It is broadly accepted that psoriasis is an immune-mediated disease with a heritable component, but it is not clear what causes inflammation in the skin. Previous research suggests that fragments of ...the keratin 17 (K17) protein, which are constitutively expressed in hair follicles, could act as autoantigens. In this study, we synthesized the K17 protein from mRNA derived from hair follicles and tested whether it elicited T cell responses depending on the patient genotype at the major susceptibility locus HLA-Cw*06:02. We treated peripheral blood-derived cells with the K17 protein and its short fragments to assess the T cell proliferation response using flow cytometry. Our analyses show a significantly stronger increase in cell proliferation among patients but not in healthy controls. We then examined whether the variation in T cell proliferation correlated with the patient HLA-Cw*06:02 risk genotype. Considering the affected status and patient genotype as two independent predictors, we fitted a linear model and showed that the HLA-Cw*06:02 allele dosage strongly predicted the T cell response. Our study findings suggest that the K17 protein likely acts as an autoantigen in psoriasis and that patients' risk genotype is strongly correlated with the magnitude of the response to this putative autoantigen.
The genetic origins of Uralic speakers from across a vast territory in the temperate zone of North Eurasia have remained elusive. Previous studies have shown contrasting proportions of Eastern and ...Western Eurasian ancestry in their mitochondrial and Y chromosomal gene pools. While the maternal lineages reflect by and large the geographic background of a given Uralic-speaking population, the frequency of Y chromosomes of Eastern Eurasian origin is distinctively high among European Uralic speakers. The autosomal variation of Uralic speakers, however, has not yet been studied comprehensively.
Here, we present a genome-wide analysis of 15 Uralic-speaking populations which cover all main groups of the linguistic family. We show that contemporary Uralic speakers are genetically very similar to their local geographical neighbours. However, when studying relationships among geographically distant populations, we find that most of the Uralic speakers and some of their neighbours share a genetic component of possibly Siberian origin. Additionally, we show that most Uralic speakers share significantly more genomic segments identity-by-descent with each other than with geographically equidistant speakers of other languages. We find that correlated genome-wide genetic and lexical distances among Uralic speakers suggest co-dispersion of genes and languages. Yet, we do not find long-range genetic ties between Estonians and Hungarians with their linguistic sisters that would distinguish them from their non-Uralic-speaking neighbours.
We show that most Uralic speakers share a distinct ancestry component of likely Siberian origin, which suggests that the spread of Uralic languages involved at least some demic component.
Abstract
The admixture between modern humans and Neandertals has resulted in ∼2% of the genomes of present-day non-Africans being composed of Neandertal DNA. Introgressed Neandertal DNA has been ...demonstrated to significantly affect the transcriptomic landscape in people today and via this molecular mechanism influence phenotype variation as well. However, little is known about how much of that regulatory impact is mediated through long-range regulatory effects that have been shown to explain ∼20% of expression variation. Here we identified 60 transcription factors (TFs) with their top cis-eQTL SNP in GTEx being of Neandertal ancestry and predicted long-range Neandertal DNA-induced regulatory effects by screening for the predicted target genes of those TFs. We show that the TFs form a significantly connected protein–protein interaction network. Among them are JUN and PRDM5, two brain-expressed TFs that have their predicted target genes enriched in regions devoid of Neandertal DNA. Archaic cis-eQTLs for the 60 TFs include multiple candidates for local adaptation, some of which show significant allele frequency increases over the last ∼10,000 years. A large proportion of the cis-eQTL-associated archaic SNPs have additional associations with various immune traits, schizophrenia, blood cell type composition and anthropometric measures. Finally, we demonstrate that our results are consistent with those of Neandertal DNA-associated empirical trans-eQTLs. Our results suggest that Neandertal DNA significantly influences regulatory networks, that its regulatory reach goes beyond the 40% of genomic sequence it still covers in present-day non-Africans and that via the investigated mechanism Neandertal DNA influences the phenotypic variation in people today.
Yermakovich et al. explore the long-range regulatory effects of Neandertal DNA in modern humans by scanning for transcription factors with eQTL variants of likely Neandertal ancestry and investigating their predicted target genes. Their results suggest that Neandertal DNA significantly influences regulatory networks-reaching beyond the 40% of genomic sequence it still covers in present-day non-Africans-and phenotypic variation in people today.
Pathogen-driven selection shaped adaptive mutations in immunity genes, including those contributing to inflammatory disorders. Functional characterization of such adaptive variants can shed light on ...disease biology and past adaptations. This popular idea, however, was difficult to test due to challenges in pinpointing adaptive mutations in selection footprints. In this study, using a local-tree-based approach, we show that 28% of risk loci (153/535) in 21 inflammatory disorders bear footprints of moderate and weak selection, and part of them are population specific. Weak selection footprints allow partial fine-mapping, and we show that in 19% (29/153) of the risk loci under selection, candidate disease variants are hitchhikers, and only in 39% of cases they are likely selection targets. We predict function for a subset of these selected SNPs and highlight examples of antagonistic pleiotropy. We conclude by offering disease variants under selection that can be tested functionally using infectious agents and other stressors to decipher the poorly understood link between environmental stressors and genetic risk in inflammatory conditions.
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.
Human Y chromosome haplogroup J1-M267 is a common male lineage in West Asia. One high-frequency region-encompassing the Arabian Peninsula, southern Mesopotamia, and the southern Levant-resides ~ ...2000 km away from the other one found in the Caucasus. The region between them, although has a lower frequency, nevertheless demonstrates high genetic diversity. Studies associate this haplogroup with the spread of farming from the Fertile Crescent to Europe, the spread of mobile pastoralism in the desert regions of the Arabian Peninsula, the history of the Jews, and the spread of Islam. Here, we study past human male demography in West Asia with 172 high-coverage whole Y chromosome sequences and 889 genotyped samples of haplogroup J1-M267. We show that this haplogroup evolved ~ 20,000 years ago somewhere in northwestern Iran, the Caucasus, the Armenian Highland, and northern Mesopotamia. The major branch-J1a1a1-P58-evolved during the early Holocene ~ 9500 years ago somewhere in the Arabian Peninsula, the Levant, and southern Mesopotamia. Haplogroup J1-M267 expanded during the Chalcolithic, the Bronze Age, and the Iron Age. Most probably, the spread of Afro-Asiatic languages, the spread of mobile pastoralism in the arid zones, or both of these events together explain the distribution of haplogroup J1-M267 we see today in the southern regions of West Asia.
The phylogenetic relationships of numerous branches within the core Y-chromosome haplogroup R-M207 support a West Asian origin of haplogroup R1b, its initial differentiation there followed by a rapid ...spread of one of its sub-clades carrying the M269 mutation to Europe. Here, we present phylogeographically resolved data for 2043 M269-derived Y-chromosomes from 118 West Asian and European populations assessed for the M412 SNP that largely separates the majority of Central and West European R1b lineages from those observed in Eastern Europe, the Circum-Uralic region, the Near East, the Caucasus and Pakistan. Within the M412 dichotomy, the major S116 sub-clade shows a frequency peak in the upper Danube basin and Paris area with declining frequency toward Italy, Iberia, Southern France and British Isles. Although this frequency pattern closely approximates the spread of the Linearbandkeramik (LBK), Neolithic culture, an advent leading to a number of pre-historic cultural developments during the past ≤10 thousand years, more complex pre-Neolithic scenarios remain possible for the L23(xM412) components in Southeast Europe and elsewhere.
The link between gut microbiota and host immunity motivated numerous studies of the gut microbiome in tuberculosis (TB) patients. However, these studies did not explore the metabolic capacity of the ...gut community, which is a key axis of impact on the host's immunity.
We used deep sequencing of fecal samples from 23 treatment-naive TB patients and 48 healthy donors to reconstruct the gut microbiome's metabolic capacity and strain/species-level content.
We show that the systematic depletion of the commensal flora of the large intestine,
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explains the strong taxonomic divergence of the gut community in TB patients. The cumulative expansion of diverse disease-associated pathobionts in patients reached 1/4 of the total gut microbiota, suggesting a heavy toll on host immunity along with MTB infection. Reconstruction of metabolic pathways showed that the microbial community in patients shifted toward rapid growth using glycolysis and excess fermentation to produce acetate and lactate. Higher glucose availability in the intestine likely drives fermentation to lactate and growth, causing acidosis and endotoxemia.
Excessive fermentation and lactic acidosis likely characterize TB patients' disturbed gut microbiomes. Since lactic acidosis strongly suppresses the normal gut flora, directly interferes with macrophage function, and is linked to mortality in TB patients, our findings highlight gut lactate acidosis as a novel research focus. If confirmed, gut acidosis may be a novel potential host-directed treatment target to augment traditional TB treatment.
Haplotype-based methods are a cost-effective alternative to characterize unobserved rare variants and map disease-associated alleles. Moreover, they can be used to reconstruct recent population ...history, which shaped distribution of rare variants and thus can be used to guide gene mapping studies. In this study, we analysed Illumina 650 k genotyped dataset on three underrepresented populations from Eastern Europe, where ancestors of Russians came into contact with two indigenous ethnic groups, Bashkirs and Tatars. Using the IBD mapping approach, we identified two rare IBD haplotypes strongly enriched in asthma patients of distinct ethnic background. We reconstructed recent population history using haplotype-based methods to reconcile this contradictory finding. Our ChromoPainter analysis showed that these haplotypes each descend from a single ancestor coming from one of the ethnic groups studied. Next, we used DoRIS approach and showed that source populations for patients exchanged recent (<60 generations) asymmetric gene flow, which supported the ChromoPainter-based scenario that patients share haplotypes through inter-ethnic admixture. Finally, we show that these IBD haplotypes overlap with asthma-associated genomic regions ascertained in European population. This finding is consistent with the fact that the two donor populations for the rare IBD haplotypes: Russians and Tatars have European ancestry.
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•Over 22% of patients with tuberculosis in Russia have multidrug-resistant strains.•44% of MDR-TB patients fail treatment.•Only 67% of DSTB patients reach treatment success.•Most of ...the MDR isolates were resistant to all first-line drugs.•High rate of drug resistance in new patients implies transmission in the general population.
Russia, together with other former Soviet Union countries, is characterized by one of the highest burdens of drug-resistant tuberculosis. Published data on the drug-resistant tuberculosis for these countries are limited, and it is not clear whether current treatment regimens remain effective against constantly evolving drug-resistant strains.
The aim of the study was to evaluate treatment efficacy of patients with multidrug-resistant (MDR), extensively drug-resistant (XDR) and drug-susceptible (DSTB) tuberculosis in the most populous region of Russia (Bashkortostan) that borders with Central Asia.
A retrospective cohort study was performed on 436 patients with pulmonary tuberculosis who were enrolled between January 1, 2016, and February 28, 2018, and received treatment according to WHO recommendations. Altogether, 369 patients completed the full course of chemotherapy. Clinical characteristics and treatment outcomes of DSTB, MDR, and XDR-TB patients were analyzed.
Of 436 patients, 169 (39%) had XDR-TB, 94 (22%) had MDR-TB and 173 (40%) had DSTB. Half of the MDR-TB patients (44%) and 82% of XDR-TB patients failed treatment. Patients with DSTB had unexpectedly poor treatment efficacy: only 67% had treatment success. We found that most of the MDR isolates from our patients were resistant to all first-line drugs, and a majority of the XDR isolates were resistant to more than 6–7 anti-TB drugs. While this can explain poor treatment efficacy in drug-resistant cases, causes of poor treatment efficacy in DSTB patients remain unclear. Finally, a considerable fraction (46%) of newly diagnosed patients had MDR-TB (27%) and XDR-TB (19%), suggesting that drug-resistant Mtb is being transmitted in the general population. To our best knowledge, this study is the first one to report XDR-TB prevalence in Russia in recent years (2016–2018).
MDR and XDR-TB became more common in recent years and treatment efficacy is declining at the face of more extensive drug resistance. There is evidence for the transmission of resistant strains in the general population, which calls for urgent changes not only in clinical practice but also in measures to prevent spread in the general population.
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