Ecological risk assessment and long-term environmental pollution caused by obsolete undisposed organochlorine pesticides.

Obsolete organochlorine pesticides (OSPs) are currently prohibited as persistent organic pollutants that contaminate the environment. If undisposed, they continue to pollute soil and water, to accumulate in the food chain and to harm plants, animals and the human body. The aim of the study was to assess water and soil pollution around the storehouses of undisposed, banned OSPs and their possible genotoxic effect. The storehouses in four villages near Almaty, Kazakhstan were investigated. Chemical analysis confirmed contamination of water and soil around storehouses with OSPs. The genotoxic effect of water and soil samples was evaluated using model objects: S.typhymurium, D.melanogaster, sheep lymphocytes cultures and human lymphocytes cultures. It was found that water and soil samples caused mutagenic effect in all model systems. They increased the frequency of revertants in Salmonella, the frequency of lethal mutations in Drosophila chromosomes, and the frequency of chromosome aberrations in cultures of human and sheep lymphocytes. Although a genotoxic effect was demonstrated for each of these models, various models showed different sensitivity to the effects of pesticides and they varied degree of response. The association between the total content of OCPs in soil and the level of mutations for different model systems was discovered.

Comprehensive assessment of unutilized and obsolete pesticides impact on genetic status and health of population of Almaty region.

The group of persistent organic pollutants (POPs) are particularly dangerous for the environment and by consequence for human health because of the risk to be transmitted in the food chain. Among them, the urgent problem of obsolete and forbidden organochlorinated pesticides (OCPs) needs a rigorous management in many countries, including Kazakhstan. The aim of our study was to evaluate the effect of pesticides content in food products on the genetic status and health of the population living on the contaminated areas near destroyed warehouses for OCPs (4 villages of Talgar district and 1 control site, Almaty region). The food products sampled in Taukaraturyk (control site), and in 4 villages where non-utilized obsolete pesticides were discovered: Beskainar, Kyzylkairat, Amangeldy, and Belbulak. The contents of 24 pesticides in food products from plant (apples, pears, tomatoes, cucumbers, sweet peppers) and animal (beef meat, cow milk, honey) origin, that grown in places of localization of non-utilized OCPs, were determined, sometimes in high and unacceptably high concentrations (before 2500 times over MRL). In pears, the pesticides content (especially DDT, γ-HCH, ß-HCH, endosulfan, and aldrin pesticide group), was higher than in other fruits. Among vegetables, the highest levels of all groups of pesticide were found in cucumbers. Beef meat samples demonstrated increased contents of ß-HCH, γ-HCH, endrin and dieldrin. In cow milk samples only the high concentration of dieldrin was found. The content of pesticides in meat was 4-5 times higher than in milk. The medical examinations, carried out among the cohorts living around the polluted by pesticides territories and control cohort from ecologically favorable village, showed that there were more individuals with high and middle levels of somatic health in the control group than in groups exposed to OCPs. The long-term effect of the pesticide contamination of the environment on genetic status of the population was assessed by chromosomal aberration (CA) frequencies. The highest level of chromosomal aberrations was identified for the examined residents of Kyzylkairat (41%) and Belbulak (38%), a high level in Amangeldy (12%), and middle level in Beskainar (6.5%). The association between the CA frequency, health status and the pesticides contents in food were assessed by a Spearman rank correlation. The low indicators of somatic health status were strictly associated with high levels of CA, and good health status indicates that the CA rates did not exceed the spontaneous level of mutagenesis. The strongest correlation was shown between high levels of chromosomal aberrations and the content of different pesticides in pears (Cr = 0.979-0.467), tomatoes (Cr = 0.877-0.476), cucumbers (Cr = 0.975-0.553) and meat (Cr = 0.839-0.368). The obtained results highlight the need to improve health protection by increasing the public awareness to the security of the storage of obsolete OCPs in order to strengthen food safety by efficient control services.

Lectin approaches for glycoproteomics in FDA-approved cancer biomarkers.

The nine FDA-approved protein biomarkers for the diagnosis and management of cancer are approaching maturity, but their different glycosylation compositions relevant to early diagnosis still remain practically unexplored at the sub-glycoproteome scale. Lectins generally exhibit strong binding to specific sub-glycoproteome components and this property has been quite poorly addressed as the basis for the early diagnosis methods. Here, we discuss some glycoproteome issues that make tackling the glycoproteome particularly challenging in the cancer biomarkers field and include a brief view for next generation technologies.

Genetic diversity and origin of Kazakh Tobet Dogs.

The Kazakh Tobet is an indigenous Kazakh dog breed that has been used to guard livestock since ancient times. To understand the genetic structure and phylogenetic relationship of the Kazakh Tobet breed with other herding and livestock guarding dog breeds, we analysed short tandem repeat data of 107 Kazakh Tobet dogs from different regions of Kazakhstan and Mongolia, as well as whole genome sequencing data from two Kazakh Tobet dogs and 43 dogs from 24 working breeds. Our results indicate a high genetic diversity of the Kazakh Tobet, with the average number of alleles per locus ranging from 6.00 to 10.22 and observed heterozygosity ranging from 76 to 78%. The breed has a complex genetic structure characterised by seven different clusters. The neighbour-joining tree constructed based on 14,668,406 autosomal and the maximum likelihood tree based on mitochondrial D-loop sequences indicate a common genetic heritage between the Kazakh Tobet, the Central Asian Shepherd Dog and the Turkish Akbash. The presence of haplotype A18 in the Kazakh Tobets supports the hypothesis of the ancient origin of the breed, which was previously suggested by archaeological finds and written sources. These results provide an important genetic basis for the ongoing efforts to improve the Kazakh Tobet breed, to ensure its preservation as an independent genetic lineage and to recognise a breed on an international level.

Association of Genetic Markers with the Risk of Early-Onset Breast Cancer in Kazakh Women.

Breast cancer is a global health problem. It is an age-dependent disease, but cases of early-onset breast cancer (eBC) are gradually increasing. There are many unresolved questions regarding eBC risk factors, mechanisms of development and screening. Only 10% of eBC cases are due to mutations in the BRCA1/BRCA2 genes, and 90% have a more complex genetic background. This poses a significant challenge to timely cancer detection in young women and highlights the need for research and awareness. Therefore, identifying genetic risk factors for eBC is essential to solving these problems. This study represents an association analysis of 144 eBC cases and 163 control participants to identify genetic markers associated with eBC risks in Kazakh women. We performed a two-stage approach in association analysis to assess genetic predisposition to eBC. First-stage genome-wide association analysis revealed two risk intronic loci in the CHI3L2 gene (p = 5.2 × 10-6) and MGAT5 gene (p = 8.4 × 10-6). Second-stage exonic polymorphisms haplotype analysis showed significant risks for seven haplotypes (p < 9.4 × 10-4). These results point to the importance of studying medium- and low-penetrant genetic markers in their haplotype combinations for a detailed understanding of the role of detected genetic markers in eBC development and prediction.

Homozygosity mapping in the Kazakh national dog breed Tazy.

The Tazy is a breed of sighthound common in Kazakhstan. The identification of runs of homozygosity (ROH) is an informative approach to assessing the history and possible patterns of directional selection pressure. To our knowledge, the present study is the first to provide an overview of the ROH pattern in the Tazy dogs from a genome-wide perspective. The ROH of the Tazy was found to be mainly composed of shorter segments (1-2 Mb), accounting for approximately 67% of the total ROH. The estimated ROH-based inbreeding coefficients (FROH) ranged from 0.028 to 0.058 with a mean of 0.057. Five genomic regions under positive selection were identified on chromosomes 18, 22, and 25. The regions on chromosomes 18 and 22 may be breed specific, while the region on chromosome 22 overlaps with regions of hunting traits in other hunting dog breeds. Among the 12 candidate genes located in these regions, the gene CAB39L may be a candidate that affects running speed and endurance of the Tazy dog. Eight genes could belong to an evolutionarily conserved complex as they were clustered in a large protein network with strong linkages. The results may enable effective interventions when incorporated into conservation planning and selection of the Tazy breed.

Kazakh national dog breed Tazy: What do we know?

The Tazy or Kazakh National sighthound has been officially recognized as the national heritage of Kazakhstan. Comprehensive genetic studies of genetic diversity and population structure that could be used for selection and conservation of this unique dog breed have not been conducted so far. The aim of this study was to determine the genetic structure of the Tazy using microsatellite and SNP markers and to place the breed in the context of the world sighthound breeds. Our results showed that all 19 microsatellite loci examined were polymorphic. The observed number of alleles in the Tazy population varied from 6 (INU030 locus) to 12 (AHT137, REN169D01, AHTh260, AHT121, and FH2054 loci) with a mean of 9.778 alleles per locus. The mean number of effective alleles was 4.869 and ranged from 3.349 f to 4.841. All markers were highly informative (PIC values greater than 0.5) and ranged from 0.543 (REN247M23 locus) to 0.865 (AHT121 locus). The observed and expected heterozygosities in a total population were 0.748 and 0.769 and ranged from 0.746 to 0.750 and 0.656 to 0.769, respectively. Overall, the results confirmed that the Tazy breed has a high level of genetic diversity, no significant inbreeding, and a specific genetic structure. Three gene pools underlie the genetic diversity of the Tazy breed. SNP analysis using the CanineHD SNP array, which contains more than 170,000 SNP markers, showed that the Tazy breed is distinct from other sighthound breeds and genetically related to ancient eastern sighthound breeds sharing the same branch with the Afghan Hound and the Saluki. The results, together with archeological findings, confirm the ancient origin of the breed. The findings can be used for the conservation and international registration of the Tazy dog breed.

Case-Control Study of the Association between Single Nucleotide Polymorphisms of Genes Involved in Xenobiotic Detoxification and Antioxidant Protection with the Long-Term Influence of Organochlorine Pesticides on the Population of the Almaty Region.

The association of genetic polymorphisms with the individual sensitivity of humans to the action of pesticide pollution is being actively studied in the world. The aim of this study was a molecular epidemiological analysis of candidate polymorphisms of genes involved in pesticide metabolism, detoxification, and antioxidant protection. Some of the selected polymorphisms also relate to susceptibility to cancer and cardiovascular, respiratory, and immune system diseases in individuals exposed to pesticides for a long time. For a case-control study of a unique cohort of people exposed to organochlorine pesticides for 10 years or more were chosen, a control cohort was selected that matched with the experimental group by the main population characteristics. PCR-PRLF and genome-wide microarray genotyping (GWAS) methods were used. We identified 17 polymorphisms of xenobiotic detoxification genes and 27 polymorphisms of antioxidant defense genes, which had a significantly high statistical association with the negative impact of chronic pesticide intoxication on human health. We also found 17 polymorphisms of xenobiotic detoxification genes and 12 polymorphisms of antioxidant defense genes that have a protective effect. Data obtained added to the list of potential polymorphisms that define a group at high risk or resistant to the negative effects of pesticides.

Integrative Functional Genomic Analysis in Multiplex Autism Families from Kazakhstan.

The study of extended pedigrees containing autism spectrum disorder- (ASD-) related broader autism phenotypes (BAP) offers a promising approach to the search for ASD candidate variants. Here, a total of 650,000 genetic markers were tested in four Kazakhstani multiplex families with ASD and BAP to obtain data on de novo mutations (DNMs), common, and rare inherited variants that may contribute to the genetic risk for developing autistic traits. The variants were analyzed in the context of gene networks and pathways. Several previously well-described enriched pathways were identified, including ion channel activity, regulation of synaptic function, and membrane depolarization. Perhaps these pathways are crucial not only for the development of ASD but also for ВАР. The results also point to several additional biological pathways (circadian entrainment, NCAM and BTN family interactions, and interaction between L1 and Ankyrins) and hub genes (CFTR, NOD2, PPP2R2B, and TTR). The obtained results suggest that further exploration of PPI networks combining ASD and BAP risk genes can be used to identify novel or overlooked ASD molecular mechanisms.

Genetic Relationship Among the Kazakh People Based on Y-STR Markers Reveals Evidence of Genetic Variation Among Tribes and Zhuz.

Ethnogenesis of Kazakhs took place in Central Asia, a region of high genetic and cultural diversity. Even though archaeological and historical studies have shed some light on the formation of modern Kazakhs, the process of establishment of hierarchical socioeconomic structure in the Steppe remains contentious. In this study, we analyzed haplotype variation at 15 Y-chromosomal short-tandem-repeats obtained from 1171 individuals from 24 tribes representing the three socio-territorial subdivisions (Senior, Middle and Junior zhuz) in Kazakhstan to comprehensively characterize the patrilineal genetic architecture of the Kazakh Steppe. In total, 577 distinct haplotypes were identified belonging to one of 20 haplogroups; 16 predominant haplogroups were confirmed by SNP-genotyping. The haplogroup distribution was skewed towards C2-M217, present in all tribes at a global frequency of 51.9%. Despite signatures of spatial differences in haplotype frequencies, a Mantel test failed to detect a statistically significant correlation between genetic and geographic distance between individuals. An analysis of molecular variance found that ∼8.9% of the genetic variance among individuals was attributable to differences among zhuzes and ∼20% to differences among tribes within zhuzes. The STRUCTURE analysis of the 1164 individuals indicated the presence of 20 ancestral groups and a complex three-subclade organization of the C2-M217 haplogroup in Kazakhs, a result supported by the multidimensional scaling analysis. Additionally, while the majority of the haplotypes and tribes overlapped, a distinct cluster of the O2 haplogroup, mostly of the Naiman tribe, was observed. Thus, firstly, our analysis indicated that the majority of Kazakh tribes share deep heterogeneous patrilineal ancestries, while a smaller fraction of them are descendants of a founder paternal ancestor. Secondly, we observed a high frequency of the C2-M217 haplogroups along the southern border of Kazakhstan, broadly corresponding to both the path of the Mongolian invasion and the ancient Silk Road. Interestingly, we detected three subclades of the C2-M217 haplogroup that broadly exhibits zhuz-specific clustering. Further study of Kazakh haplotypes variation within a Central Asian context is required to untwist this complex process of ethnogenesis.

Ancient genomic time transect from the Central Asian Steppe unravels the history of the Scythians.

The Scythians were a multitude of horse-warrior nomad cultures dwelling in the Eurasian steppe during the first millennium BCE. Because of the lack of first-hand written records, little is known about the origins and relations among the different cultures. To address these questions, we produced genome-wide data for 111 ancient individuals retrieved from 39 archaeological sites from the first millennia BCE and CE across the Central Asian Steppe. We uncovered major admixture events in the Late Bronze Age forming the genetic substratum for two main Iron Age gene-pools emerging around the Altai and the Urals respectively. Their demise was mirrored by new genetic turnovers, linked to the spread of the eastern nomad empires in the first centuries CE. Compared to the high genetic heterogeneity of the past, the homogenization of the present-day Kazakhs gene pool is notable, likely a result of 400 years of strict exogamous social rules.

Neoadjuvant Therapy with Drug Arglabin for Breast Cancer with Expression of H-Ras Oncoproteins.

BACKGROUNDS: In breast cancer, blocking of Ras signaling and inhibition of H-Ras is quite promising. H-Ras may become a target for farnesyl transferase inhibitors, and in combination with other immunohistochemical factors it will contribute to the progression of a breast tumor. PURPOSE: The aim of this study was to evaluate the effectiveness of neoadjuvant therapy for breast cancer with the inclusion of farnesyl transferase inhibitor, arglabin interfering with the expression and concentration of H-Ras oncoproteins. METHODS: Depending on the presence of H-Ras oncoproteins after Western-blot hybridization, the patients were divided a negative and positive expression of H-Ras groups. RESULTS: Correlation analysis of methods used for determining the expression ability and concentration of H-Ras oncoproteins (immunohistochemistry and Western-blot analysis) demonstrated substantial statistical relationship Rs=0.71, p=0.03. The H-Ras oncoproteins were absent in patients receiving either "Arglabin" or standard AC regimen. However, in the AC + Arglabin group, there was a varying degrees of positive concentration of H-Ras oncoproteins (Kruskal-Wallis=6.92; p=0.03). CONCLUSION: These results indicate that Arglabin attenuates H-Ras oncoproteins expression which is a promising therapeutic target for breast cancer.

No Association between the rs1799836 Polymorphism of the Monoamine Oxidase B Gene and the Risk of Autism Spectrum Disorders in the Kazakhstani Population.

Autism spectrum disorders (ASDs) are heterogeneous diseases that are triggered by a number of environmental and genetic factors. The aim of the current study was to investigate an association of the rs1799836 genetic variant of the neurotransmitter-related gene MAOB with ASDs. In total, 262 patients diagnosed with ASDs and their 126 healthy siblings were included in the present study. All individuals represented a Kazakhstani population. The distributions of the rs1799836 genotype were in accordance with the Hardy-Weinberg equilibrium among both cases and controls. No statistically significant differences were found in the allelic distributions of this polymorphism between ASD and control subjects (A/G: for males OR = 1.11, 95% 0.59-2.06, p = 0.75; for females OR = 1.14, 95% 0.70-1.86, p = 0.76). However, the increased score in the overall CARS was significantly associated with the A allele of rs1799836 MAOB for females (OR = 2.31, 95% 1.06-5.04, p = 0.03). The obtained results suggest that the rs1799836 polymorphism of the MAOB gene may have little contribution to the development of ASDs but may be involved in pathways contributing to ASD symptom severity in females. Further large-scale investigations are required to uncover possible relationships between rs1799836 MAOB and ASD progression in a gender-specific manner and their possible application as a therapeutic target.

The genetic history of admixture across inner Eurasia.

The indigenous populations of inner Eurasia-a huge geographic region covering the central Eurasian steppe and the northern Eurasian taiga and tundra-harbour tremendous diversity in their genes, cultures and languages. In this study, we report novel genome-wide data for 763 individuals from Armenia, Georgia, Kazakhstan, Moldova, Mongolia, Russia, Tajikistan, Ukraine and Uzbekistan. We furthermore report additional damage-reduced genome-wide data of two previously published individuals from the Eneolithic Botai culture in Kazakhstan (~5,400 BP). We find that present-day inner Eurasian populations are structured into three distinct admixture clines stretching between various western and eastern Eurasian ancestries, mirroring geography. The Botai and more recent ancient genomes from Siberia show a decrease in contributions from so-called 'ancient North Eurasian' ancestry over time, which is detectable only in the northern-most 'forest-tundra' cline. The intermediate 'steppe-forest' cline descends from the Late Bronze Age steppe ancestries, while the 'southern steppe' cline further to the south shows a strong West/South Asian influence. Ancient genomes suggest a northward spread of the southern steppe cline in Central Asia during the first millennium BC. Finally, the genetic structure of Caucasus populations highlights a role of the Caucasus Mountains as a barrier to gene flow and suggests a post-Neolithic gene flow into North Caucasus populations from the steppe.