Biology subjects

Belokopytova, P.

Publications and source records attributed to Belokopytova, P..

6 recordsLinked to original sources

bioRxiv2025

Zooming into rearranged genome: applying pipeline of cytological, genomic, and transcriptomic methods for structural variant interpretation

Recent advances in genomic technologies have greatly enhanced our understanding of genotype-phenotype relationships and improved diagnostic of genetic diseases. However, the dissection of complex structural variants remains challenging due to the limitations of current methods in resolving their breakpoint and interpreting phenotypes involving multiple disrupted genes. In this study, we demonstrate how an integrative approach--combining cytological, genomic, and transcriptomic methods--enables the detection, structural and functional characterization of a complex structural variants affecting the MBD5, USP34, and XPO1 genes. Our findings underscore the utility of the Exo-C, a modified chromosome conformation capture technique, in resolving complex rearrangements. We also report, for the first time, a composite neurodevelopmental phenotype resulting from the combined effects of MBD5-associated intellectual disability and 2p15p16.1 microdeletion syndromes.

genomics↗

bioRxiv2024

A novel approach for simultaneous detection of structural and single-nucleotide variants based on a combination of chromosome conformation capture and exome sequencing

Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type--whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs). We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy. Through several case studies, we demonstrate how Exo-Cs multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders.

genomics↗

bioRxiv2023

Charm is a flexible pipeline to simulate chromosomal rearrangements on Hi-C-like data.

Identifying structural variants (SVs) remains a pivotal challenge within genomic studies. The recent advent of chromosome conformation capture (3C) techniques has emerged as a promising avenue for the accurate identification of SVs. However, development and validation of computational methods leveraging 3C data necessitate comprehensive datasets of well-characterized chromosomal rearrangements, which are presently lacking. In this study, we introduce Charm (https://zenodo.org/doi/10.5281/zenodo.10653353): a robust computational framework tailored for Hi-C data simulation. Our findings demonstrate Charms efficacy in benchmarking both novel and established tools for SV detection. Additionally, we furnish an extensive dataset of simulated Hi-C maps, paving the way for subsequent benchmarking endeavors.

bioinformatics↗

bioRxiv2022

TAD border deletion at the Kit locus causes tissue-specific ectopic activation of a neighboring gene

Topologically associated domains (TADs) restrict promoter-enhancer interactions, thereby maintaining the spatiotemporal pattern of gene activity. However, rearrangements of the TADs boundaries do not always lead to significant changes in the activity pattern. Here, we investigated the consequences of the TAD boundaries deletion on the expression of developmentally important genes encoding tyrosine kinase receptors: Kit, Kdr, Pdgfra. We used genome editing in mice to delete the TADs boundaries at the Kit locus and characterized chromatin folding and gene expression in pure cultures of fibroblasts, mast cells, and melanocytes. We found that although Kit is highly active in both mast cells and melanocytes, deletion of the TAD boundary between the Kit and Kdr genes results in ectopic activation only in melanocytes. Thus, the epigenetic landscape, namely the mutual arrangement of enhancers and actively transcribing genes, is important for predicting the consequences of the TAD boundaries removal. We also found that mice without a TAD border between the Kit and Kdr genes have a phenotypic manifestation of the mutation -- a lighter coloration. Thus, the data obtained shed light on the principles of interaction between the 3D chromatin organization and epigenetic marks in the regulation of gene activity.

genetics↗

bioRxiv2020

Anopheles mosquitoes revealed new principles of 3D genome organization in insects

Chromosomes are hierarchically folded within cell nuclei into territories, domains and subdomains, but the functional importance and evolutionary dynamics of these hierarchies are poorly defined. Here, we comprehensively profiled genome organizations of five Anopheles mosquito species and showed how different levels of chromatin architecture influence contacts between genomic loci. Patterns observed on Hi-C maps are associated with known cytological structures, epigenetic profiles, and gene expression levels. At the level of individual loci, we identified specific, extremely long-ranged looping interactions, conserved for ~100 million years. We showed that the mechanisms underlying these looping contacts differ from previously described Polycomb-dependent interactions and clustering of active chromatin.

genomics↗

bioRxiv2019

Quantitative prediction of enhancer-promoter interactions

Recent experimental and computational efforts provided large datasets describing 3-dimensional organization of mouse and human genomes and showed interconnection between expression profile, epigenetic status and spatial interactions of loci. These interconnections were utilized to infer spatial organization of chromatin, including enhancer-promoter contacts, from 1-dimensional epigenetic marks. Here we showed that predictive power of some of these algorithms is overestimated due to peculiar properties of biological data. We proposed an alternative approach, which gives high-quality predictions of chromatin interactions using only information about gene expression and CTCF-binding. Using multiple metrics, we confirmed that our algorithm could efficiently predict 3-dimensional architecture of normal and rearranged genomes.

genomics↗