Biology subjects

Pankratov, V.

Publications and source records attributed to Pankratov, V..

13 recordsLinked to original sources

bioRxiv2026

Massively parallel characterization reveals context-dependent and non-additive regulatory effects of closely spaced variant pairs

Precise control of gene expression relies in part on cis-regulatory elements (CREs), including enhancers. Genetic variation within enhancers can alter their regulatory activity and contribute to variation in gene expression, yet the effects of multiple nearby variants within the same enhancer remain poorly understood. To address this, we designed a massively parallel reporter assay (MPRA) to test the regulatory effect of 7,285 pairs of close-proximity single-nucleotide variants (SNVs) selected from blood-specific and broadly active enhancers. To enrich for functionality, we required at least one variant in each pair to be annotated as an eQTL in eQTLGen dataset. We measured the regulatory activity of all four haplotypes in K562 leukemia cells, where 57% of tested variant pairs had at least one derived haplotype that differed significantly in activity from the ancestral haplotype. The effects of individual variants frequently depended on the allelic background provided by the neighboring variant, with some variants showing opposite effects in different allelic backgrounds. Among a smaller, high-confidence subset selected for analysis of additivity, 59% (105/178) of variant pairs showed non-additive effects, and non-additive pairs were located closer together than additive pairs. Among pairs in which both single-derived haplotypes increased activity, the double-derived haplotype generally showed a smaller effect than expected under additivity. Together, our results demonstrate that nearby variants within the same enhancer can jointly shape regulatory activity and highlight the importance of considering local allelic context when interpreting the functional effects of regulatory variation.

genomics↗

bioRxiv2026

A Curated Genome-Scale Nucleotide Diversity Panel of Non-Human Primates

BackgroundPrimates constitute one of the most phylogenetically and ecologically diverse Eutherian mammalian orders, with a central role in advancing our knowledge of human evolution, speciation processes and conservation biology. While thousands of whole-genome sequences have been generated across a multitude of primate taxa, discrepancies in data processing - particularly the lack of ploidy-aware variant calling in sex-linked regions - have limited the utility of existing datasets for large-scale comparative analyses. ResultsHere, we utilized publicly available short-read sequencing data of non-human primates, recently published primate genome assemblies and a ploidy-aware variant calling procedure to generate a genome-scale nucleotide diversity panel comprising 3,240 individuals from 269 species and 71 genera. To further facilitate cross-species comparisons, we generated a multiple-genome alignment of primate assemblies used for variant calling. ConclusionThis curated resource of non-human primate diversity provides a foundation for future research in primate evolutionary biology, speciation, and sex chromosome evolution (https://pure.au.dk/portal/en/datasets/primate-diversity-panel/).

genomics↗

bioRxiv2026

Sex-specific associations between education-related genetic factors and fertility extend beyond educational attainment

Educational attainment (EA) is strongly associated with fertility, yet the mechanisms underlying this relationship remain poorly understood. Using data from ~40,000 women and ~10,000 men in the Estonian Biobank, we examine sex-specific associations between EA polygenic scores (EA PGS) and completed fertility. The EA PGS captures an individual's genetic predisposition to completing higher levels of education, and can also be constructed separately for cognitive and non-cognitive EA components. We find that EA PGS is negatively associated with fertility among women, with a significantly stronger association for the non-cognitive than the cognitive EA polygenic score. The association of EA PGS with fertility is only partly explained by EA and is moderated by EA and reproductive timing, changing sign across age-at-first-pregnancy strata. Within-family estimates are not attenuated relative to population estimates, consistent with a predominant role of direct genetic effects. Among men, associations between EA PGS and fertility are non-significant or slightly positive. Overall, education-related genetic variation is associated with fertility through pathways largely independent of EA, operating through sex-specific and timing-dependent mechanisms. These results contribute to our understanding of the micro-level mechanisms shaping macro-level demographic change.

genetics↗

bioRxiv2026

Comparison of the Distribution of Fitness Effects Across Primates

The distribution of fitness effects (DFE) of mutations is a key determinant of both the efficacy of natural selection and the genetic load of populations. It also provides an indirect summary of the underlying fitness landscape, so the extent to which the DFE is conserved across species is informative about the invariance of those landscapes. Here, we infer the DFE of amino-acid-changing mutations in 38 catarrhine subspecies using site-frequency spectrum (SFS)-based methods. We find that effective population size (Ne) is the dominant axis of cross-species variation in the population-scaled DFE for deleterious mutations, with the apparent clade-level clustering of estimates explained mainly by shared Ne rather than by clade-specific effects. A quantile-based test further shows that the underlying unscaled DFE does not vary significantly across species, so differences are consistent with Ne-rescaling of a single conserved DFE. Consistent with this, the deleterious (non-adaptive) substitution rate {omega}na declines significantly with Ne, reflecting more efficient purging of slightly deleterious mutations in larger populations. Turning to adaptive substitution, we find weaker, suggestive evidence that the adaptive rate {omega}a increases with Ne. These conclusions are robust to the choice of DFE parametrization, phylogenetic regression framework, the effect of GC-biased gene conversion, and ancestral misidentification. We also extend the DFE estimation procedure to relax the assumption of additive fitness effects, finding that dominance is only weakly identifiable from the SFS but has minimal impact on comparative DFE inference.

evolutionary biology↗

bioRxiv2026

Genetic influences on educational outcomes during and after the Soviet era: Revisiting evidence from Estonia

The origins of individual differences in socioeconomic outcomes, including educational attainment and occupational status, reflect a combination of genetic and environmental factors whose relative contributions may differ across historical contexts. Previous research suggested a doubling of the relative role of genetics in explaining variation in these traits in independent Estonia compared with the Soviet era. Using the Estonian Biobank, now tenfold larger than at the time of the original study, we aimed to replicate and extend these findings. We found converging evidence that the relative contribution of genetic factors to educational attainment, but not to occupational status, was higher in the post-Soviet era, although the differences were smaller than previously reported and varied across analytical approaches. However, analyses using narrower birth cohorts revealed a more complex pattern, with the relative genetic contribution to educational attainment decreasing gradually across successive cohorts. Thus, while the Soviet-to-post-Soviet transition was associated with an increase in the relative role of genetic factors in explaining individual differences in educational attainment, it represents only one component of the broader historical changes that have shaped genetic associations with educational attainment in Estonia over the last century.

genetics↗

bioRxiv2024

Denisovan admixture facilitated environmental adaptation in Papua New Guinean populations

Neandertals and Denisovans, having inhabited distinct regions in Eurasia and possibly Oceania for over 200,000 years, experienced ample time to adapt to diverse environmental challenges these regions presented. Among present-day human populations, Papua New Guineans (PNG) stand out as one of the few carrying substantial amounts of both Neandertal and Denisovan DNA, a result of past admixture events with these archaic human groups. This study investigates the distribution of introgressed Denisovan and Neandertal DNA within two distinct PNG populations, residing in the highlands of Mt Wilhelm and the lowlands of Daru Island. These locations exhibit unique environmental features, some of which may parallel the challenges that archaic humans once confronted and adapted to. Our results show that Denisovan-like haplotypes exhibit increased levels of population differentiation between PNG highlanders and lowlanders. The highly differentiated haplotypes, more common among highlanders, reside in genomic areas linked to brain development genes. Conversely, those more frequent in lowlanders overlap with genes enriched in immune response processes. Furthermore, Denisovan-like haplotypes displayed pronounced signatures of diversification within the major histocompatibility complex. Our findings suggest that Denisovan DNA has provided a valuable source of genetic variation to PNG genomes that facilitated adaptive responses to environmental challenges.

genomics↗

bioRxiv2023

Assessing the impact of 20th century internal migrations on the genetic structure of Estonia

There is emerging evidence that migration behaviour can be selective with respect to individuals genotypes. As a result, it can generate genotype-environment correlations at migration-associated loci that cannot be corrected by standard methods used in genetic association studies. Here, we explore this phenomenon by looking into the dynamics of the spatial distribution of polygenic scores (PGSs) in the Estonian Biobank. We show that contemporary migrations intensify inter-regional differences in PGSs for many traits, with the effect of educational attainment (EA) PGS being the strongest and, to a large extent, explaining inter-regional differences in other PGSs. This differentiation is mainly driven by the migration of individuals with relatively high PGS for EA to the two largest cities from the rest of the country. Importantly, we replicate this pattern within families: individuals migrating to the major cities have, on average, higher PGS for EA relative to their siblings residing in other regions of Estonia. This trend is observed for the period starting from the mid-20th century to the present, despite substantial changes in Estonian society during this period. Thus, we show that there is increasing genetic differentiation at trait-associated loci between most urbanized regions of Estonia versus the rest of the country, leading to genotype-environment correlations that cannot be fully corrected using standard approaches. We also provide evidence for direct genetic effects on migration behaviour based on sibling analysis and discuss potential links between migration and EA.

genetics↗

bioRxiv2023

Ancestral genetic components are consistently associated with the complex trait landscape in European biobanks

The genetic structure in Europe was mostly shaped by admixture between the Western Hunter-Gatherer, Anatolian Neolithic and Steppes Yamnaya ancestral components. Such structure is regarded as a confounder in GWAS and follow-up studies, and gold-standard methods exist to correct for it. However, it is still poorly understood to which extent these ancestral components contribute to complex trait variation in present-day Europe. In this work we harness the UK Biobank to address this question. By extensive demographic simulations and incorporating previous results obtained using the Estonian Biobank, we carefully evaluate the significance and scope of our findings. Heart rate, platelet count, monocyte percentage and many other traits show stratification similar to height and pigmentation traits, likely targets of selection and divergence across ancestral groups. The consistency of our results across biobanks indicates that these ancestry-specific genetic predispositions act as a source of variability and as potential confounders in Europe as a whole.

genomics↗

bioRxiv2022

Positive selection in the genomes of two Papua New Guinean populations at distinct altitude levels

Highlanders and lowlanders of Papua New Guinea (PNG) have faced distinct environmental conditions. These environmental differences lead to specific stress on PNG highlanders and lowlanders, such as hypoxia and environment-specific pathogen exposure, respectively. We hypothesise that these constraints induced specific selective pressures that shaped the genomes of both populations. In this study, we explored signatures of selection in newly sequenced whole genomes of 54 PNG highlanders and 74 PNG lowlanders. Based on multiple methods to detect selection, we investigated the 21 and 23 genomic top candidate regions for positive selection in PNG highlanders and PNG lowlanders, respectively. To identify the most likely candidate SNP driving selection in each of these regions, we computationally reconstructed allele frequency trajectories of variants in each of these regions and chose the SNP with the highest likelihood of being under selection with CLUES. We show that regions with signatures of positive selection in PNG highlanders genomes encompass genes associated with the hypoxia-inducible factors pathway, brain development, blood composition, and immunity, while selected genomic regions in PNG lowlanders contain genes related to immunity and blood composition. We found that several candidate driver SNPs are associated with haematological phenotypes in the UK biobank. Moreover, using phenotypes measured from the sequenced Papuans, we found that two candidate SNPs are significantly associated with altered heart rates in PNG highlanders and lowlanders. Furthermore, we found that 16 of the 44 selection candidate regions harboured archaic introgression. In four of these regions, the selection signal might be driven by the introgressed archaic haplotypes, suggesting a significant role of archaic admixture in local adaptation in PNG populations.

evolutionary biology↗

bioRxiv2021

Prioritising Autoimmunity Risk Variants for Functional Analyses by Fine-Mapping Mutations Under Natural Selection

Pathogens imposed selective pressure on humans and shaped genetic variation in immunity genes. This can also be true for a fraction of causal variants implicated in chronic inflammatory disorders. Hence, locating adaptive mutations among candidate variants for these disorders can be a promising way to prioritize and decipher their functional response to microbial stimuli and contribution to pathogenesis. This idea has been discussed for decades, but challenges in locating adaptive SNPs hindered its application in practice. Our study addresses this issue and shows that a fraction of candidate variants for inflammatory conditions evolved under moderate and weak selection regimes (sweeps), and such variants are mappable. Using a novel powerful local-tree-based methodology, we show that 204 out of 593 risk loci for 21 autoimmune disorders contain at least one candidate SNP with strong evidence of selection. More importantly, in 28% of cases, these candidates for causal variants colocalize with SNPs under natural selection that we fine-mapped in this study. Causal SNPs under selection represent promising targets for functional experiments. Such experiments will help decipher molecular events triggered by infectious agents, a likely early event in autoimmunity. Finally, we show that a large fraction (60%) of candidate variants are either hitchhikers or linked with the selected mutation. Our findings, thus, support both hitchhiking and natural selection models, with the latter having important practical implications in medicine.

genetics↗

bioRxiv2021

Long-range regulatory effects of Neandertal DNA in modern humans

The admixture between modern humans and Neandertals has resulted in [~]2% of the genomes of present-day non-Africans being composed of Neandertal DNA. Association studies have shown that introgressed DNA significantly influences phenotypic variation in people today and that several of the phenotype-associated archaic variants had links to expression regulation as well. In general, introgressed DNA has been demonstrated to significantly affect the transcriptomic landscape in people today. However, little is known about how much of that 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 being of Neandertal ancestry in GTEx and predicted long-range Neandertal DNA-induced regulatory effects by screening for the predicted target genes of those TFs. We show that genes in regions devoid of Neandertal DNA are enriched among the target genes of some of these TFs. Furthermore, archaic cis-eQTLs for these TFs included multiple candidates for local adaptation and have associations with various immune traits, schizophrenia, blood cell type composition and anthropometric measures. Finally, we show that our results can be replicated in empirical trans-eQTLs with Neandertal variants. Our results suggest that the regulatory reach of Neandertal DNA goes beyond the 40% of genomic sequence that it still covers in present-day non-Africans and that via this mechanism Neandertal DNA additionally influences the phenotypic variation in people today.

genomics↗

bioRxiv2021

Ancestral contributions to contemporary European complex traits

The contemporary European genetic makeup formed in the last 8000 years as the combination of three main genetic components: the local Western Hunter-Gatherers, the incoming Neolithic Farmers from Anatolia and the Bronze Age component from the Pontic Steppes. When meeting into the post-Neolithic European environment, the genetic variants accumulated during their three distinct evolutionary histories mixed and came into contact with new environmental challenges. Here we investigate how this genetic legacy reflects on the complex trait landscape of contemporary European populations, using the Estonian Biobank as a case study. For the first time we directly connect the phenotypic information available from biobank samples with the genetic similarity to these ancestral groups, both at a genome-wide level and focusing on genomic regions associated with each of the 27 complex traits we investigated. We also found SNPs connected to pigmentation, cholesterol, sleep, diastolic blood pressure, and body mass index (BMI) to show signals of selection following the post Neolithic admixture events. We recapitulate existing knowledge about pigmentation traits, corroborate the connection between Steppe ancestry and height and highlight novel associations. Among others, we report the contribution of Hunter Gatherer ancestry towards high BMI and low blood cholesterol levels. Our results show that the ancient components that form the contemporary European genome were differentiated enough to contribute ancestry-specific signatures to the phenotypic variability displayed by contemporary individuals in at least 11 out of 27 of the complex traits investigated here.

genomics↗

bioRxiv2020

Revisiting the Out of Africa event with a novel Deep Learning approach

Anatomically modern humans evolved around 300 thousand years ago in Africa1. Modern humans started to appear in the fossil record outside of Africa about 100 thousand years ago though other hominins existed throughout Eurasia much earlier2-4. Recently, several researchers argued in favour of a single out of Africa event for modern humans based on whole-genome sequences analyses5-7. However, the single out of Africa model is in contrast with some of the findings from fossil records, which supports two out of Africa8,9, and uniparental data, which proposes back to Africa movement10,11. Here, we used a novel deep learning approach coupled with Approximate Bayesian Computation and Sequential Monte Carlo to revisit these hypotheses from the whole genome sequence perspective. Our results support the back to Africa model over other alternatives. We estimated that there are two successive splits between Africa and out of African populations happening around 60-80 thousand years ago and separated by 12-13 thousand years. One of the populations resulting from the more recent split has to a large extent replaced the older West African population while the other one has founded the out of Africa populations.

genetics↗