Biology subjects

Kuznetsova, A.

Publications and source records attributed to Kuznetsova, A..

9 recordsLinked to original sources

bioRxiv2026

Estimation of splicing metrics for NMD-sensitive transcripts

Alternative splicing is commonly quantified using the Percent-Spliced-In (PSI) metric, which measures the relative abundances of alternatively spliced isoforms. However, some transcript isoforms are targeted by the nonsense-mediated decay (NMD) pathway, introducing a strong bias that leads to underestimation of their true splicing rates. To correct for this bias, we developed an analytical framework and a set of statistical models employing a linear fractional transformation depending on a single parameter capturing the degradation rate of NMD-sensitive transcripts relative to normal mRNA decay. Using Gaussian mixture models, we demonstrated a clear separation of splicing events into two classes, responders and non-responders, with the former exhibiting strong upregulation upon NMD inhibition and the latter showing little or no response. Moreover, non-responders displayed higher coding potential and stronger translation signals both upstream and downstream of the stop codon, which are characteristic of NMD escape through translational readthrough. We further showed that incorporation of event-specific relative decay rates improves the interpretation of differential splicing patterns for NMD-sensitive transcripts. In sum, our results provide a solid framework for unbiased estimation of splicing metrics in NMD-sensitive transcripts from short-read RNA-seq data, without requiring NMD inhibition experiments.

bioinformatics↗

bioRxiv2026

The population structure and genetic health of European wolves

Once nearly eradicated from Europe, grey wolves (Canis lupus) have recently undergone a remarkable demographic recovery, but their long-term survival remains precarious. By analyzing 1,001 genomes, we uncover a mosaic of distinct evolutionary lineages, not a single recovering population. Northern populations exhibit Asian wolf ancestry, while southern populations preserve ancient Holocene lineages, with dog introgression varying by region. Isolated wolves from the Scandinavian, Italian, and Iberian peninsulas harbored particularly high levels of inbreeding and fixed deleterious mutations. Signatures of genome erosion were widespread across Europe, with many populations falling well short of the minimum size recommended for long-term survival. Our study reveals the complex tapestry of wolf ancestry and variation across Europe, which calls for nuanced, regional conservation plans founded in genetic monitoring.

genomics↗

bioRxiv2025

A comparative study of genital lichen sclerosus transcriptomes

Genital lichen sclerosus (GLS) is a chronic inflammatory dermatosis that affects the genital skin. Despite different clinical manifestations, the pathogenesis of GLS in men and women is thought to be common and is attributed to a combination of autoimmune and genetic factors. In this study, we compared the transcriptomic profiles of penile (mGLS) and vulvar lichen sclerosus (VLS) with the objective to identify commonly deregulated genes. We observed a substantial heterogeneity of the transcriptomic signatures in mGLS samples which is driven by different compositions of immune infiltrates. In mGLS, gene expression signatures strongly indicate epidermis dysfunction and overexpression of epithelial inflammation marker Keratin 6 (KRT6) and chitinase CHIT1. No significant changes in the expression levels of known GLS markers such as VIM, CTNNB1, LGALS7 and ECM1 were detected, however, changes in the expression levels of genes associated with autoimmune diseases and genes upregulated in squamous cell carcinoma were observed, including TNF, CCNB1 and RUNX3. There was no enrichment in HCV-derived polyU/UC insertions that were reported previously. Instead, we have identified a long non-coding RNA DRAIC with a large coding potential that is commonly upregulated in mGLS and VLS. Together, our results represent a comprehensive catalog of shared transcriptomic signatures including novel biomarkers and potential therapeutic targets.

bioinformatics↗

bioRxiv2025

Novel examples of NMD escape through alternative intronic polyadenylation

The nonsense-mediated mRNA decay (NMD) surveillance system detects and selectively eliminates transcripts with premature stop codons. A stop codon is considered premature if it is followed by an exon-exon junction more than 50 nucleotides downstream. Pruning of the 3-untranslated region containing such junctions through alternative polyadenylation may provide a mechanism of NMD escape. Here, we systematically examine a subclass of poison exons that carry a premature stop codon for the presence of polyadenylation sites in the downstream intron. Using data from the GTEx consortium, we observed that poison exons are more often followed by an active polyadenylation site compared with cassette exons. We also identified tissue-specific switches between NMD-targeted and NMD-escape isoforms in several human genes, including the vaccinia-related kinase VRK3, nuclear transcription factor NFX1, Notch pathway regulator TM2D3, and RNA helicase DDX31. Blocking the cleavage and polyadenylation sites in these genes using antisense oligonucleotides in human cells led to a switch from NMD-escape to NMD-target isoform, accompanied by a decrease in gene expression levels. This study reveals that NMD escape via alternative polyadenylation is a widespread, yet currently overlooked post-transcriptional mechanism of gene expression regulation.

bioinformatics↗

bioRxiv2024

Experience in developing the human genome standard E701

The first Russian human genome standard E701 was developed through a collaborative research involving four laboratories: Pirogov Russian National Research Medical University, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov, National Research Center Kurchatov Institute, and National Medical Research Radiological Centre. Whole-genome sequencing of short reads on various platforms (MGI Tech, Illumina) and alignment to the reference human genome GRCh38.p14 were performed for the E701 sample. Subsequently, 3842877 high confidence genomic variants were identified, which can be used as a standard for calculating statistical quality metrics while analyzing sequencing data. Furthermore, 9096 biallelic variants were identified on the autosomes and the X chromosome, with a minor allele frequency exceeding 0.4. Additionally, mitochondrial DNA sequencing was performed with the breadth of coverage over 99.9% at 1000X.

genomics↗

bioRxiv2024

Comparative framework and adaptation of ACME HS approach to single cell isolation from fresh-frozen endocrine tissues

Current scRNA-seq studies of solid tissues mostly rely on enzymatic dissociation of fresh samples or the fallback on nuclei isolation from frozen or partially fixed samples. However, due to the complex tissue organization or cell fragility, it could be challenging to apply these approaches to the sensitive endocrine tissues. That is, dissociating intact cells from such problematic fresh-frozen samples routinely collected by biobanks remains challenging. In this study, we adapted the acetic-methanol dissociation method - ACME High Salt (ACME HS) to effectively isolate intact single cells from fresh-frozen endocrine tumor samples, including adrenal gland neoplasms, thyroid carcinomas, and pituitary neuroendocrine tumors. We compared the ability of enzymatic, ACME HS, and nuclear isolation methods to preserve the integrity of major cell types and gene expression across 41 tissue samples of different origins. We demonstrated that ACME HS simultaneously dissociates and fixes cells, thus preserving morphology and a high RNA integrity number in problematic cell types. This finding renders the ACME HS dissociation method a valuable alternative in scRNA-seq protocols for challenging tissues where obtaining live cell suspension is difficult or impossible.

genomics↗

bioRxiv2020

Local propagation dynamics of MEG interictal spikes: source reconstruction with traveling-wave priors

AO_SCPLOWBSTRACTC_SCPLOWEpilepsy is one of the most common neurological disorders, with about 30% of cases being drug-resistant and requiring surgical intervention. To localize the epileptogenic zone (EZ), the pathological area that has to be surgically removed, brain regions are inspected for the presence of spikes during the interictal periods. This procedure maps irritative zones where spikes are present, but it is still challenging to determine which of the irritative zones generate seizures. To localize the source of seizures more precisely, a large-scale approach could be applied where the causal relationship is assessed between the signals recorded in a finite number of irritative zones [27]. This method however, does not reveal the fine-grained spatiotemporal patterns of spikes, which could provide valuable information regarding EZ location and increase the likelihood of surgery success [33]. Here we present a framework to noninvasively investigate the fine patterns of interictal spikes present in magnetoencephalographic (MEG) data. We use a traveling wave model, previously employed in the analysis of cortical alpha oscillations [16], to regularize the MEG inverse problem and to determine the cortical paths of spike traveling waves. Our algorithm represents spike propagation patterns as a superposition of local waves traveling along radial paths stemming from a single origin. With the help of the positively constrained LASSO technique we scan over wave onset moment and propagation velocity parameters to determine their combination that yields the best fit to the MEG sensor data of each spike. We first used realistically simulated MEG data to validate the algorithm ability to successfully track interictal activity on a millimeter-millisecond scale. Next, we examined MEG data from three patients with drug-resistant epilepsy. Wave-like spike patterns with clear propagation dynamics were found in a fraction of spikes, whereas the other fraction could not be explained by the wave propagation model with a small number of propagation directions. Moreover, in agreement with the previous work [33], the spike waves with clear propagation dynamics exhibited spatial segregation and matched the clinical records on seizure onset zones (SOZs) available for two patients out of three.

neuroscience↗

bioRxiv2019

Modified covariance beamformer for solving MEG inverse problem in the environment with correlated sources

AO_SCPLOWBSTRACTC_SCPLOWMagnetoencephalography (MEG) is a neuroimaging method ideally suited for non-invasive studies of brain dynamics. MEGs spatial resolution critically depends on the approach used to solve the ill-posed inverse problem in order to transform sensor signals into cortical activation maps. Over recent years non-globally optimized solutions based on the use of adaptive beamformers (BF) gained popularity. When operating in the environment with a small number of uncorrelated sources the BFs perform optimally and yield spatial super-resolution. However, the BFs are known to fail when dealing with correlated sources acting like poorly tuned spatial filters with low signal-to-noise ratio (SNR) of the output timeseries and often meaningless cortical maps of power distribution. This fact poses a serious limitation on the broader use of this promising technique especially since fundamental mechanisms of brain functioning, its inherent symmetry and task-based experimental paradigms result into a great deal of correlation in the activity of cortical sources. To cope with this problem, we developed a novel beamformer approach that preserves high spatial resolution in the environments with correlated sources. At the core of our method is a projection operation applied to the vectorized sensor-space covariance matrix. This projection does not remove the activity of the correlated sources from the sensor-space covariance matrix but rather selectively handles their contributions to the covariance matrix and creates a sufficiently accurate approximation of an ideal data covariance that could hypothetically be observed should these sources be uncorrelated. Since the projection operation is reciprocal to the PSIICOS method developed by us earlier (Ossadtchi et al. (2018)) we refer to the family of algorithms presented here as ReciPSIICOS. We asses the performance of the novel approach using realistically simulated MEG data and show its superior performance in comparison to the well established MNE and classical BF approaches. We have also applied our approach to the MEG datasets from the two experiments involving two different auditory tasks. The analysis of experimental MEG datasets showed that beamformers from ReciPSIICOS family, but not MNE and the classical BF, discovered the expected bilateral focal sources in the primary auditory cortex and detected motor cortex activity associated with the audio-motor task. Moreover, ReciPSIICOS beamformers yielded cortical activity estimates with amplitude an order of magnitude higher than that obtained with the classical BF, which indicates the severeness of the signal cancellation problem when applying classical beamformers to MEG signals generated by synchronous sources.

neuroscience↗

bioRxiv2016

Localizing hidden regularities with known temporal structure in the EEG evoked response data

In this paper we describe a novel data driven spatial filtering technique that can be applied to the ERP analysis in order to find statistically significant hidden differential activations in the EEG data. The technique is based on the known morphological characteristics of the response. Underlying optimization problem is formulated as a generalized Rayleigh quotient maximization problem. We supply our tech-nique with a relevant randomization-based statistical test to assess the significance of the discovered phenomenon. Furthermore, we describe an application of the proposed method to the EEG data acquired in the study devoted to the analysis of the auditory neuroplasticity. We show how the mismatch negativity component, a tiny and short-lasting negative response that hallmarks the novel stimuli activating primary error-detection mechanisms, can be detected after filtration.

animal behavior and cognition↗