Sequencing and characterizing short tandem repeats in the human genome

Nature Reviews Genetics, Год журнала: 2024, Номер 25(7), С. 460 - 475

Опубликована: Фев. 16, 2024

Язык: Английский

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Chromatin accessibility in the Drosophila embryo is determined by transcription factor pioneering and enhancer activation

Developmental Cell, Год журнала: 2023, Номер 58(19), С. 1898 - 1916.e9

Опубликована: Авг. 8, 2023

Chromatin accessibility is integral to the process by which transcription factors (TFs) read out cis-regulatory DNA sequences, but it difficult differentiate between TFs that drive and those do not. Deep learning models learn complex sequence rules provide an unprecedented opportunity dissect this problem. Using zygotic genome activation in Drosophila as a model, we analyzed high-resolution TF binding chromatin data with interpretable deep performed genetic validation experiments. We identify hierarchical relationship pioneer Zelda involved axis patterning. consistently pioneers proportional motif affinity, whereas patterning augment contexts where they mediate enhancer activation. conclude occurs two tiers: one through pioneering, makes enhancers accessible not necessarily active, second when correct combination of leads

Язык: Английский

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Epigenomic insights into common human disease pathology

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Апрель 11, 2024

Abstract The epigenome—the chemical modifications and chromatin-related packaging of the genome—enables same genetic template to be activated or repressed in different cellular settings. This multi-layered mechanism facilitates cell-type specific function by setting local sequence 3D interactive activity level. Gene transcription is further modulated through interplay with factors co-regulators. human body requires this epigenomic apparatus precisely installed throughout development then adequately maintained during lifespan. causal role epigenome pathology, beyond imprinting disorders tumour suppressor genes, was brought into spotlight large-scale sequencing projects identifying that mutations machinery genes could critical drivers both cancer developmental disorders. Abrogation providing new molecular insights pathogenesis. However, deciphering full breadth implications these changes remains challenging. Knowledge accruing regarding disease mechanisms clinical biomarkers, pathogenically relevant surrogate tissue analyses, respectively. Advances include consortia generated reference epigenomes, high-throughput DNA methylome association studies, as well ageing-related diseases from biological ‘clocks’ constructed machine learning algorithms. Also, 3rd-generation beginning disentangle complexity modification haplotypes. Cell-free methylation a biomarker has clear utility potential assess organ damage across many Finally, understanding aetiology brings it opportunity for exact therapeutic alteration CRISPR-activation inhibition.

Язык: Английский

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In silico analysis of mitochondrial DNA genes: implication for conservation of Tor putitora (Hamilton, 1822)

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 2, 2025

Tor putitora is an endangered cyprinid fish constrained to cold water and also considered indicator of a healthy aquatic ecosystem. The present study aimed examine the haplotypic diversity, genetic variation population structure T. isolates using COI Cyt b gene sequences submitted in GenBank. Bioinformatic analysis was carried out 106 183 as well 2 reference genome sequences. Analysis reveals 18 85 haplotypes respectively. Mutation observed at 44 different sites 173 Haplotype 4 haplotype 37 were ancestral moderate diversity (0.630) low Nucleotide (0.00662) whereas has higher (0.804) (0.00582). Moreover, neutrality test such Tajima's D, Fu's Fs showed negative values both sequences, suggesting expansion attributed habitat destruction. So, comprehending variability within among crucial for conserving managing this species. Integration into conservation planning can enhance effectiveness breeding programs restoration efforts.

Язык: Английский

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The human intelligence evolved from proximal cis‐regulatory saltations

Quantitative Biology, Год журнала: 2025, Номер 13(2)

Опубликована: Янв. 3, 2025

Abstract The divergence rate between the alignable genomes of humans and chimpanzees is as little 1.23%. Their phenotypical difference was hypothesized to be accounted for by gene regulation. We construct cis ‐regulatory element frequency (CREF) matrix represent proximal regulatory sequences each species. Each CREF further decomposed into dual eigen‐modules. By comparing modules four existing hominid species, we examine their quantitative qualitative changes along evolution. identified two saltations: one 4th 5th, other 9th 10th eigen‐levels. cognition intelligence unique are thus found from saltations at molecular level. They include long‐term memory, cochlea/inner ear morphogenesis that enables development human language/music, social behavior allows us live together peacefully work collaboratively, visual/observational/associative learning. Moreover, exploratory crucial humans’ creativity, GABA‐B receptor activation protects our neurons, serotonin biosynthesis/signaling regulates happiness. observed a remarkable increase in number motifs present on Alu elements 4th/9th motif‐eigenvectors. can, large, using only profiles without any priori. Although gradual evolution might mode mutations protein sequences, regulation has both saltational modes, which could explained framework

Язык: Английский

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Mutations to transcription factor MAX allosterically increase DNA selectivity by altering folding and binding pathways

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 14, 2025

Understanding how proteins discriminate between preferred and non-preferred ligands ('selectivity') is essential for predicting biological function a central goal of protein engineering efforts, yet the biophysical mechanisms underpinning selectivity remain poorly understood. Towards this end, we study variants promiscuous transcription factor (TF) MAX (H. sapiens) alter DNA specificity selectivity, yielding >1700 Kds >500 rate constants in complex with multiple sequences. Twenty-two 240 assayed point mutations enhance none these occur at residues that contact nucleotides published structures. By applying thermodynamic kinetic models to results previous observations highly similar far more selective TF Pho4 (S. cerevisiae), find by altering partitioning or affinity within conformations different intrinsic providing mechanistic basis allosteric modulation ligand selectivity. These highlight importance conformational heterogeneity determining sequence can guide future efforts engineer proteins. In work, high-throughput microfluidic assays reveal substitutions folding-and-binding pathways shape landscapes human MAX.

Язык: Английский

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NanoMnT: an STR analysis tool for Oxford Nanopore sequencing data driven by a comprehensive analysis of error profile in STR regions

GigaScience, Год журнала: 2025, Номер 14

Опубликована: Янв. 1, 2025

Abstract Oxford Nanopore Technology (ONT) sequencing is a third-generation technology that enables cost-effective long-read sequencing, with broad applications in biological research. However, its high error rate low-complexity regions hampers short tandem repeat (STR)–related To address this, we generated comprehensive STR profile of ONT by analyzing publicly available datasets. We show the influenced not only length but also unit and flanking sequences regions. Interestingly, certain were associated higher accuracy, suggesting loci are more suitable for compared to other loci. While base quality scores substitution errors within lower than those correctly sequenced bases, such patterns observed indel errors. Furthermore, choosing most recent basecaller version using super accuracy model significantly improved accuracy. Finally, present NanoMnT, lightweight Python tool corrects data estimates allele sizes. NanoMnT leverages characteristics when estimating size exhibits superior results 1-bp- 2-bp existing tools. By integrating our findings, estimation Ax10 repeats from 55% 78% up 85% excluding unfavorable sequences. Using utility findings identifying microsatellite instability status cancer data. at https://github.com/18parkky/NanoMnT.

Язык: Английский

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EvoAug: improving generalization and interpretability of genomic deep neural networks with evolution-inspired data augmentations

Genome biology, Год журнала: 2023, Номер 24(1)

Опубликована: Май 4, 2023

Deep neural networks (DNNs) hold promise for functional genomics prediction, but their generalization capability may be limited by the amount of available data. To address this, we propose EvoAug, a suite evolution-inspired augmentations that enhance training genomic DNNs increasing genetic variation. Random transformation DNA sequences can potentially alter function in unknown ways, so employ fine-tuning procedure using original non-transformed data to preserve integrity. Our results demonstrate EvoAug substantially improves and interpretability established across prominent regulatory prediction tasks, offering robust solution DNNs.

Язык: Английский

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Transcription factor stoichiometry, motif affinity and syntax regulate single-cell chromatin dynamics during fibroblast reprogramming to pluripotency

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 4, 2023

Ectopic expression of

Язык: Английский

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Indels: computational methods, evolutionary dynamics, and biological applications

Molecular Biology and Evolution, Год журнала: 2024, Номер 41(9)

Опубликована: Авг. 22, 2024

Abstract Insertions and deletions constitute the second most important source of natural genomic variation. make up to 25% variants in humans are involved complex evolutionary processes including rearrangements, adaptation, speciation. Recent advances long-read sequencing technologies allow detailed inference insertions deletion variation species populations. Yet, despite their importance, studies have traditionally ignored or mishandled due a lack comprehensive methodologies statistical models dynamics. Here, we discuss methods for describing modeling over time. We provide practical advice tackling sequences illustrate our discussion with examples deletion-induced effects human other populations contribution processes. outline promising directions future developments that would researchers analyze large data sets incorporate inference.

Язык: Английский

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