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The search for the molecular markers of osteoporosis (OP), based on the analysis of differential deoxyribonucleic acid (DNA) methylation in bone cells and peripheral blood cells, is promising for developments in the field of the early diagnosis and targeted therapy of the disease. The Runt-related transcription factor 2 (RUNX2) gene is one of the key genes of bone metabolism, which is of interest in the search for epigenetic signatures and aberrations associated with the risk of developing OP. Based on pyrosequencing, the analysis of the RUNX2 methylation profile from a pool of peripheral blood cells in men and women over 50 years of age of Russian ethnicity from the Volga-Ural region of Russia was carried out. The level of DNA methylation in three CpG sites of the RUNX2 gene was assessed and statistically significant hypomethylation was revealed in all three studied CpG sites in men (U = 746.5, p = 0.004; U = 784, p = 0.01; U = 788.5, p = 0.01, respectively) and in one CpG site in women (U = 537, p = 0.03) with primary OP compared with control. In the general sample, associations were preserved for the first CpG site (U = 2561, p = 0.0001766). The results were obtained for the first time and indicate the existence of potentially new epigenetic signatures of RUNX2 in individuals with OP.
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Biomarcadores , Subunidade alfa 1 de Fator de Ligação ao Core , Ilhas de CpG , Metilação de DNA , Osteoporose , Humanos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Masculino , Feminino , Osteoporose/genética , Pessoa de Meia-Idade , Ilhas de CpG/genética , Idoso , Epigênese GenéticaRESUMO
Calvarial doughnut lesions (CDL) with bone fragility with or without spondylometaphyseal dysplasia (MIM: #126550) is a rare autosomal dominant skeletal disorder characterized by low bone mineral density, spinal and peripheral fractures, and specific sclerotic lesions of the cranial bones. In the current classification of skeletal disorders, the disease is included in the group of bone fragility disorders along with osteogenesis imperfecta. The disease is caused by pathogenic variants in the SGMS2 gene, the protein product of which is sphingomyelin synthase 2, which primarily contributes to sphingomyelin (SM) synthesis-the main lipid component of the plasma membrane essential for bone mineralization. To date, 15 patients from eight families with CDL with bone fragility have been described in the literature, and a recurrent variant c.148C>T (p.Arg50Ter) in the SGMS2 gene has been identified, which was found in patients from six families. We diagnosed the disease in 11 more patients from three unrelated families, caused by the same heterozygous nonsense variant c.148C>T (p.Arg50Ter) in the SGMS2 gene. Our results show wide interfamilial and intrafamilial phenotypic variability in patients with a detected recurrent variant in the SGMS2 gene, the presence of which must be taken into consideration in the diagnosis of the disease. The primary analysis of this variant will contribute to optimal molecular genetic diagnostics, which can reduce diagnostic costs and time.
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Fraturas Ósseas , Osteocondrodisplasias , Osteogênese Imperfeita , Humanos , Calcificação Fisiológica , Fraturas Ósseas/genética , Heterozigoto , Osteogênese Imperfeita/genéticaRESUMO
Osteoporosis (OP) is a multifactorial bone disease belonging to the metabolic osteopathies group. Using the polygenic score (PGS) approach, we combined the effects of bone mineral density (BMD) DNA loci, affecting osteoporosis pathogenesis, based on GEFOS/GENOMOS consortium GWAS meta-analysis. We developed models to predict the risk of low fractures in women from the Volga-Ural region of Russia with efficacy of 74% (AUC = 0.740; OR (95% CI) = 2.9 (2.353-3.536)), as well as the formation of low BMD with efficacy of 79% (AUC = 0.790; OR (95% CI) = 3.94 (2.993-5.337)). In addition, we propose a model that predicts fracture risk and low BMD in a comorbid condition with 85% accuracy (AUC = 0.850; OR (95% CI) = 6.6 (4.411-10.608)) in postmenopausal women.
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Doenças Ósseas Metabólicas , Fraturas Ósseas , Osteoporose Pós-Menopausa , Osteoporose , Densidade Óssea/genética , Feminino , Fraturas Ósseas/etiologia , Humanos , Herança Multifatorial , Osteoporose/complicações , Osteoporose/genética , Osteoporose Pós-Menopausa/genéticaRESUMO
The paternal haplogroup (hg) N is distributed from southeast Asia to eastern Europe. The demographic processes that have shaped the vast extent of this major Y chromosome lineage across numerous linguistically and autosomally divergent populations have previously been unresolved. On the basis of 94 high-coverage re-sequenced Y chromosomes, we establish and date a detailed hg N phylogeny. We evaluate geographic structure by using 16 distinguishing binary markers in 1,631 hg N Y chromosomes from a collection of 6,521 samples from 56 populations. The more southerly distributed sub-clade N4 emerged before N2a1 and N3, found mostly in the north, but the latter two display more elaborate branching patterns, indicative of regional contrasts in recent expansions. In particular, a number of prominent and well-defined clades with common N3a3'6 ancestry occur in regionally dissimilar northern Eurasian populations, indicating almost simultaneous regional diversification and expansion within the last 5,000 years. This patrilineal genetic affinity is decoupled from the associated higher degree of language diversity.
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Cromossomos Humanos Y/genética , Haplótipos/genética , Idioma , Ásia , Europa (Continente) , Humanos , Filogeografia , Fatores de TempoRESUMO
It is commonly thought that human genetic diversity in non-African populations was shaped primarily by an out-of-Africa dispersal 50-100 thousand yr ago (kya). Here, we present a study of 456 geographically diverse high-coverage Y chromosome sequences, including 299 newly reported samples. Applying ancient DNA calibration, we date the Y-chromosomal most recent common ancestor (MRCA) in Africa at 254 (95% CI 192-307) kya and detect a cluster of major non-African founder haplogroups in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck in Y-chromosome lineages dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.
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Cromossomos Humanos Y/genética , Evolução Molecular , Grupos Raciais/genética , Sequência de Bases , DNA Mitocondrial/genética , Variação Genética/genética , Genética Populacional , Haplótipos/genética , Humanos , Masculino , Modelos Genéticos , Filogenia , Análise de Sequência de DNARESUMO
The Turkic peoples represent a diverse collection of ethnic groups defined by the Turkic languages. These groups have dispersed across a vast area, including Siberia, Northwest China, Central Asia, East Europe, the Caucasus, Anatolia, the Middle East, and Afghanistan. The origin and early dispersal history of the Turkic peoples is disputed, with candidates for their ancient homeland ranging from the Transcaspian steppe to Manchuria in Northeast Asia. Previous genetic studies have not identified a clear-cut unifying genetic signal for the Turkic peoples, which lends support for language replacement rather than demic diffusion as the model for the Turkic language's expansion. We addressed the genetic origin of 373 individuals from 22 Turkic-speaking populations, representing their current geographic range, by analyzing genome-wide high-density genotype data. In agreement with the elite dominance model of language expansion most of the Turkic peoples studied genetically resemble their geographic neighbors. However, western Turkic peoples sampled across West Eurasia shared an excess of long chromosomal tracts that are identical by descent (IBD) with populations from present-day South Siberia and Mongolia (SSM), an area where historians center a series of early Turkic and non-Turkic steppe polities. While SSM matching IBD tracts (> 1cM) are also observed in non-Turkic populations, Turkic peoples demonstrate a higher percentage of such tracts (p-values ≤ 0.01) compared to their non-Turkic neighbors. Finally, we used the ALDER method and inferred admixture dates (~9th-17th centuries) that overlap with the Turkic migrations of the 5th-16th centuries. Thus, our results indicate historical admixture among Turkic peoples, and the recent shared ancestry with modern populations in SSM supports one of the hypothesized homelands for their nomadic Turkic and related Mongolic ancestors.
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Cromossomos/genética , Fluxo Gênico , Genética Populacional , Migração Humana/história , Ásia , Povo Asiático/genética , Povo Asiático/história , China , Cromossomos Humanos Y/genética , Etnicidade/genética , Etnicidade/história , Europa (Continente) , Genótipo , História do Século XV , História do Século XVI , História do Século XVII , História Medieval , Humanos , Idioma , Oriente Médio , Mongólia , Polimorfismo de Nucleotídeo Único/genética , SibériaRESUMO
BACKGROUND: The history of human populations occupying the plains and mountain ridges separating Europe from Asia has been eventful, as these natural obstacles were crossed westward by multiple waves of Turkic and Uralic-speaking migrants as well as eastward by Europeans. Unfortunately, the material records of history of this region are not dense enough to reconstruct details of population history. These considerations stimulate growing interest to obtain a genetic picture of the demographic history of migrations and admixture in Northern Eurasia. RESULTS: We genotyped and analyzed 1076 individuals from 30 populations with geographical coverage spanning from Baltic Sea to Baikal Lake. Our dense sampling allowed us to describe in detail the population structure, provide insight into genomic history of numerous European and Asian populations, and significantly increase quantity of genetic data available for modern populations in region of North Eurasia. Our study doubles the amount of genome-wide profiles available for this region. We detected unusually high amount of shared identical-by-descent (IBD) genomic segments between several Siberian populations, such as Khanty and Ket, providing evidence of genetic relatedness across vast geographic distances and between speakers of different language families. Additionally, we observed excessive IBD sharing between Khanty and Bashkir, a group of Turkic speakers from Southern Urals region. While adding some weight to the "Finno-Ugric" origin of Bashkir, our studies highlighted that the Bashkir genepool lacks the main "core", being a multi-layered amalgamation of Turkic, Ugric, Finnish and Indo-European contributions, which points at intricacy of genetic interface between Turkic and Uralic populations. Comparison of the genetic structure of Siberian ethnicities and the geography of the region they inhabit point at existence of the "Great Siberian Vortex" directing genetic exchanges in populations across the Siberian part of Asia. Slavic speakers of Eastern Europe are, in general, very similar in their genetic composition. Ukrainians, Belarusians and Russians have almost identical proportions of Caucasus and Northern European components and have virtually no Asian influence. We capitalized on wide geographic span of our sampling to address intriguing question about the place of origin of Russian Starovers, an enigmatic Eastern Orthodox Old Believers religious group relocated to Siberia in seventeenth century. A comparative reAdmix analysis, complemented by IBD sharing, placed their roots in the region of the Northern European Plain, occupied by North Russians and Finno-Ugric Komi and Karelian people. Russians from Novosibirsk and Russian Starover exhibit ancestral proportions close to that of European Eastern Slavs, however, they also include between five to 10 % of Central Siberian ancestry, not present at this level in their European counterparts. CONCLUSIONS: Our project has patched the hole in the genetic map of Eurasia: we demonstrated complexity of genetic structure of Northern Eurasians, existence of East-West and North-South genetic gradients, and assessed different inputs of ancient populations into modern populations.
Assuntos
Emigração e Imigração/história , Etnicidade/genética , Genética Populacional , Algoritmos , Ásia , DNA , Conjuntos de Dados como Assunto , Europa (Continente) , Feminino , Variação Genética , Técnicas de Genotipagem , História do Século XV , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , História Medieval , Humanos , Masculino , Federação RussaRESUMO
Osteoarthritis is a chronic progressive joint disease that clinically debuts at the stage of pronounced morphologic changes, which makes treatment difficult. In this regard, an important task is the study of genetic markers of the disease, which have not been definitively established, due to the clinical and ethnic heterogeneity of the studied populations. To find the genetic markers for the development of knee osteoarthritis (OA) in women from the Volga-Ural region of Russia, we conducted research in two stages using different genotyping methods, such as the restriction fragment length polymorphism (RFLP) measurement, TaqMan technology and competitive allele-specific PCR-KASPTM. In the first stage, we studied polymorphic variants of candidate genes (ACAN, ADAMTS5, CHST11, SOX9, COL1A1) for OA development. The association of the *27 allele of the VNTR locus of the ACAN gene was identified (OR = 1.6). In the second stage, we replicated the GWAS results (ASTN2, ALDH1A2, DVWA, CHST11, GNL3, NCOA3, FILIP/SENP1, MCF2L, GLT8D, DOT1L) for knee OA studies. The association of the *T allele of the rs7639618 locus of the DVWA gene was detected (OR = 1.54). Thus, the VNTR locus of ACAN and the rs7639618 locus of DVWA are risk factors for knee OA in women from the Volga-Ural region of Russia.
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Omics technologies accumulated an enormous amount of data that advanced knowledge about the molecular pathogenesis of type 1 diabetes mellitus and identified a number of fundamental problems focused on the transition to personalized diabetology in the future. Among them, the most significant are the following: (1) clinical and genetic heterogeneity of type 1 diabetes mellitus; (2) the prognostic significance of DNA markers beyond the HLA genes; (3) assessment of the contribution of a large number of DNA markers to the polygenic risk of disease progress; (4) the existence of ethnic population differences in the distribution of frequencies of risk alleles and genotypes; (5) the infancy of epigenetic research into type 1 diabetes mellitus. Disclosure of these issues is one of the priorities of fundamental diabetology and practical healthcare. The purpose of this review is the systemization of the results of modern molecular genetic, transcriptomic, and epigenetic investigations of type 1 diabetes mellitus in general, as well as its individual forms. The paper summarizes data on the role of risk HLA haplotypes and a number of other candidate genes and loci, identified through genome-wide association studies, in the development of this disease and in alterations in T cell signaling. In addition, this review assesses the contribution of differential DNA methylation and the role of microRNAs in the formation of the molecular pathogenesis of type 1 diabetes mellitus, as well as discusses the most currently central trends in the context of early diagnosis of type 1 diabetes mellitus.
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The Caucasus, inhabited by modern humans since the Early Upper Paleolithic and known for its linguistic diversity, is considered to be important for understanding human dispersals and genetic diversity in Eurasia. We report a synthesis of autosomal, Y chromosome, and mitochondrial DNA (mtDNA) variation in populations from all major subregions and linguistic phyla of the area. Autosomal genome variation in the Caucasus reveals significant genetic uniformity among its ethnically and linguistically diverse populations and is consistent with predominantly Near/Middle Eastern origin of the Caucasians, with minor external impacts. In contrast to autosomal and mtDNA variation, signals of regional Y chromosome founder effects distinguish the eastern from western North Caucasians. Genetic discontinuity between the North Caucasus and the East European Plain contrasts with continuity through Anatolia and the Balkans, suggesting major routes of ancient gene flows and admixture.
Assuntos
Emigração e Imigração/história , Fluxo Gênico , Algoritmos , Antropologia Física , Povo Asiático/genética , Cromossomos Humanos Y , Análise por Conglomerados , DNA , DNA Mitocondrial/genética , Genética Populacional , História Antiga , Humanos , Linguística , Transcaucásia , População Branca/genéticaRESUMO
Peak bone mass is the amount of bone tissue that is formed when a stable skeletal state is achieved at a young age. To date, there are no established peak bone mass standards nor clear data on the age at which peak bone mass occurs. At the same time, the level of peak bone mass at a young age is an important predictor of the onset of primary osteoporosis. The purpose of this review is to analyze the results of studies of levels of peak bone mass in general, the age of its onset, as well as factors influencing its formation. Factors such as hormonal levels, body composition, physical activity, nutrition, heredity, smoking, lifestyle, prenatal predictors, intestinal microbiota, and vitamin and micronutrient status were considered, and a comprehensive scheme of the influence of these factors on the level of peak bone mass was created. Determining the standards and timing of the formation of peak bone mass, and the factors affecting it, will help in the development of measures to prevent its shortage and the consequent prevention of osteoporosis and concomitant diseases.
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Osteogenesis imperfecta (OI) is an inherited disease of bone characterized by increased bone fragility. Here, we report the results of the molecular architecture of osteogenesis imperfecta research in patients from Bashkortostan Republic, Russia. In total, 16 mutations in COL1A1, 11 mutations in COL1A2, and 1 mutation in P3H1 and IFIMT5 genes were found in isolated states; 11 of them were not previously reported in literature. We found mutations in CLCN7, ALOX12B, PLEKHM1, ERCC4, ARSB, PTH1R, and TGFB1 that were not associated with OI pathogenesis in patients with increased bone fragility. Additionally, we found combined mutations (c.2869C>T, p. Gln957* in COL1A1 and c.1197+5G>A in COL1A2; c.579delT, p. Gly194fs in COL1A1 and c.1197+5G>A in COL1A2; c.2971G>C, p. Gly991Arg in COL1A2 and c.212G>C, p.Ser71Thr in FGF23; c.-14C>T in IFITM5 and c.1903C>T, p. Arg635* in LAMB3) in 4 patients with typical OI clinic phenotypes.
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Colágeno Tipo I/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Mutação , Osteogênese Imperfeita/patologia , Prolil Hidroxilases/genética , Proteoglicanas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese Imperfeita/epidemiologia , Osteogênese Imperfeita/genética , Fenótipo , Federação Russa , Adulto JovemRESUMO
Osteogenesis imperfecta (OI) is a large group of genetically heterogeneous diseases resulting from decreased bone density and an abnormal microarchitecture, which are clinically manifested by abnormal bone fractures. A distinctive clinical feature of this group of diseases is the presence of spontaneous fractures and skeletal deformities. However, the clinical manifestations of different types of OI are characterized by marked polymorphism with variable severity of skeletal and extra-skeletal features. Previous studies have shown that a mutation (c.-14C>T) in the IFITM5 gene is responsible for autosomal dominant OI type V. However, the mutation has a variable expression pattern and marked clinical heterogeneity. In this study, a clinical and genetic analysis of 12 cases with molecularly confirmed OI type V from 12 unrelated families was performed. Significant clinical heterogeneity of the disease with the same molecular defect was detected. In six subjects (50%), there were no classic signs of OI type V (formation of a hyperplastic bone callus, calcification of the interosseous membrane and dislocation of the radial head). In all cases, the mutation occurred de novo.
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The immune system is severely compromised in patients with COVID-19. The representative group of 43 patients were selected from the cohort of 342 patients with COVID-19 and pneumonia. This group of 43 patients was examined for the levels of C-reactive protein, biomarker of systemic inflammation, and for the subsets of adaptive immune cells. The immunological parameters were correlated with the metabolic parameters and cardiovascular pathology history. We identified that a decrease in the absolute number of T-lymphocytes, T-cytotoxic, T-activated and B-lymphocytes correlated with the higher levels of CRP. The absolute number of T-helpers and the absolute number of double positive T-lymphocytes positively correlated with the levels of iron in serum (Z= 0,310 and Z=0,394). The absolute numbers of T-activated lymphocytes positively correlated with serum levels of LDH (Z = 0,422), ferritin (Z = 0,407) and iron (Z = 0,418). When studying subpopulations of lymphocytes, depending on the combined pathology, we found that the absolute numbers of B-lymphocytes and double positive T-lymphocytes in the peripheral blood were significantly reduced in patients with arterial hypertension (p=0,0074 and p=0,0227, correspondingly). The increased levels of NK cell were found in patients with a history of coronary heart disease (p=0,0108). In addition, we found that deficiencies in the adaptive immune system correlated with the deficiencies in iron metabolism. The cardiovascular pathology upsets the balance in the adaptive and innate immune system in the circulation of patient with severe COVID-19.
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COVID-19 , Proteína C-Reativa , Humanos , Ferro , Células Matadoras Naturais , Subpopulações de LinfócitosRESUMO
Over the past decades, numerous studies on the genetic markers of osteoarthritis (OA) have been conducted. MiRNA targets sites are a promising new area of research. In this study, we analyzed the polymorphic variants in 3' UTR regions of COL1A1, COL11A1, ADAMTS5, MMP1, MMP13, SOX9, GDF5, FGF2, FGFR1, and FGFRL1 genes to examine the association between miRNA target site alteration and the incidence of OA in women from the Volga-Ural region of Russia using competitive allele-specific PCR. The T allele of the rs9659030 was associated with generalized OA (OR = 2.0), whereas the C allele of the rs229069 was associated with total OA (OR = 1.43). The T allele of the rs13317 was associated with the total OA (OR = 1.67). After Benjamini-Hochberg correction, only rs13317 remained statistically significant. According to ethnic heterogeneity, associations between the T allele (rs1061237) with OA in women of Russian descent (OR = 1.77), the G allele (rs6854081) in women of Tatar descent (OR = 4.78), the C allele (rs229069) and the T allele (rs73611720) in women of mixed descent and other ethnic groups (OR = 2.25 and OR = 3.02, respectively) were identified. All associations remained statistically significant after Benjamini-Hochberg correction. Together, this study identified miRNA target sites as a genetic marker for the development of OA in various ethnic groups.
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Hearing impairment is one of the most common disorders of sensorineural function and the incidence of profound prelingual deafness is about 1 per 1000 at birth. GJB2 gene mutations make the largest contribution to hereditary hearing impairment. The spectrum and prevalence of some GJB2 mutations are known to be dependent on the ethnic origin of the population. This study presents data on the carrier frequencies of major GJB2 mutations, c.35delG, c.167delT and c.235delC, among 2308 healthy persons from 18 various populations of Eurasia: Russians, Bashkirs, Tatars, Chuvashes, Udmurts, Komi-Permyaks and Mordvins (Volga-Ural region of Russia); Belarusians and Ukrainians (East Europe); Abkhazians, Avars, Cherkessians and Ingushes (Caucasus); Kazakhs, Uighurs and Uzbeks (Central Asia); and Yakuts and Altaians (Siberia). The data on c.35delG and c.235delC mutation prevalence in the studied ethnic groups can be used to investigate the prospective founder effect in the origin and prevalence of these mutations in Eurasia and consequently in populations around the world.
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Povo Asiático/genética , Conexinas/genética , Surdez/genética , Triagem de Portadores Genéticos/métodos , Mutação , População Branca/genética , Ásia Central/etnologia , Conexina 26 , Surdez/etnologia , Europa Oriental/etnologia , Frequência do Gene , Genética Populacional , Heterozigoto , Humanos , Polimorfismo Genético , Federação Russa/etnologiaRESUMO
Kalmyks, the only Mongolic-speaking population in Europe, live in the southeast of the European Plain, in Russia. They adhere to Buddhism and speak a dialect of the Mongolian language. Historical and linguistic evidence, as well a shared clan names, suggests a common origin with Oirats of western Mongolia; yet, only a limited number of genetic studies have focused on this topic. Here we compare the paternal genetic relationship of Kalmyk clans with ethnographically related groups from Mongolia, Kyrgyzstan and China, within the context of their neighbouring populations. A phylogeny of 37 high-coverage Y-chromosome sequences, together with further genotyping of larger sample sets, reveals that all the Oirat-speaking populations studied here, including Kalmyks, share, as a dominant paternal lineage, Y-chromosomal haplogroup C3c1-M77, which is also present in several geographically distant native Siberian populations. We identify a subset of this clade, C3c1b-F6379, specifically enriched in Kalmyks as well as in Oirat-speaking clans in Inner Asia. This sub-clade coalesces at around 1500 years before present, before the Genghis Khan era, and significantly earlier than the split between Kalmyks and other Oirat speakers about 400 years ago. We also show that split between the dominant hg C variant among Buryats-C3-M407-and that of C3-F6379, took place in the Early Upper Palaeolithic, suggesting an extremely long duration for the dissipation of hg C3-M217 carriers across northern Eurasia, which cuts through today's major linguistic phyla.
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Povo Asiático/genética , Cromossomos Humanos Y , Genética Populacional , Mapeamento Cromossômico , Europa (Continente) , Genótipo , Geografia , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , Mongólia , Filogenia , Polimorfismo Genético , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND AND PURPOSE: Genomewide DNA linkage analysis identified a susceptibility locus for intracranial aneurysm (IA) on chromosome 19q13 in the Finnish population, a region including the kallikrein gene cluster. We investigated the association of single nucleotide polymorphisms (SNPs) in the kallikrein gene cluster with IA in the Finnish population. METHODS: We genotyped 18 haplotype-tagging SNPs spanning a 244 kbp region in the kallikrein gene cluster for 266 Finnish IA cases and 290 Finnish control subjects. In a second phase, we genotyped 2 SNPs (rs1722561 and rs1701946) in an additional set of 102 Finnish IA cases and 102 Finnish control subjects; and in a third phase, we genotyped these 2 SNPs in 156 Russian IA cases and 186 Russian control subjects. Both single-marker and haplotype-based tests of association were performed. RESULTS: In phase I, SNPs rs1722561 and rs1701946 were significantly associated with IA in the Finnish population for single locus models (rs1722561: P=0.0395; rs1701946: P=0.0253). A 2-SNP haplotype block (rs1722561-rs1701946) identified in phase I was also associated with IA in the expanded Finnish (phase II) data set (asymptotic P=0.012; empirical P=0.019). In the Finnish and Russian combined data set (phase III) with 524 cases and 578 control subjects, the same 2 SNPs (OR: 1.35, 95% CI: 1.14, 1.60; P=0.0005 for rs1722561 and OR: 1.32, 95% CI: 1.12, 1.57; P=0.0011 for rs1701946) were significantly associated with IA. These SNPs are located in the intronic region of KLK8, although linkage disequilibrium could extend from rs268912-rs2250066, a approximately 76-kbp region that includes KLK5-KLK10. CONCLUSIONS: Polymorphisms within the kallikrein gene cluster are associated with IA suggesting that the kallikreins are important candidate genes for IA.
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Aneurisma Intracraniano/genética , Calicreínas/genética , Família Multigênica/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Finlândia , Marcadores Genéticos , Genoma Humano , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Federação RussaRESUMO
A large part of Y chromosome lineages in East European and East Asian human populations belong to haplogroup (hg) NO, which is composed of two sister clades N-M231 and O-M175. The O-clade is relatively old (around 30 thousand years (ky)) and encompasses the vast majority of east and Southeast Asian male lineages, as well as significant proportion of those in Oceanian males. On the other hand, our detailed analysis of hg N suggests that its high frequency in east Europe is due to its more recent expansion westward on a counter-clock northern route from inner Asia/southern Siberia, approximately 12-14 ky ago. The widespread presence of hg N in Siberia, together with its absence in Native Americans, implies its spread happened after the founder event for the Americas. The most frequent subclade N3, arose probably in the region of present day China, and subsequently experienced serial bottlenecks in Siberia and secondary expansions in eastern Europe. Another branch, N2, forms two distinctive subclusters of STR haplotypes, Asian (N2-A) and European (N2-E), the latter now mostly distributed in Finno-Ugric and related populations. These phylogeographic patterns provide evidence consistent with male-mediated counter-clockwise late Pleistocene-Holocene migratory trajectories toward Northwestern Europe from an ancestral East Asian source of Paleolithic heritage.
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Cromossomos Humanos Y/classificação , Cromossomos Humanos Y/genética , Genética Populacional , Haplótipos , Sudeste Asiático , Europa Oriental , Humanos , Masculino , Filogenia , Análise de Sequência de DNARESUMO
In order to explore the diversity and selective signatures of duplication and deletion human copy-number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single-nucleotide-variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.