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A study was carried out to identify the spectrum and frequency of pathogenic changes in the BRCA1 and BRCA2 genes in tumor tissue preparations of 70 women with triple negative breast cancer (TNBC) and 50 women with serous type of ovarian malignant neoplasms (ON) from the Republic of Bashkortostan using a new generation sequencing technology (NGS). Thus, 27 pathogenic variants were identified in the BRCA1/2 genes were identified (14 in the BRCA1 gene and 9 in the BRCA2 gene) in 38.0% of women with ON and 41.4% of patients with TNBC. Mutations c.181T> G (rs886040898) and c.5266dupC (rs80357906) in the BRCA1 gene were found in women with both TNBC and ON, other pathogenic changes did not intersect. In the BRCA1 gene, 7 pathogenic and 1 probably pathogenic variant were identified in women with breast cancer, the most common mutation was c.5266dupC, which was found in 17.14% of women. The second most frequent mutation c.181T> G- was found in 4.29% of women with TNBC, the third c.3700_3704del - 2.86%. Mutations c.1918C> T, c.3779T> G, c.5453A> G, c.68_69delAG were found in isolated cases. The c.5266dupC mutation in the BRCA1 gene was also the most frequent in patients with ON (10%). The c.4035delA mutation was found in two patients, the remaining 7 mutations were found in isolated cases. In the BRCA2 gene, 5 pathogenic and 2 probable pathogenic variants were identified in patients with TNBC, as well as 4 pathogenic and 2 probable pathogenic variants in women with ON, each mutation was detected in only one woman and is a unique variant not found in other patients. The results obtained demonstrate the high efficiency of mass parallel sequencing for searching for mutations in targeted genes in tumor tissue.

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.

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.

Osteogenesis imperfecta (imperfect osteogenesis in the Russian literature) is the most common hereditary form of bone fragility, it is a genetically and clinically heterogeneous disease with a wide range of clinical severity, often leading to disability from early childhood. It is based on genetic disorders leading to a violation of the structure of bone tissue, which leads to frequent fractures, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, renal impairment, hearing loss. Osteogenesis imperfecta occurs in both men and women, the disease is inherited in both autosomal dominant and autosomal recessive types, there are sporadic cases of the disease due to de novo mutations, as well as X-linked forms. The term "osteogenesis imperfecta" was coined by W. Vrolick in the 1840s. The first classification of the disease was made in 1979 and has been repeatedly reviewed due to the identification of the molecular cause of the disease and the discovery of new mechanisms for the development of osteogenesis imperfecta. In the early 1980s, mutations in two genes of collagen type I (COL1A1 and COL1A2) were first associated with an autosomal dominant inheritance type of osteogenesis imperfecta. Since then, 18 more genes have been identified whose products are involved in the formation and mineralization of bone tissue. The degree of genetic heterogeneity of the disease has not yet been determined, researchers continue to identify new genes involved in its pathogenesis, the number of which has reached 20. In the last decade, it has become known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes, encoding proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells, cause imperfect osteogenesis. A large number of causative genes complicated the classical classification of the disease and, due to new advances in the molecular basis of the disease, the classification of the disease is constantly being improved. In this review, we systematized and summarized information on the results of studies in the field of clinical and genetic aspects of osteogenesis imperfecta and reflected the current state of the classification criteria for diagnosing the disease.Незавершенный остеогенез (несовершенный остеогенез в русскоязычной литературе) – наиболее распространенная наследственная форма ломкости костей, генетически и клинически гетерогенное заболевание с широким спектром клинической тяжести, основное клиническое проявление которого – множественные переломы начиная с натального периода жизни, зачастую приводящие к инвалидизации с детского возраста. К основным клиническим признакам незавершенного остеогенеза относятся голубые склеры, потеря слуха, аномалия дентина, повышенная ломкость костей, нарушение роста и осанки с развитием характерных инвалидизирующих деформаций костей и сопутствующих проблем, включающих дыхательные, неврологические, сердечные, почечные нарушения. Незавершенный остеогенез встречается и у мужчин, и у женщин, заболевание наследуется как по аутосомно-доминантному, так и аутосомно-рецессивному типам, существуют спорадические случаи заболевания, обусловленные мутациями de novo, а также обнаружены Х-сцепленные формы. Термин «незавершенный остеогенез» был введен W. Vrolick в 1840-х гг. Первая классификация заболевания сделана в 1979 г. и неоднократно пересматривалась из-за идентификации молекулярной причины заболевания и открытия новых механизмов развития незавершенного остеогенеза. В начале 1980-х гг. мутации в двух генах коллагена типа I (COL1A1 и COL1A2) впервые были ассоциированы с аутосомно-доминантным типом наследования незавершенного остеогенеза. С тех пор идентифицированы еще 18 генов, продукты которых участвуют в процессах формирования и минерализации костной ткани. До сих пор не определена степень генетической гетерогенности заболевания, исследователи продолжают идентифицировать новые гены, вовлеченные в его патогенез, число которых достигло 20. В последнее десятилетие стало известно, что аутосомно-рецессивные, аутосомно-доминантные и Х-связанные мутации в широком спектре генов, кодирующих белки, участвующие в синтезе коллагена типа I, его процессинге, секреции и посттрансляционной модификации, а также в белках, регулирующих дифференцировку и активность костеобразующих клеток, вызывают несовершенный остеогенез. Большое количество причинных генов усложнило классическую классификацию заболевания, и в связи с новыми достижениями в области молекулярных основ незавершенного остеогенеза постоянно совершенствуется и классификация. В этом обзоре мы систематизировали и обобщили информацию о результатах исследований в области изучения клинико-генетических аспектов незавершенного остеогенеза и отразили современное состояние классификационных критериев диагностики заболевания.

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.

Osteoporosis is one of multifactorial diseases, it develops from interactions between the genetic component and the environment. However, the universal epigenetic markers of osteoporosis are not yet defined. Finding the risk factors will predict the risk of osteoporosis at the preclinical stage, help define the course and severity of the disease, and develop preventive measures based on them to reduce the risk of fractures. Expanding knowledge in the field of bone biology, especially in the genetics of osteoporosis and osteoimmunology, showed that osteoporosis is a disease that occurs not only due to hormonal or mechanical disorders, but also as a clinically and genetically heterogeneous disease, and there are still unknown pathogenetic links in its structure. Decreases in bone mass and matrix mineralization as well as changes in bone microarchitecture can have different pathogenetic patterns of development and, moreover, there are unknown links of the pathogenesis of osteoporosis. It is possible that DNA methylation is one of these links and a mechanism for epigenetic regulation of gene expression. Evidence exists that this mechanism alongside regulatory miRNAs and post-translational modifications makes a significant contribution to the central processes of bone remodeling; however, the results of various studies vary greatly, and, therefore, there is a need to understand the significance of the accumulated data and to make them consistent. The purpose of this review is to compile and systematize data on the role of DNA methylation in bone metabolism in normal and pathological conditions, in the formation of osteoporosis, and to assess achievements and trends in this field of research and technologies for studying DNA methylation.

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.

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.

In recent genome-wide association studies (GWAS), several polymorphic loci of the osteoprotegerin (OPG) gene were significantly associated with bone mineral density (BMD) and fractures in men over 50 years of age and postmenopausal women. The objective of our study was to search for associations of rs3102735, rs3134069, rs2073617, rs2073618, rs3102734 and rs7844539 of the OPG gene with the risk of osteoporotic fractures and the level of BMD in individual and comorbid conditions in men and women from the Volga-Ural region of Russia. Material and Methods — 828 women and 496 men of various ethnic groups (Russians, Turks) were examined using two-energy x-ray absorptiometry (DEXA) in the femoral neck and lumbar spine. 1324 deoxyribonucleic acid (DNA) samples were genotyped using a fluorescent endpoint genotyping system, after that we searched for associations of these polymorphic loci with fractures and low BMD levels of various localizations. As a result, there was a significant association of rs3134069 and rs3102734 with fractures in general and in the peripheral parts of the skeleton, as well as rs7844539 and rs3102734 in women and rs2073618 in men with low BMD. Another significant association of rs3102734 and rs2073618 with low bone mineral density in the femoral neck was found in both genders. Conclusion — Polymorphic variants rs3134069, rs3102734, rs7844539 and rs3102734 are potential markers of the risk of osteoporetic fractures and the formation of low BMD in men and women from the Volga-Ural region of Russia.

Intracranial aneurysm (IA) is a complex disease resulting in subarachnoid hemorrhage (SAH) due to a rupture. The average worldwide prevalence of this disease is about 2–5 %, with 50 % of them ending in death or neurological disorders of varying severity, with a high probability of recurrence of hemorrhage during the frst half of the year after rupture. Subarachnoid hemorrhage is annually registered in at least 18 thousand people in Russia. Associations of polymorphic variantsrs594942andrs11603042of theVEGFBgene in intracranial aneurysm development in the Volga-Ural region of the Russian Federation with the presence of the symptom complex of undifferentiated connective tissue dysplasia (uDST) and arterial hypertension (AH) were investigated. TheC* allelers594942andrs11603042of theVEGFBgene is a marker of an increased risk of IA as a whole (p= 0.025; χ2 = 5.052; OR = 1.32) in women as a whole (p= 0.001; χ2 = 10.124; OR = 1.70) and in comorbid state with uDCT (p= 0.002; χ2 = 9.501; OR = 2.34) and AG (p= 0.006; χ2 = 7.385; OR = 2.109). We found that the genotype *C*Cof locusrs594942of theVEGFBgene is a marker of an increased risk of intracranial aneurysm in general (p= 0.017; χ2 = 5.702; OR = 1.49) and among women in general (p= 0.0005; χ2 = 12.078; OR = 2.25) and with the symptomatic complex uCTD (p= 0.007; χ2 = 7.173; OR = 2.67) and AH (p= 0.010; χ2 = 6.471; OR = 2.51). We have obtained new results on the role of polymorphic variants of theVEGFBgene in the formation of intracranial aneurysm, taking into account the presence of the symptom complex uDCT and AH among the residents of the Volga-Ural region of Russia. A burdened comorbid background and the presence of undifferentiated connective tissue dysplasia and arterial hypertension can contribute to an increased risk of intracranial aneurysm, as evidenced by the results of our study.

Objective — The aim of the work was to study serum concentrations of magnesium, copper, zinc, phosphorus and calcium in individuals with undifferentiated connective tissue dysplasia (uCTD) and joint hypermobility (JH) in an isolated and combined state. Material and methods — the concentrations of magnesium, copper, zinc, phosphorus and calcium were measured by the direct colorimetric method in 55 people with joint hypermobility and in 34 – without hypermobility. Results — There were no significant differences between serum concentrations of microelementsin groups with and without JH. In patients with mild and severe uCTD significant decrease in serum magnesium concentrations was noted (U=2.12, p=0.034 and U=3.7, p=0.012). In patients with isolated JH significant serum zinc concentrationdecrease was revealed compared with the control group (U=3.12, p=0.022). Serum magnesium concentrations were reduced in all patients with uCTD and JH; in the groups with isolated dysplasia and combined pathology, the differences reached the level of statistical significance (U=2.78, p=0.024 and U=3.2, p=0.018). Conclusion — The study revealed significant associations of a decrease in serum magnesium concentrations with the development of uCTD in an isolated and combined with JH state and decrease in serum zinc concentrations with the development of isolated JH.

A clinical assessment of the presence of osteoarthritis (OA) with various localizations, undifferentiated connective tissue dysplasia (uCTD) and joint hypermobility (JHM) in 484 individuals of both sexes of different age groups was carried out. We searched for associations of 4 polymorphic variants of matrix metalloproteinase genes (rs35068180 (MMP3), rs2252070 (MMP13) ), rs226794 and rs2830585 (ADAMTS5)) with the development of osteoarthrosis as a whole, taking into account the localization of the pathological process, the age of the patients, the ethnic origin of the study groups and the presence of undifferentiated connective tissue dysplasia as a whole and its individual phenotypic markers, as well as in the comorbid state with osteoarthritis was carried out. 158 patients had osteoarthritis, 252 had a symptom complex of uCTD, 92 of them were in the comorbid state with OA. The significance of the polymorphic loci of MMP3, MMP13, ADAMTS5 genes in the formation of the symptom complex of uCTD in general and its individual phenotypes was detected. The polymorphic locus of MMP3 gene was associated with OA in the comorbid state with uCTD. Statistically significant models based on clinical-genetic data using the method of multiple logistic regression, that allow predicting the development of osteoarthrosis of knee, hip joints and polyosteoarthrosis were calculated.

Analysis of the carrier frequency of p.Arg408Trp, p.Arg261Gln, and p.Arg261X mutations in the PAH gene was carried out in different unrelated indigenous individuals representing 58 populations of Eurasia taking into account their linguistic identity and territorial location. Mutation p.Arg408Trp in the PAH gene was found in 14 studied populations with the highest average carrier frequency of 0.0127 in the Volga-Ural region and 0.0134 in the representatives of the Slavic language group. Mutation p.Arg261Gln in the PAH gene was detected only in two populations with average carrier frequency rate of 0.0012 in the Volga-Ural region. Mutation p.Arg261X in the PAH gene was identified in four North Caucasus populations with highest carrier frequency in Karachays—at 0.0526. All PAH gene mutations in populations of Eurasia were identified in the heterozygous state.

We conducted an association study of ten polymorphisms in six candidate genes of OA (rs1799750 (MMP1), rs35068180 (MMP3), rs2252070 (MMP13), rs63118460 and rs2276455 (COL2A1), rs143383 (GDF5), rs1544410, rs7975232, rs731236, and rs2228570 (VDR)) with the development of osteoarthritis (OA) in 333 women taking into account the localization of the pathological process, the age of disease manifestation, and ethnicity and investigated the presence of signs of undifferentiated connective tissue dysplasia (UCTD). On the basis of clinical and genetic data, we revealed statistically significant models to predict the development of osteoarthritis of various localizations (knee, hip, and generalized forms).

The genetic diversity in two ethnic groups of the central part of the North Caucasus (Balkars and Karachays) using 50 diallelic loci in the non-recombining region of the Y chromosome was analyzed. For the first time, an analysis of distribution of frequencies of Y-chromosome haplogroups in Balkars considering different subethnic groups (Baksans, Chegems, Kholams, Bezengiyevs, and Malkars) was conducted. The major Y-chromosome haplogroups in the studied groups of Balkars and Karachays were G2a-P16 and R1a- Z2123. In addition, for a better understanding of genetic relationship between the male lineages in the studied populations and other populations of the Caucasus, we performed an analysis of R1a-M198 subhaplogroups in 22 populations of this region. The principal component analysis demonstrated that a greater difference was observed between Kholams and the other Balkar subgroups. According to the F st analysis, Chegems, for which the prevalence of haplogroup R1b-M478 (32.2%) was reported, demonstrated the maximum difference from the other subpopulations of Balkars and Karachays.

An analysis of genetic diversity in nine ethnic groups of the Volga-Ural region was carried out using 15 biallelic loci in the nonrecombining region of the Y-chromosome. The major Y-chromosome haplogroups in the region are R1a-M198, R1b-M269, and N-M231. It was found that Bashkirs show the greatest difference from other populations of the Volga-Ural region according both to F st and to the principal component analysis. In addition, analysis of the frequency distribution of Y-chromosome haplogroups was carried out in the Besermyan population, which was not studied previously from the Y-chromosome perspective. The results of this study revealed the predominance of haplogroup N-M231 (54.7%) in this ethnic group, which may indicate the prevalence of the Finno-Ugric component in the formation of the patrilineal component in the gene pool of the Besermyan ethnic group.

We examined nine exons of transforming growth factor β receptor type 1 (TGFβR1) gene in patients with chronic heart failure with different types of heart remodelling. We identified two missense mutations (c.457G>A (p.V1531) and c.1285A>C (p.Y229S)) and two synonym substitutions (c.1125A>C (p.Y377Y) and c.516A>G (p.S172S)), as well as polymorphisms at splicing site c.1024+24G>A (rs334354). Substitutions c.1285A>C (p.Y229S) and c.516A>G (p.S172S) were not previously described.

An analysis of the frequency of H63D (c.187C>G) mutations in the HFE gene in 19 populations from Central Eurasia demonstrated that the distribution of the mutation in the region of interest was not uniform and that there were the areas of H63D accumulation. The investigation of three polymorphic variants, c.340+4T>C (rs2071303, IVS2(+4)T>C), c.893-44T>C (rs1800708, IVS4(-44)T>C), and c.1007-47G>A (rs1572982, IVS5(-47)A>G), in the HFE gene in individuals homozygous for H63D mutations in the HFE gene revealed the linkage of H63D with three haplotypes, *CTA, *TTG, and *TTA. These findings indicated the partial spread of the mutation in Central Eurasia from Western Europe, as well as the possible repeated appearance of the mutation on the territory on interest.

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans., Facultad de Ciencias Naturales y Museo

High-coverage whole-genome sequence studies have so far focused on a limited number1 of geographically restricted populations2, 3, 4, 5, or been targeted at specific diseases, such as cancer6. Nevertheless, the availability of high- resolution genomic data has led to the development of new methodologies for inferring population history7, 8, 9 and refuelled the debate on the mutation rate in humans10. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record11, and admixture between AMHs and Neanderthals predating the main Eurasian expansion12, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75, 000 years ago.

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.

Genetic diversity has been analyzed in 22 ethnic groups of the Caucasus on the basis of data on Y-chromosome and mitochondrial DNA (mtDNA) markers, as well as genome-wide data on autosomal single-nucleotide polymorphisms (SNPs). It has been found that the West Asian component is prevailing in all ethnic groups studied except for Nogays. This Near Eastern ancestral component has proved to be characteristic of Caucasian populations and almost entirely absent in their northern neighbors inhabiting the Eastern European Plain. Turkic-speaking populations, except Nogays, did not exhibit an increased proportion of Eastern Eurasian mtDNA or Y-chromosome haplogroups compared to some Abkhaz-Adyghe populations (Adygs and Kabardians). Genome-wide SNP analysis has also shown substantial differences of Nogays from all other Caucasian populations studied. However, the characteristic difference of Nogays from other populations of the Caucasus seems somewhat ambiguous in terms of the R1a1a-M17(M198) and R1b1b1-M73 haplogroups of the Y chromosome. The state of these haplogroups in Turkic-speaking populations of the Caucasus requires further study.

Nucleotide sequences of exon 51, adjacent intron areas, and regulatory region of the α1 chain of type I collagen (COL1A1) gene were analyzed in 41 patients with osteogenesis imperfecta (OI) from 33 families and their 68 relatives residing at Bashkortostan Republic (BR). Six mutations (four nonsense mutations c.967G>T (p.Gly323X), c.1081C>T (p.Arg361X), c.1243C>T (p.Arg415X), and c.2869C>T (p.Gln957X)) in patients of the Russian origin and two frameshift mutations (c.579delT (p.Gly194ValfsX71), and c.2444delG (p.Gly815AlafsX293)) in patients with OI of Tatar ethnicity as well as 14 single nucleotide polymorphisms in the COL1A1 gene were revealed. Mutations c.967G>T (p.Gly323X) and three alterations in the nucleotide sequence c.544-24C>T, c.643-36delT, and c.957 + 10insA were described for the first time.

Evidence continues to accrue implicating mitochondrial dysfunction in the etiology of a number of neurodegenerative diseases. For example, Parkinson's disease (PD) can be induced by mitochondrial toxins, and nuclear DNA (nDNA) loci linked to PD have been associated with mitochondrial dysfunction. Although conclusions about the role of mitochondrial DNA (mtDNA) variants in PD vary, we argue here that this is attributable to the novel genetics of the mtDNA and the fact that clinically relevant mtDNA variation encompasses ancient adaptive polymorphisms, recent deleterious mutations, and somatic mutations. An mtDNA association with PD is supported by an analysis of the Russian Tatar population which revealed that polymorphisms associated with haplogroup H mtDNAs increased PD risk (odds ratio [OR]= 2.58, P= 0.0001), whereas those associated with haplogroup UK cluster mtDNAs were protective (OR = 0.38, P= 0.003). Moreover, mtDNA sequencing revealed that PD patients with either haplogroup H or UK cluster mtDNAs can harbor additional recent variants that might further modulate PD risk. Therefore, the complexity of PD genetics may reflect the complex mitochondrial genetics.

The analysis of −1997G/T, −1663indelT, and +1245G/T polymorphic loci of the 5′-region of COLIA1 gene in 124 females aged from 50 to 70 years old with low numbers of traumatic fractures as well as 150 healthy individuals from Volga-Ural region has been conducted. The association of −1663indelT and +1245G/T loci with the risk of osteoporotic fractures has been discovered. It has been shown that −1997*G*G/−1663*I*D/+1245*G*T genotype combination and −1997*G/−1663*D/+1245*T haplotype can be considered as markers for fracture development.

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 (asymptoticP=0.012; empiricalP=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 ofKLK8, although linkage disequilibrium could extend from rs268912–rs2250066, a ≈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.

Sudmant, Peter H. et al., 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., This project has been funded in part with federal funds from the National Cancer Institute, NIH, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work was also partly supported by NIH grant 2R01HG002385 and a grant (11631) from the Paul G. Allen Family Foundation to E.E.E. The sequencing for this study was supported by a grant from the Simons Foundation to D.R. (SFARI 280376) and by a HOMINID grant from the NSF to D.R. (BCS-1032255). T.K. is supported by a European Research Council Starting Investigator grant (FP7 - 26213). R.S. and S.D. received support from the Ministry of Education and Science, Russian Federation (14.Z50.31.0010). H.S., E.M., R.V., and M.M. are supported by Institutional Research Funding from the Estonian Research Council IUT24-1 and by the European Regional Development Fund (European Union) through the Centre of Excellence in Genomics to Estonian Biocentre and University of Tartu. S.A.T. is supported by NIH grants 5DP1ES022577 05, 1R01DK104339-01, and 1R01GM113657-01. C.T.-S. is supported by Wellcome Trust grant 098051. C.M.B. is supported by the NSF (award numbers 0924726 and 1153911). E.E.E. and D.R. are investigators of the Howard Hughes Medical Institute. Data are deposited into ENA (PRJEB9586 or ERP010710), and variant calls are deposited in dbVar (PRJNA285786). E.E.E. is on the scientific advisory board of DNAnexus, Incorporated, and is a consultant for Kunming University of Science and Technology (KUST) as part of the 1000 China Talent Program.

It is commonly thought that human genetic diversity in non-African populations was primarily shaped by a recent out-of-Africa dispersal. Here we present a large geographical Y chromosome study using 459 high coverage sequences, including 302 newly reported here. We date the Y chromosomal Most Recent Common Ancestor (MRCA) in Africa at 254 (95% CI 192- 307) kya and differentiation of African and non-African lineages 52-121 kya. The age estimates for major non-African founder haplogroups cluster closely 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. We find that the highest basal Y chromosome diversity outside Africa has been preserved in South and Southeast Asians while extant Y chromosome diversity in Europe and the Near East stems from a small number of mid-Holocene founders. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck, followed by a fast recovery in Old World populations dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.

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., Author Summary Centuries of nomadic migrations have ultimately resulted in the distribution of Turkic languages over a large area ranging from Siberia, across Central Asia to Eastern Europe and the Middle East. Despite the profound cultural impact left by these nomadic peoples, little is known about their prehistoric origins. Moreover, because contemporary Turkic speakers tend to genetically resemble their geographic neighbors, it is not clear whether their nomadic ancestors left an identifiable genetic trace. In this study, we show that Turkic-speaking peoples sampled across the Middle East, Caucasus, East Europe, and Central Asia share varying proportions of Asian ancestry that originate in a single area, southern Siberia and Mongolia. Mongolic- and Turkic-speaking populations from this area bear an unusually high number of long chromosomal tracts that are identical by descent with Turkic peoples from across west Eurasia. Admixture induced linkage disequilibrium decay across chromosomes in these populations indicates that admixture occurred during the 9th–17th centuries, in agreement with the historically recorded Turkic nomadic migrations and later Mongol expansion. Thus, our findings reveal genetic traces of recent large-scale nomadic migrations and map their source to a previously hypothesized area of Mongolia and southern Siberia.

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.

Thirty exons of the fibrillin-1 gene (FBN1) were screened in patients with Marfan syndrome (MFS), and eleven point mutations, insertions, and deletions were detected. These included two missense mutations resulting in conformational changes of the calcium-binding EGF-like domains of FBN1 and nine polymorphisms located in both coding and noncoding regions of FBN1. Three intragenic polymorphic microsatellite loci—MTS-1, MTS-2, and MTS-4—were analyzed in MFS patients and unrelated healthy controls, and significant differences between these two groups were found for the MTS-2 and MTS-4 allele frequency distributions. Haplotype frequency distributions on wild-type and mutant chromosomes of MFS patients were also significantly different. The predominant haplotype was 2-11-8 on wild-type chromosomes, and 2-2-8 on mutant chromosomes. These data are a prerequisite to working out DNA diagnosis of MFS.

We examined genetic variation in nine populations of Dagestan using 11 autosomal Alu insertion polymorphisms to investigate the genetic structure of indigenous groups and to assess their genetic relationship with world populations. Genetic differentiation among mountain inhabitants (GST = 2%) is comparable to that for European populations. Traces of genetic drift are detectable only for endogamous and small Ando-Dido-speaking ethnic groups, and they coincide with the most linguistically diverse region of Dagestan. Multidimensional scaling analyses among West Eurasian populations revealed that mountain inhabitants of Dagestan are closely related to Anatolian and Cyprus Turks. Thus our frequency data are consistent with the available Y-chromosome data, according to which the Middle East and the Caucasus share a considerable portion of the gene pool. Overall, our results corroborate the initially suggested genetic contribution of Middle Eastern populations to Caucasus populations.

Eight nuclear DNA loci, including six Alu insertions (ACE, APOA1, PV92, TPA25, Ya5NBC27, and Ya5NBC148), 32-bp deletion in the CCR5 gene, and VNTR locus at the eNOS gene, were examined in three ethnogeographic groups of Kazakhs (342 individuals). The individuals examined lived in southeastern, central, and southwestern regions of Kazakhstan, and according to their tribal attribution, belonged to the Senior, Middle, and Junior Zhuzes. The Alu insertions appeared to be polymorphic in all populations examined: the insertion frequency varied from 0.264 in the populations of the Senior and Middle Zhuzes at the Ya5NBC27 and Ya5NBC148 loci, to 0.827 in Kazakhs of the Middle Zhuz at the APOA1 locus. In Kazakh groups examined only two alleles of the eNOS VNTR locus were detected with the number of repeats constituting four (A) and five (B) copies. The highest frequency of A allele was found in Kazakhs from the Junior Zhuz (0.113), while the highest frequency of B allele was detected in population of the Senior Zhuz (0.893). The frequency of the 32-bp deletion in the chemokine receptor CCR5 gene varied from 0.027 in the Junior Zhuz to 0.045 in the Senior Zhuz. Kazakhs showed high genetic diversity (Hex = 0.376). In general, in three ethnogeographic groups of Kazakhs, the coefficient of gene differentiation (GST) over eight diallelic markers of nuclear genome constituted 1.1%. The differences in the Alu insertions made the highest contribution to the among-population diversity (GST = 1.2%).

The allele frequency distribution of the (CTG)n repeat located in the 3′-terminal region of the myotonin protein kinase gene (DMPK) was compared for populations of Yakutia (three ethnogeographic groups of Yakuts, Evenks, Evens, Yukaghirs, and Dolgans) and Central Asia (Kazakhs, Uzbeks, and Uighurs) and other ethnic groups. The populations of the two regions proved to considerably differ from each other: features characteristic of Asian Mongoloids were more distinct in the populations of Yakutia, while the Central Asian populations were closer to European populations. The (CTG)n allele spectrum of Yakuts was considered in connection with the high incidence of myotonic dystrophy in Yakutia. The results support the hypothesis of the founder effect for the spread of myotonic dystrophy in Yakuts. Data on the (CTG)n polymorphism were used to estimate the phylogenetic relationships of the populations under study.

Direct molecular genetic testing carried out in 59 Huntington's disease patients belonging to 46 families from Bashkortostan revealed the (CAG)n repeat expansion in exon 1 of the IT15 gene in 57 of them. By use of this analysis the disease status was not confirmed in two patients with atypical form of the disease and negative family history. The (CAG)n repeat expansion was identified in 27 out of 127 asymptomatic at-risk individuals. Analysis of the mutant (CAG)n allele inheritance demonstrated extremely high instability and high mutation rate predominantly leading to the appearance of the alleles with increasing number of (CAG)n repeats in subsequent generations. The instability was mostly observed in cases of paternal transmission. Almost complete linkage disequilibrium between the (CCG)7 mutant alleles and the del2642 deletion was demonstrated. Three major haplotypes revealed, (CCG)7/del–, (CCG)7/del+, and (CCG)10/del–, implied the existence of at least three sources of the origin of Huntington's disease in Bashkortostan. The identified haplotype frequency distribution patterns displayed similarities with those in European populations. The contribution of a number of genetic factors to the age of onset of Huntington's disease was analyzed.

NineAlu loci (Ya5NBC5, Ya5NBC27, Ya5NBC148, Ya5NBC182, YA5NBC361, ACE, ApoA1, PV92, TPA25) were analyzed in six ethnic populations (Trans-Ural Bashkirs, Tatars-Mishars, Mordovians-Moksha, Mountain Maris, Udmurts, and Komi-Permyaks) of the Volga–Ural region and in three Central Asian populations (Uzbeks, Kazakhs, and Uigurs). All Alu insertions analyzed appeared to be polymorphic in all populations examined. The frequency of insertion varied from 0.110 in Mountain Maris at the Ya5NBC5 locus to 0.914 in Tatars at the ApoA1 locus. The data on the allele frequency distribution at nine loci point to the existence of substantial genetic diversity in the populations examined. The value of the observed heterozygosity averaged over nine Alu insertions varied from 0.326 in Mountain Maris to 0.445 in Kazakhs and Uigurs. The level of the interpopulation genetic differences for the Volga–Ural population (F st = 0.061) was higher than for the populations of Central Asia (F st = 0.024), Europe (F st = 0.02), and Southeastern Asia (F st = 0.018). The populations examined were highly differentiated both in respect of linguistic characteristics and the geographical position. The data obtained confirmed the effectiveness of the marker system used for the assessment of genetic differentiation and the relationships between the ethnic groups.

VNTR allelic polymorphism at the phenylalanine hydroxilase (PAH) and endothelial constitutive nitric oxide synthase (eNOS) genes and the prevalence of the CCR5 chemokine receptor gene 32-bp deletion were examined in four populations of Northern Caucasus: Adygs, Kumyks, Karachais, and Nogais (Kuban and Karanogais). Population-specific features of the allele and genotype frequency distribution patterns of the polymorphisms examined were described. The data obtained were compared to those obtained from literature. The results of the study confirmed that the frequency and occurrence of the PAH polymorphic alleles exhibit substantial interpopulation differences. In the populations of Northern Caucasus, the eNOS minisatellite polymorphism alleles and genotypes frequency distribution patterns were close to those described earlier for populations of the Volga–Ural region (VUR), and also for the Australian Caucasoids, Japanese, and Turks. In the populations examined, the mean frequency of the CCR5 gene deletion was 0.055, which was somewhat lower than in the populations of VUR (0.070) and Europe (0.081), and practically identical to that in Asian populations (0.050). For each population observed and expected heterozygosities at each locus were calculated. In general, the gene pool of Northern Caucasian populations showed substantial differentiation at the loci examined: the GST value was 0.0274. The data for individual loci showed that the greater contribution to the interpopulation diversity was made by the differences in the PAH VNTR allele frequencies (GST = 0.04), while the differences at the eNOSand CCR5 loci were small (GST = 0.0025 and GST = 0.0039, respectively).

We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes1,2,3,4 with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians3, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations’ deep relationships and show that early European farmers had ∼44% ancestry from a ‘basal Eurasian’ population that split before the diversification of other non-African lineages., Instituto Multidisciplinario de Biología Celular

Study of DBP gene (TAAA) n polymorphism in women of postmenopausal age revealed a significantly lower incidence of DBP * 10 allele and a higher incidence of DBP * 11 allele in Russian women with bone fractures in comparison with the relevant controls (χ2 = 4.47, p = 0.034 and χ2 = 4.28, p = 0.038, respectively). Allele DBP * 11 is a high risk marker (OR = 1.93; 95%CI 1.06-3.48), while allele DBP*10 a marker of low risk of bone fractures (OR = 0.59; 95%CI 0.37-0.94). A trend to a reduction of mineral density of the femoral neck and of the lumbar vertebrae in women with DBP * 10 * 8 genotype of DBP gene polymorphic locus (TAAA) n in comparison with DBP * 10 * 10 and DBP * 10 * 11 genotype carriers is traced.