Search bioRxiv⌕ Search

bioRxiv · 10.1101/2023.06.24.546344

Twenty novel nsSNPs may affect FLT3 gene leading to Acute Myeloid Leukemia (AML) using in silico analysis

Abstract

Background: Mutations within the FMS-like tyrosine kinase 3 (FLT3) gene represent one of the most common genetic alteration that disturb intracellular signaling networks with a key role in leukemia pathogenesis. laboratory studies considerable obstacle to identify functional SNPs in a specific gene. Thus, the "in silico" technique is possible now to carry out research investigations without the need for extensive lab work. Methodology: data retrieved from NCBI database and different algorithm used to analyse nsSNPs which they are: SIFT, Polyphen-2, Provean, SNAP2, P-Mut, I-Mutant, Project Hope, Raptor X, PolymiRTS and Gene MANIA. Result: Our study reveals twenty novel SNPs regarded to be the most damaging SNPs that affect structure and function of FLT3 gene using different bioinformatics algorithm. Conclusion: This study revealed 20 damaging SNPs considered to be novel nsSNP in FLT3 gene that leads to AML, by using different algorithms. Additionally, 69 functional classes were predicted in 12 SNPs in the 3UTR, among them, 31 alleles disrupted a conserved miRNA site and 37 derived alleles created a new site of miRNA. This might result in the de regulation of the gene function. These results could be valuable for molecular studying, diagnosis and treatment of AML patients.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Alsheikh, T., Ameer, T., NjmEldin, A., Omer, D., Agbash, A., Abdalmonem, Z., Suliman, H., Hamad, H., A. ayoub, S. E., A. Hassan, M.. 2023-06-26. Twenty novel nsSNPs may affect FLT3 gene leading to Acute Myeloid Leukemia (AML) using in silico analysis. https://doi.org/10.1101/2023.06.24.546344

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Targeted finetuning enables co-folding models to learn ligand-induced protein conformational states

Advances in protein structure prediction have enabled all-atom protein-ligand co-folding models that predict bound conformations directly from sequence and small-molecule structure. However, these models often fail to generalize to novel binding sites or alternative protein conformational states, limiting their utility for chemical biology and drug discovery. Here we show this limitation reflects training data bias rather than architectural constraints and can be overcome through targeted finetuning. Using ten previously unseen X-ray structures of Werner (WRN) helicase from a drug discovery program, we finetune Boltz-1 to learn both an allosteric binding site and a large conformational change locking the enzyme in an inactive state, while preserving accuracy on the ATP-bound state. The finetuned model generalizes to different chemical series and transfers the conformational logic across RecQ-family helicases in a binding-site sequence-dependent manner. This approach provides a blueprint for adapting foundation models as new structural and mechanistic data emerge, enabling co-folding networks to capture ligand-induced conformational switches and binding poses absent from their training data but central to biological regulation and therapeutic intervention.

bioinformatics↗

Benchmarking single-cell foundation models for aging biology

Single cell foundation models (scFMs) provide representations of cellular states, but their utility across biological questions in aging research remains unclear. We established a benchmark of cellular representations for aging research, evaluating ten general-purpose scFMs, three aging-specific models and conventional methods across five biological questions using more than 2.5 million single cell transcriptomes. Using frozen pretrained representations, Geneformer performed best among scFMs for chronological age prediction and age pseudotime concordance, although 2,000 highly variable genes achieved higher mean performance. Several scFMs captured positive molecular age shifts across three disease contexts, consistent with reported aging-associated changes. SCimilarity performed well for rare cellular state identification across out-of-distribution datasets, exceeding aging specific models and conventional baselines. At the gene level, scGPT showed the highest recovery of reference TF target interactions, including aging-related regulatory hubs. Overall, scFMs supported diverse aging analyses, but performance depended on the biological question, highlighting their utility for rare cellular state identification and regulatory analysis.

bioinformatics↗

CryoMV: Structure-Prior-Guided Modeling and Real-Particle Validation of Continuous Conformational Transitions in Cryo-EM

Continuous protein conformations are essential for understanding fundamental biological processes and supporting drug discovery. Although cryo-EM can resolve individual states at high resolution, recovering continuous heterogeneity from 2D particle images remains challenging. High noise, motion blur, and limited structural priors make it difficult to accurately generate and validate high-resolution continuous conformations using raw particle data. Here, we introduce cryoMV, a framework that integrates structure-prior-guided modeling with real-particle validation for continuous conformational transitions. CryoMV uses reference density maps to establish structural anchors and motion priors, models candidate transition paths between selected conformations, and transfers the learned representation to raw 2D cryo-EM particle images. Each candidate conformation is subsequently evaluated using the estimated particle poses and contrast transfer functions. Supported conformations are reconstructed through raw particle back-projection and assessed using canonical half-maps and Fourier shell correlation. On EMPIAR-10516 and EMPIAR-10345, cryoMV achieves excellent performance in terms of robustness, verifiability, and reconstruction resolution. By incorporating structure-prior modeling and evidence from the raw particles, cryoMV offers an explicit mechanism for assessing whether generated conformations are supported by experimental data and provides a practical approach to reducing model-induced artifacts in continuous cryo-EM heterogeneity analysis.

bioinformatics↗