoloid origin. On the other hand, for the MNS system the high level of MS is typically Caucasoid. The high total M is found in Asia both in Caucasoids and Mongoloids. The presence of the Lu^a allele and the relatively high frequency of the K allele are more Caucasoid than Mongoloid, but the presence of even one Diego (Di^a) positive among the Timuri and related tribes suggests a Mongoloid contribution to the gene pool. The low frequency of P₁, though always a little suspect on travelled specimens, is consistent with this. All of the Iranian populations tested may be regarded as essentially Caucasoid from the blood group point of view. The Baltis and Nepalis show certain Mongoloid characteristics. The Timuri are distinctly more Mongoloid than the former but less so than the latter. In summary, the Timuri appear to be intermediate in allele frequencies between Caucasoid and Mongoloid populations, with unmistakable evidence of both in their ancestry.     

Polymorphisms in the 5'-UTR of PTEN and other gene polymorphisms in normal Japanese individuals

Polymorphisms are distributed differently in populations, including those of regions, ethnic groups, and diseased patients. In order to investigate variation in nucleotide sequences in normal individuals, we isolated genomic DNA from the blood of healthy Japanese individuals and sequenced the 5'-untranslated region (5'-UTR) of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene and the gene promoter, intron, and exon nucleotides of p53, p14(ARF), murine double minute 2 (MDM2), and the beta2- and beta3-adrenoceptor (-AR). We found polymorphisms in these regions, including a deletion at positions -465 to -463 and a substitution at position -404 in PTEN and a substitution at position -4924 in p14(ARF), in normal individuals. Individuals with or without the PTEN polymorphism harbored a different distribution of polymorphisms, including simultaneous alterations in nucleotides of p53, MDM2, and beta3-AR, and also harbored some polymorphic nucleotides located in the same set of associatively altered nucleotides. Our results show that multiple nucleotides, including the PTEN nucleotides, are altered in normal Japanese individuals and provide useful information for genotyping studies in individuals and populations.