Mechanisms of NLRP3 activation and inhibition elucidated by functional analysis of disease-associated variants

Nature Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

The NLRP3 inflammasome is a multiprotein complex that mediates caspase-1 activation and the release of proinflammatory cytokines, including interleukin (IL)-1β IL-18. Gain-of-function variants in gene encoding (also called cryopyrin) lead to constitutive excessive IL-1β production cryopyrin-associated periodic syndromes (CAPS). Here we present functional screening automated analysis 534 from international INFEVERS registry ClinVar database. This resource captures effect on ASC speck formation spontaneously, at low temperature, after stimulation with specific inhibitor MCC950. Most notably, our facilitated updated classification INFEVERS. Structural suggested multiple mechanisms by which CAPS activate NLRP3, enhanced ATP binding, stabilizing active conformation, destabilizing inactive promoting oligomerization pyrin domain. Furthermore, identified pathogenic can hypersensitize response nigericin cold temperature exposure. We also found most CAPS-related be inhibited MCC950; however, changes proline affecting helices near binding site are resistant MCC950, as domain, likely trigger directly domain ASC. Our findings could help stratify population for clinical trials methodologies implemented molecules different mechanism laboratories worldwide interested adding new functionally validated resource. Overall, study provides improved diagnosis patients CAPS, mechanistic insight into stratification future application targeted therapeutics.

Language: Английский

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Genome modeling and design across all domains of life with Evo 2

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Abstract All of life encodes information with DNA. While tools for sequencing, synthesis, and editing genomic code have transformed biological research, intelligently composing new systems would also require a deep understanding the immense complexity encoded by genomes. We introduce Evo 2, foundation model trained on 9.3 trillion DNA base pairs from highly curated atlas spanning all domains life. train 2 7B 40B parameters to an unprecedented 1 million token context window single-nucleotide resolution. learns sequence alone accurately predict functional impacts genetic variation—from noncoding pathogenic mutations clinically significant BRCA1 variants—without task-specific finetuning. Applying mechanistic interpretability analyses, we reveal that autonomously breadth features, including exon–intron boundaries, transcription factor binding sites, protein structural elements, prophage regions. Beyond its predictive capabilities, generates mitochondrial, prokaryotic, eukaryotic sequences at genome scale greater naturalness coherence than previous methods. Guiding via inference-time search enables controllable generation epigenomic structure, which demonstrate first scaling results in biology. make fully open, parameters, training code, inference OpenGenome2 dataset, accelerate exploration design complexity.

Language: Английский

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Guidelines for releasing a variant effect predictor

Genome biology, Journal Year: 2025, Volume and Issue: 26(1)

Published: April 15, 2025

Abstract Computational methods for assessing the likely impacts of mutations, known as variant effect predictors (VEPs), are widely used in assessment and interpretation human genetic variation, well other applications like protein engineering. Many different VEPs have been released, there is tremendous variability their underlying algorithms, outputs, ways which methodologies predictions shared. This leads to considerable difficulties users trying navigate selection application VEPs. Here, address these issues, we provide guidelines recommendations release novel

Language: Английский

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Saturation genome editing-based clinical classification of BRCA2 variants

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

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Functional evaluation and clinical classification of BRCA2 variants

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Germline BRCA2 loss-of function variants, which can be identified through clinical genetic testing, predispose to several cancers1–5. However, variants of uncertain significance limit the utility test results. Thus, there is a need for functional characterization and classification all facilitate management individuals with these variants. Here we analysed possible single-nucleotide from exons 15 26 that encode DNA-binding domain hotspot pathogenic missense To enable this, used saturation genome editing CRISPR–Cas9-based knock-in endogenous targeting human haploid HAP1 cells6. The assay was calibrated relative nonsense silent validated using benign standards ClinVar results homology-directed repair assay7. Variants (6,959 out 6,960 evaluated) were assigned seven categories pathogenicity based on VarCall Bayesian model8. Single-nucleotide loss-of-function associated increased risks breast cancer ovarian cancer. integrated into models ClinGen, American College Medical Genetics Genomics, Association Molecular Pathology9 Using this approach, 91% classified as or likely benign. These improve variant. Results comprehensive evaluation particularly significance, provide useful resource who carry such

Language: Английский

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