Stone Age Yersinia pestis genomes shed light on the early evolution, diversity, and ecology of plague.

The bacterial pathogen Yersinia pestis gave rise to devastating outbreaks throughout human history, and ancient DNA evidence has shown it afflicted human populations as far back as the Neolithic. Y. pestis genomes recovered from the Eurasian Late Neolithic/Early Bronze Age (LNBA) period have uncovered key evolutionary steps that led to its emergence from a Yersinia pseudotuberculosis-like progenitor; however, the number of reconstructed LNBA genomes are too few to explore its diversity during this critical period of development. Here, we present 17 Y. pestis genomes dating to 5,000 to 2,500 y BP from a wide geographic expanse across Eurasia. This increased dataset enabled us to explore correlations between temporal, geographical, and genetic distance. Our results suggest a nonflea-adapted and potentially extinct single lineage that persisted over millennia without significant parallel diversification, accompanied by rapid dispersal across continents throughout this period, a trend not observed in other pathogens for which ancient genomes are available. A stepwise pattern of gene loss provides further clues on its early evolution and potential adaptation. We also discover the presence of the flea-adapted form of Y. pestis in Bronze Age Iberia, previously only identified in in the Caucasus and the Volga regions, suggesting a much wider geographic spread of this form of Y. pestis. Together, these data reveal the dynamic nature of plague's formative years in terms of its early evolution and ecology.

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.

Association of DCC, MLH1, GSTT1, GSTM1, and TP53 gene polymorphisms with colorectal cancer in Kazakhstan.

This study presents the first results of a molecular-genetic study of colorectal cancer (CRC) in Kazakhstan. Blood samples were collected from patients diagnosed with rectal or colon cancer (249 individuals) as well as a control cohort of healthy volunteers (245 individuals), taking into account the age, gender, ethnicity, and smoking habits of the CRC patients. Combined analysis of data obtained from individuals of either Kazakh or Russian decent showed a significant association with increased CRC risk in the following genotypes: DCC (32008376G/G and G/A versus A/A; OR = 3.45, 95 % confidence interval (95 %CI) = 1.75-6.81, χ (2) = 14.07, p < 0.0002), MLH1 (-93G/G versus G/A and A/A; OR = 1.45, 95 %CI = 1.02-2.07, χ (2) = 4.21, p < 0.04), TP53 (Pro72Pro; OR = 3.80, 95 %CI = 2.46-5.88, χ (2) = 61.27, p < 0.0001), combination GSTT1 deletions with heterozygotes versus normal homozygotes (OR = 1.43, 95 %CI = 1.00-2.04, χ (2) = 3.90, p < 0.05), and GSTM1 deletions (OR = 1.83, 95 %CI = 1.28-2.63, χ (2) = 11.04, p < .001). Analysis for ethnicity and smoking for each of the investigated polymorphisms showed that some genotypes can have a predictive value for susceptibility to CRC, at least those that demonstrate statistically significant ORs either for the combined mixed population of Kazakhstan or for both main ethnic groups separately (Kazakhs and Russians): TP53 Pro72Pro homozygous (for Kazakh-OR = 3.40, 95 %CI = 1.63-7.06, χ (2) = 11.35, p < 0.003; for Russian-OR = 4.69, 95 %CI = 2.53-8.66, χ (2) = 53.19, p < 0.0001) and GSTM1 deletions (for Kazakh-OR = 2.30, 95 %CI = 1.21-4.40, χ (2) = 8.42, p < 0.01; for Russian-OR = 1.64, 95 %CI = 1.01-2.66, χ (2) = 7.82, p < 0.02).

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.

Individual Risk Assessment for Population Living on the Territories Long-Term Polluted by Organochlorine Pesticides.

The long-term storage of unutilized pesticides raised new problems of long-term environmental contamination. The study presents the results of surveying 151 individuals in 7 villages living close to pesticide-contaminated localities. All individuals have been surveyed concerning their consumption habits and lifestyle characteristics. An assessment of the general exposure risks of the local population was carried out using the analysis of pollutants in food products and the average levels of their consumption in the region. The cohort risk evaluation revealed that the greatest risk was associated with the regular consumption of cucumbers, pears, bell peppers, meat, and milk. The new model to estimate individual risks of long-term pesticide pollution was proposed as a calculation of the combined action of 9 risk factors, including individual genotypes, age, lifestyle, and personal pesticide consumption rates. The analysis of the predictive ability of this model showed that the final score for individual health risks corresponded to the development of chronic diseases. A high level of chromosomal aberrations was evidenced for individual genetic risk manifestations. The combined influence of all risk factors revealed contributions of 24.7% for health status and 14.2% for genetic status, while other impacts go to all unaccounted factors.

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.

The effects of DNA repair polymorphisms on chromosome aberrations in the population of Kazakhstan.

Purpose: To analyze the effects of DNA repair polymorphism and other factors on the frequency chromosome aberrations in an irradiated cohort of subjects living around the Semipalatinsk nuclear test site and non-exposed group of subjects from ecologically favorable zones of Kazakhstan.Materials and methods: Blood samples were collected in the rural areas of the East Kazakhstan district around the Semipalatinsk nuclear test site and ecologically favorable zones of Almaty region of Kazakhstan. Chromosome aberrations in the fresh and cryopreserved peripheral blood lymphocyte cultures were analyzed by Giemsa staining. Single nucleotide polymorphisms at eight DNA repair genes (XRCC1 rs1799782, XRCC1 rs25487, XRCC3 rs861539, ATM rs1801516, XPD rs1799793, XPD rs13181, APEX1 rs1130409, and hOGG1 rs1052133) were determined by PCR-RFLP method.Results: The age of donors and smoking significantly affected the frequency of chromosome aberrations among the irradiated and control subjects. In the irradiated and control cohorts, the frequency of chromosome aberrations was significantly increased in the heterozygous ATM rs1801516 (1853 Asp/Asn) individuals; for the rest of the loci no significant associations between polymorphism and the frequency of chromosome aberrations were detected.Conclusions: The age of donors, smoking, and the ATM rs1801516 polymorphism significantly affect the frequency of chromosome aberrations among individuals inhabiting contaminated area around the Semipalatinsk nuclear weapon test site, as well as among those inhabiting ecologically favorable zones of Kazakhstan.

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.

Association of GCLM -588C/T and GCLC -129T/C Promoter Polymorphisms of Genes Coding the Subunits of Glutamate Cysteine Ligase with Ischemic Heart Disease Development in Kazakhstan Population.

BACKGROUND: Glutamate cysteine ligase (GCL) is a rate-limiting enzyme in synthesis of glutathione. Evidence suggests that genetic variations in the promoter region of genes coding a catalytic subunit (GCLC -129T/C) and a modifier subunit (GCLM -588C/T) of GCL have a functional impact on their transcriptional activity and were associated with various disorders. Hence, we hypothesize whether these two polymorphic variants of GCLM and GCLC genes are associated with the risk of ischemic heart disease (IHD) development in the population of Kazakhstan. METHODS: We evaluated 360 patients with IHD and 341 control subjects. Allele frequencies of studied promoters' polymorphisms were detected by PCR-RFLP analysis. Multiple logistic regression analysis was applied to assess the risk for different genotypes obtained. RESULTS: The presence of -588T allele in GCLM and -129T allele in GCLC gene genotypes was associated with an increased risk of IHD (GCLM -588T: OR = 3.92, p = 0.003; GCLC -129T: OR = 3.22, p = 0.03) for general ethnically mixed group. Analysis of each ethnical groups separately showed the higher risk tendency for Kazakhs as for GCLM -588T (OR = 4.79; p = 0.03) and as for GCLC -129T (OR = 4.79, p = 0.03). For Russians, statistically differences for two polymorphisms were not observed. CONCLUSION: The two promoter polymorphisms of GCLM (-588C/T) and GCLC (-128T/C) are associated with an increased risk of IHD in Kazakhstan population.

The determination of genetic markers of age-related cancer pathologies in populations from Kazakhstan.

Aging associates with a variety of pathological conditions such as cancer, cardiovascular, neurodegenerative, autoimmune diseases, and metabolic disorders. The oncogenic alterations overlap frequently with the genes linked to aging. Here, we show that several aging related genes may serve as the genetic risk factors for cervical and esophagus cancers. In our study, we analyzed samples obtained from 115 patients with esophageal and 207 patients with cervical cancer. The control groups were selected to match the ethnicity and age of cancer patients. We examined the genes involved in the processes of xenobiotics detoxification (GSTM1 and GSTT1), DNA repair (XRCC1 and XRCC3), and cell cycle regulation and apoptosis (CCND1 and TP53). Our study revealed that deletions of GSTT1 and GSTM1 genes or the distinct point mutations of XRCC1 gene are associated with cervical and esophageal cancers. These results will lead to development of screening for detection of individuals susceptible to esophageal and cervical cancers. Introduction of the screening programs will allow the early and effective preventive measures that will reduce cancer incidence and mortality in Kazakhstan.