Nature Protocols, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 12, 2025
Language: Английский
Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 24(3), P. 161 - 177
Published: Nov. 7, 2022
Language: Английский
Citations
309
Nature Biotechnology, Journal Year: 2023, Volume and Issue: 42(6), P. 927 - 935
Published: Aug. 17, 2023
Abstract Understanding cellular responses to genetic perturbation is central numerous biomedical applications, from identifying interactions involved in cancer developing methods for regenerative medicine. However, the combinatorial explosion number of possible multigene perturbations severely limits experimental interrogation. Here, we present graph-enhanced gene activation and repression simulator (GEARS), a method that integrates deep learning with knowledge graph gene–gene relationships predict transcriptional both single using single-cell RNA-sequencing data perturbational screens. GEARS able outcomes perturbing combinations consisting genes were never experimentally perturbed. exhibited 40% higher precision than existing approaches predicting four distinct interaction subtypes screen identified strongest twice as well prior approaches. Overall, can phenotypically effects thus guide design experiments.
Language: Английский
Citations
109
Cell stem cell, Journal Year: 2023, Volume and Issue: 30(3), P. 312 - 332.e13
Published: Feb. 15, 2023
Human genome variation contributes to diversity in neurodevelopmental outcomes and vulnerabilities; recognizing the underlying molecular cellular mechanisms will require scalable approaches. Here, we describe a "cell village" experimental platform used analyze genetic, molecular, phenotypic heterogeneity across neural progenitor cells from 44 human donors cultured shared vitro environment using algorithms (Dropulation Census-seq) assign phenotypes individual donors. Through rapid induction of stem cell-derived cells, measurements natural genetic variation, CRISPR-Cas9 perturbations, identified common variant that regulates antiviral IFITM3 expression explains most inter-individual susceptibility Zika virus. We also detected QTLs corresponding GWAS loci for brain traits discovered novel disease-relevant regulators proliferation differentiation such as CACHD1. This approach provides ways elucidate effects genes on phenotypes.
Language: Английский
Citations
65
Cancer Cell, Journal Year: 2023, Volume and Issue: 41(2), P. 288 - 303.e6
Published: Jan. 19, 2023
Interferon-γ (IFN-γ) signaling mediates host responses to infection, inflammation and anti-tumor immunity. Mutations in the IFN-γ pathway cause immunological disorders, hematological malignancies, resistance immune checkpoint blockade (ICB) cancer; however, function of most clinically observed variants remains unknown. Here, we systematically investigate genetic determinants response colorectal cancer cells using CRISPR-Cas9 screens base editing mutagenesis. Deep mutagenesis JAK1 with cytidine adenine editors, combined pathway-wide screens, reveal loss-of-function gain-of-function mutations, including causal malignancies mutations detected patients refractory ICB. We functionally validate uncertain significance primary tumor organoids, where engineering missense enhanced or reduced sensitivity autologous tumor-reactive T cells. identify more than 300 predicted altering activity, generating a valuable resource for interpreting gene variant function.
Language: Английский
Citations
52
Frontiers in Bioengineering and Biotechnology, Journal Year: 2024, Volume and Issue: 11
Published: Jan. 8, 2024
Clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing (GED) technologies have unlocked exciting possibilities for understanding genes and improving medical treatments. On the other hand, Artificial intelligence (AI) helps achieve more precision, efficiency, affordability in tackling various diseases, like Sickle cell anemia or Thalassemia. AI models been use designing guide RNAs (gRNAs) CRISPR-Cas systems. Tools DeepCRISPR, CRISTA, DeepHF capability to predict optimal a specified target sequence. These predictions take into account multiple factors, including genomic context, Cas protein type, desired mutation on-target/off-target scores, potential off-target sites, impacts of on gene function phenotype. aid optimizing different technologies, such as base, prime, epigenome editing, which are advanced techniques introduce precise programmable changes DNA sequences without relying homology-directed repair pathway donor templates. Furthermore, AI, collaboration with precision medicine, enables personalized treatments based genetic profiles. analyzes patients' data identify mutations, variations, biomarkers associated diseases Cancer, Diabetes, Alzheimer's, etc. However, several challenges persist, high costs, suitable delivery methods CRISPR cargoes, ensuring safety clinical applications. This review explores AI's contribution CRISPR-based addresses existing challenges. It also discusses areas future research AI-driven technologies. The integration opens up new genetics, biomedicine, healthcare, significant implications human health.
Language: Английский
Citations
41
Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)
Published: Feb. 19, 2024
Abstract Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there a paucity of demonstrating it. The All Us Research Program collecting including whole-genome sequences, health records, and surveys for at least million participants with diverse ancestry access to healthcare, representing one the largest biomedical research repositories its kind. Here, we examine pathogenic likely variants that were identified cohort. European subgroup showed highest overall rate variation, 2.26% having variant. Other groups had lower rates 1.62% African group 1.32% Latino/Admixed American group. Pathogenic most frequently observed genes related Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies many consistent from public gnomAD database, some notable exceptions resolved using subsets. Differences variant frequency between ancestral generally indicate biases ascertainment knowledge about those variants, deviations may be indicative differences disease prevalence. This work will allow targeted precision medicine efforts revealed disparities.
Language: Английский
Citations
19
Nature Immunology, Journal Year: 2024, Volume and Issue: 25(3), P. 405 - 417
Published: Feb. 27, 2024
Language: Английский
Citations
18
Nature Biotechnology, Journal Year: 2024, Volume and Issue: 42(8), P. 1199 - 1217
Published: July 29, 2024
Language: Английский
Citations
18
Cell, Journal Year: 2024, Volume and Issue: 187(25), P. 7045 - 7063
Published: Dec. 1, 2024
Cells are essential to understanding health and disease, yet traditional models fall short of modeling simulating their function behavior. Advances in AI omics offer groundbreaking opportunities create an virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent simulate the behavior molecules, cells, tissues across diverse states. This Perspective provides vision on design how collaborative efforts build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, guiding experimental studies, offering new for cellular functions fostering interdisciplinary collaborations open science.
Language: Английский
Citations
16
Nature, Journal Year: 2025, Volume and Issue: 638(8050), P. 351 - 359
Published: Feb. 12, 2025
Language: Английский
Citations
3