Genomics

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7 papers in the last four weeks, up 40% on the four weeks before. 0.1% of all new papers.

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Latest papers 79

May 20, 2026cs.LG

$\textit{BlockFormer}$ : Transformer-based inference from genomic contact maps

Locating genomic features from genomic contact maps, such as centromere identification from genome-wide chromosome conformation capture techniques, notably Hi-C, can be formulated as an inverse problem: infer one parameter per entity given a map summarizing pairwise interactions through blocks of variable numbers and sizes. In this work, we introduce a data-driven approach that leverages shared structure between these contact maps, such as global alignment between localized patterns, while handling the variability in number and size of chromosomes arising in real-world data. Our approach relies on a transformer architecture capable of handling such variability and a custom simulator to generate abundant, yet computationally cheap synthetic data for training. Applied to the problem of centromere localization, the method recovers genomic positions at or below the map resolution across species with various genome sizes using a coarse-to-fine refinement step when chromosome sizes fall outside the training range. We concentrate our evaluation on Hi-C data, where the block structure is well characterized and ground truth is available.

Eloïse Touron, Pedro L. C. Rodrigues, Julyan Arbel +2

Univ. Grenoble Alpes, Inria CNRS, Grenoble INP, LJK, France · TIMC, Univ. Grenoble Alpes CNRS, Grenoble INP, France

Genomics Inverse Problems

May 18, 2026cs.LG

FLAG: Foundation model representation with Latent diffusion Alignment via Graph for spatial gene expression prediction

Predicting spatial gene expression from routine H&E enables large-scale molecular profiling, yet current models treat this as isolated pointwise tasks, thereby overlooking essential biological structures like gene coordination and spatial distribution. To preserve these relationships, we introduce \textbf{FLAG}, a diffusion-based framework that redefines this task as structured distribution modeling. At the same time, we identify the critical \textbf{Gene Dimension Curse}, where joint modeling gene expression and their spatial interactions fail in high-dimensional spaces, and FLAG solves this challenge by integrating a spatial graph encoder for topological consistency and utilizing Gene Foundation Model (GFM) alignment for gene-gene fidelity in the generation process. To rigorously assess model performance, we propose a set of novel structural evaluation metrics, including Gene Structural Correlation (\textbf{GSC}) and Spatial Structural Correlation (\textbf{SSC}). Our experiments demonstrate that FLAG is highly competitive in traditional accuracy (PCC/MSE) while achieving significantly enhanced structural fidelity in capturing both gene-gene and gene-spatial relationships. The code is available at https://github.com/darkflash03/FLAG.

Qi Si, Penglei Wang, Yushuai Wu +5

Shanghai Academy of Artificial Intelligence for Science, Shanghai, China. · School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. · Artificial Intelligence Innovation and Incubation Institute, Fudan University, Shanghai, China.

Spatial Transcriptomics Spatial Gene Expression Prediction Genomics Gene Expression Prediction from Histopathology Images Diffusion Models

May 13, 2026cs.LG

AttnGen: Attention-Guided Saliency Learning for Interpretable Genomic Sequence Classification

Deep neural networks have achieved strong performance in genomic sequence classification; however, relating their predictions to biologically meaningful sequence patterns remains challenging. In this work, we present AttnGen, an attention-guided training framework that embeds interpretability directly into the optimization process. AttnGen computes nucleotide-level importance scores using an attention mechanism and progressively suppresses low-contribution positions during training. This encourages the model to focus its predictions on a compact set of informative regions while reducing reliance on noisy sequence elements. We evaluate AttnGen on the standardized demo_human_or_worm benchmark, a binary classification task over 200-nucleotide sequences. With moderate masking, AttnGen achieves a validation accuracy of 96.73%, outperforming a conventional CNN baseline with 95.83% accuracy, while also exhibiting faster convergence and improved training stability. To assess whether the learned importance scores reflect functionally relevant signal, we conduct perturbation-based analysis by removing high-saliency nucleotides. This causes accuracy to drop from 96.9% to near chance level on a 3,000-sequence evaluation set, indicating that the model relies on a relatively small subset of informative positions. Our analysis shows that masking 10--20% of positions provides the most favorable trade-off between predictive performance and interpretability. These results suggest that attention-guided masking not only improves classification performance but also reshapes how models distribute importance across sequence positions. Although this study focuses on short genomic sequences, the proposed approach may extend to more complex interpretable sequence modeling settings.

Rayhaneh Shabani Nia, Ali Karkehabadi

University of California, Davis California, USA

Neural Network Interpretability Attention Mechanisms Feature Selection Genomics Sequence Modeling

May 12, 2026q-bio.GN

Set-Aggregated Genome Embeddings for Microbiome Abundance Prediction

Microbiome functions are encoded within the genes of the community-wide metagenome. A natural question is whether properties of a microbial community can be predicted just from knowing the raw DNA sequences of its members. In this work, we employ set-aggregated genome embeddings (SAGE) to predict community-level abundance profiles, exploiting the few-shot learning capabilities of genomic language models (GLMs). We benchmark this approach to show improved generalization on novel genomes compared to classical bioinformatics approaches. Model ablation shows that community-level latent representations directly result in improved performance. Lastly, we demonstrate the benefits of intermediate transformations between latent representations and demonstrate the differences between GLM embedding choices.

Younhun Kim, Georg K. Gerber, Travis E. Gibson

1Brigham and Women’s Hospital, Boston, MA, USA · 2Harvard Medical School, Boston, MA, USA

Representation Learning Genomics Molecular Representation Learning

May 12, 2026cs.CV

RNA-FM: Flow-Matching Generative Model for Genome-wide RNA-Seq Prediction

Histopathology whole-slide images (WSIs) are routinely acquired in clinical practice and contain rich tissue morphology but lack direct molecular architecture and functional programs defining pathological states, whereas RNA sequencing (RNA-seq) provides genome-wide transcriptional profiles at substantial cost, thereby motivating WSI-based genome-wide transcriptomic prediction. Existing approaches for predicting gene expression from WSIs predominantly rely on deterministic regression with one-to-one mapping, limiting their ability to capture biological heterogeneity and predictive uncertainty. We propose RNA-FM, a flow-matching generative framework for genome-wide bulk RNA-seq prediction from WSIs. RNA-FM formulates transcriptomic prediction as a continuous-time conditional transport problem, learning a velocity field that maps a simple prior to the target gene expression distribution conditioned on morphologies. By integrating pathway-level structure, RNA-FM enables scalable and biologically interpretable genome-wide gene expression imputation. Extensive experiments demonstrate that RNA-FM consistently outperforms state-of-the-art approaches while maintaining biological meaningfulness. Code is available at https://github.com/YXSong000/RNA-FM.

Yaxuan Song, Jianan Fan, Tianyi Wang +4

School of Computer Science, The University of Sydney, Australia · Biological Systems and Engineering Division, Lawrence Berkeley National Lab, USA · Berkeley Biomedical Data Science Center, Lawrence Berkeley National Lab, USA +1

Computational Pathology Genomics Gene Expression Prediction from Histopathology Images Whole-Slide Image Analysis

May 12, 2026cs.LG

LPDP: Inference-Time Reward Control for Variable-Length DNA Generation with Edit Flows

We study the application of recent Edit Flows for inference-time reward control for DNA sequence generation. Unlike most reward-guided DNA generation frameworks, which operate on fixed-length sequence spaces, Edit Flows have a potential to generate variable-length DNA through biologically plausible insertion, deletion, and substitution operations. In particular, we propose Local Perturbation Discrete Programming (LPDP), a training-free, intermediate-state and action-aware local re-solving operator for variable-length DNA edit-action generators at inference time. More specifically, at each guided rollout step, LPDP scores one-step root edits, retains a near-best root band, and re-ranks each retained root by solving a bounded local discrete program around its child sequence. This local program uses the typed geometry of edit actions to focus on coherent substitution, insertion, or deletion subgraphs, and aggregates local continuations with either a hard Max backup or a soft log-sum-exponential (LSE) backup. We instantiate LPDP in two regimes: front-loaded reward tilting for enhancer optimization, where early edits are critical for establishing global regulatory sequence structure, and back-loaded reward tilting for exon-intron-exon inpainting, where late edits fine-tune splice-boundary contexts.

Jeongchan Kim, Yunkyung Ko, Jong Chul Ye

KAIST AI

Inference-Time Search Generative Modeling Molecular Generation Genomics Inference-Time Guidance

May 10, 2026q-bio.GN

SCOPE: Siamese Contrastive Operon Pair Embeddings for Functional Sequence Representation and Classification

Identifying operons is a fundamental step in understanding prokaryotic gene regulation, as classifying genes into operons supports the reconstruction of regulatory networks, functional annotation of unannotated genes, and drug candidate development. Experimental approaches such as RT-PCR and RNA-seq provide precise evidence of operon structure, but are laborious and largely limited to well-studied model organisms, making scalable computational methods essential for genome-wide operon identification. Prior computational approaches have employed traditional classifiers such as logistic regression and decision trees, motivating our use of these as physicochemical baselines. The DGEB benchmark evaluates operonic pair classification by embedding each sequence independently with a pre-trained protein language model and computing pairwise cosine similarity. In contrast, our Siamese MLP learns a classifier over the fused embedding space, which is theoretically better motivated for binary classification, as cosine similarity can yield meaningless scores depending on the regularization of the embedding model. While protein language model embeddings substantially outperform physicochemical features in ROC-AUC, a learned Siamese MLP head does not significantly improve over unsupervised cosine similarity in Average Precision, suggesting that the geometry of the embedding space already captures the functional relationships needed for this task. Nonetheless, our Siamese MLP achieves a ROC-AUC of 0.71, competitive with state-of-the-art models on the DGEB leaderboard. These findings indicate that protein language model embeddings are a viable, scalable foundation for operonic pair classification across diverse microbial genomes, with implications for automated genome annotation, regulatory network reconstruction, and characterization of organisms lacking experimental operon annotations.

Akarsh Gupta, Kenneth Rodrigues, Sagnik Chatterjee

Genomics Molecular Representation Learning

May 9, 2026cs.LG

MicroFuse: Protein-to-Genome Expert Fusion for Microbial Operon Reasoning

Predicting microbial operon co-membership requires integrating two complementary biological signals: protein-scale molecular identity and genome-context organization. While recent biological foundation models provide powerful representations of each view independently, naive concatenation of these modalities ignores a key biological property -- protein identity and genomic context may agree when adjacent genes form a coherent functional module, or conflict when sequence similarity is misleading but genomic layout indicates independent regulation. We present MicroFuse, a protein-to-genome expert fusion framework that integrates structure-aware protein representations from ProstT5 with genome-context representations from Bacformer through a four-expert Mixture-of-Experts module (protein, genome-context, agreement, and conflict experts) with a learned soft router. Training combines binary cross-entropy with symmetric cross-modal InfoNCE alignment and disagreement-weighted supervised contrastive shaping. We further construct OG-Operon100K, a 100,000-pair scaffold-level benchmark from the OMG metagenomic corpus with biologically grounded positive and negative criteria. On OG-Operon100K, MicroFuse achieves the strongest AUROC, AUPRC, mAP, and mAR among ProstT5-only, Bacformer-only, and Concat MLP baselines. Ablations identify cross-modal contrastive alignment as the dominant component, and a hard sequence-conflict subset reveals MicroFuse's largest gains precisely in biologically ambiguous cases where protein identity alone is misleading.

Seungik Cho

Department of Physics and Astronomy, Rice University, Texas, USA.

Genomics Multimodal Fusion Feature Fusion

May 7, 2026cs.AI

Wisteria: A Unified Multi-Scale Feature Learning Framework for DNA Language Model

DNA language model aims to decipher the regulatory grammar and semantic of genomes by capturing long range dependencies in DNA sequences. Existing methods emphasize long range token interactions but often ignore the interplay between local motifs and global dependencies. In this paper, we propose Wisteria, a genomic language model that integrates multi scale feature learning within a unified framework for DNA sequence. Specifically, Wisteria augments the Mamba based architecture with gated dilated convolutions to capture local motifs and regulatory patterns, while gated multilayer perceptrons refine global dependencies. We further introduce a Fourier based attention mechanism to support frequency domain modeling, periodic extension and length generalization. Across four experimental settings with both short and long range dependencies, Wisteria demonstrates strong performance on downstream benchmarks against competitive DNA language model baselines. These results indicate that Wisteria effectively unifies local and global dependency modeling for multi scale genomic sequence analysis.

Weihua Wang, Haoji Li, Feilong Bao +2

College of Computer Science, Inner Mongolia University, Hohhot, Inner Mongolia, 010021, China · National and Local Joint Engineering Research Center of Intelligent Information Processing Technology for Mongolian, Hohhot, Inner Mongolia, 010021, China · Inner Mongolia Key Laboratory of Multilingual Artificial Intelligence Technology, Hohhot, Inner Mongolia, 010021, China +1

Representation Learning Language Modeling Genomics Sequence Modeling

May 6, 2026cs.LG

When Does Gene Regulatory Network Inference Break? A Controlled Diagnostic Study of Causal and Correlational Methods on Single-Cell Data

Despite theoretical advantages, causal methods for Gene Regulatory Network (GRN) inference from single-cell RNA-seq data consistently fail to match or outperform correlation-based baselines in many realistic benchmarks, a persistent puzzle which casts doubt on the value of causality for this task. We argue that existing benchmarks are insufficiently controlled to answer this question because they evaluate on real or semi-real data where multiple pathologies co-occur, confounding failure modes, and obscuring the specific conditions under which different inference methods excel or fail. To address this gap, we introduce a controlled diagnostic framework that isolates seven biologically motivated pathologies (dropout, latent confounders, cell-type mixing, feedback loops, network density, sample size, and pseudotime drift) and measure how six representative methods spanning three inference paradigms degrade as each pathology intensifies. Across 6,120 controlled experiments, we find that causal methods genuinely dominate in clean and structurally favorable regimes, but specific pathologies (notably dropout and latent confounders) selectively neutralize their advantages. We further introduce an error-type decomposition that reveals methods with similar aggregate accuracy commit qualitatively different errors. To probe whether single-pathology effects persist when multiple stressors co-occur, we perform an interaction sweep over the three most impactful pathologies and find that their joint effects are sub-additive, while also exposing density-conditional cross-overs invisible to single-dial analysis. Our findings offer a nuanced understanding of when and why different methods succeed or fail for GRN inference, providing actionable insights for method development and practical guidance for practitioners.

Miguel Fernandez-de-Retana, Ruben Sanchez-Corcuera, Unai Zulaika +2

Faculty of Engineering University of Deusto Bilbao, Spain

Causal Discovery Gene Regulatory Network Inference Spurious Correlation Robustness Genomics Single-Cell RNA Sequencing

May 2, 2026q-bio.GN

EFGPP: Exploratory framework for genotype-phenotype prediction

Predicting complex human traits from genetic data is challenging because different genetic, clinical, and molecular data sources often contain different parts of the signal. Here, we present EFGPP, a reproducible framework for generating, ranking, and combining multiple types of data for genotype-to-phenotype prediction. We applied EFGPP to migraine prediction using UK Biobank data from 733 individuals. The framework combined genotype-derived features, principal components, clinical and metabolomic covariates, and polygenic risk scores generated from migraine and depression GWAS using PLINK, PRSice-2, AnnoPred, and LDAK-GWAS. The best single data type achieved a test AUC of 0.644, while combining multiple data types improved performance to 0.688 using migraine-focused inputs and 0.663 using cross-trait depression-derived inputs. Genetic features alone did not outperform the covariates-only baseline, but genotype-derived features performed better than PRS alone, and depression-derived PRS showed useful predictive signal. Overall, EFGPP provides a practical proof-of-concept framework for prioritising and integrating heterogeneous genetic data sources for complex phenotype prediction.

Muhammad Muneeb, David B. Ascher

School of Chemistry and Molecular Biology, The University of Queensland, Brisbane, 4067, Australia · Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, 3004, Australia

Genomics Multimodal Fusion Clinical Risk Prediction

Apr 30, 2026q-bio.GN

CellxPert: Inference-Time MCMC Steering of a Multi-Omics Single-Cell Foundation Model for In-Silico Perturbation

In this work, we introduce CellxPert, a scalable multimodal foundation model that unifies single-cell and spatial multi-omics within a common representation space. CellxPert jointly encodes transcriptomic (scRNA-seq), chromatin-accessibility (ATAC-seq), and surface-proteomic (CITE-seq) measurements, while directly incorporating MERFISH and imaging mass-cytometry data as 2D or 3D spatial-visual layers. CellxPert facilitates four key downstream tasks out of the box: (i) cell-type annotation across a broad ontology of 154 largely overlapping identities -- the largest label space addressed to date and a stringent test of fine-grained discrimination, (ii) efficient fine-tuning using Low Rank Adaptation (LoRA), (iii) genome-wide transcriptomic response prediction to in-silico perturbations (ISP), and (iv) seamless multi-omic integration across various assays and platforms. Unlike current single-cell foundation models, which approximate gene perturbations by deleting or reordering tokenized gene expression ranks, CellxPert employs a Metropolis-Hastings sampler whose proposal kernel uses the model's masked conditional distributions to transition to new transcriptomic states conditioned on the perturbed genes. This Markov-chain procedure mitigates out-of-distribution artifacts introduced by abrupt token manipulation and produces trajectories that are biologically interpretable. Evaluations on PBMC68K, Replogle Perturb-seq, Systema, and BMMC benchmarks show that CellxPert surpasses classical and state-of-the-art baselines in cell-type annotation, perturbation response prediction, and multi-omic integration.

Andac Demir, Erik W. Anderson, Jeremy L. Jenkins +1

Novartis Biomedical Research

Single-Cell Perturbation Modeling Genomics Single-Cell RNA Sequencing

Apr 28, 2026cs.DB

Mining Negative Sequential Patterns to Improve Viral Genomic Feature Representation and Classification

Viruses represent the most abundant biological entities on Earth and play a pivotal role in microbial ecosystems, yet, as prominent human pathogens, they are closely linked to human morbidity and mortality. Accurate identification of viral sequences from viral genome sequences is therefore essential, but existing genome-based classification models that largely relying on composition- or frequency-based subsequence features often suffer from limited interpretability and reduced accuracy, particularly on complex or imbalanced datasets. To address these limitations, we propose GeneNSPCla (Genomic Negative Sequential Pattern-based Classification), a novel viral classification framework based on Negative Sequential Patterns (NSPs) that extracts discriminative absence-based features from nucleotide sequences of RNA viral genomes. By transforming these NSPs into numerical feature vectors and integrating them into multiple supervised classifiers, GeneNSPCla effectively captures both presence and absence signals in viral sequences. Furthermore, we propose a negative pattern mining algorithm adapted for processing genomic data: GONPM+, which can discover longer and more biologically meaningful negative sequential patterns. The experimental results demonstrate that the average accuracy of GONPM+ in 8 classifiers has improved by 10.03% compared to the original negative pattern mining algorithm and by 24.75% compared to the positive pattern mining algorithm. These findings highlight the effectiveness of incorporating absence-based sequential information, providing a new and complementary perspective for viral genome analysis and classification.

Wenxi Zhu, Wensheng Gan, Zhenlian Qi

College of Information Science and Technology, Jinan University, Guangzhou 510632, China · College of Cyber Security, Jinan University, Guangzhou 510632, China · Guangdong Eco-Engineering Polytechnic, Guangzhou 510520, China

Genomics Sequence Modeling

Apr 27, 2026cs.AI

MIMIC: A Generative Multimodal Foundation Model for Biomolecules

Biological function emerges from coupled constraints across sequence, structure, regulation, evolution, and cellular context, yet most foundation models in biology are trained within one modality or for a fixed forward task. We present MIMIC, a generative multimodal foundation model trained on our newly curated and aligned dataset, LORE, linking nucleic acid, protein, evolutionary, structural, regulatory, and semantic/contextual modalities within partially observed biomolecular states. MIMIC uses a split-track encoder-decoder architecture to condition on arbitrary subsets of observed modalities and reconstruct or generate missing components of molecular state across the genome, transcriptome, and proteome. Multimodal conditioning consistently improves MIMIC's sequence reconstruction relative to sequence-only inputs, while its learned representations enable state-of-the-art performance on RNA and protein downstream tasks. MIMIC achieves state-of-the-art splicing prediction, and its joint generative formulation enables isoform-aware inference that further improves performance. Beyond prediction, the same generative framework supports constrained design. For RNA, MIMIC identifies corrective edits in a clinically relevant HBB splice-disrupting mutation without reverting it by using evolutionary and structural signals. For proteins, jointly conditioning on shape and surface chemistry of PD-L1 and hACE2 binding sites produces diverse, high-confidence sequences with strong in silico support for target binding. Finally, MIMIC uses experimental context as semantic conditioning to model assay-dependent RNA chemical probing, rather than treating context as a fixed output. Together, these results position MIMIC's aligned multimodal generative modeling as a strong foundation for unifying representation learning, conditional prediction, and constrained biomolecular design within a single model.

Siavash Golkar, Jake Kovalic, Irina Espejo Morales +28

Polymathic AI · Center for Data Science, New York University · Department of Applied Physics, Yale University +17

Molecular Generation Genomics Molecular Representation Learning

Apr 24, 2026cs.LG

StackFeat RL: Reinforcement Learning over Iterative Dual Criterion Feature Selection for Stable Biomarker Discovery

Feature selection in high-dimensional genomic data (

d \gg n

) demands methods that are simultaneously accurate, sparse, and stable. Existing approaches either require manual threshold specification (mRMR, stability selection), produce unstable selections under data perturbation (Lasso, Boruta), or ignore biological structure entirely. We introduce StackFeat-RL, a meta-learning framework that optimises the hyperparameters of an iterative dual-criterion feature selection algorithm via REINFORCE policy gradients. The dual criterion, requiring both coefficient consistency and selection frequency, guards against two failure modes missed by single-criterion methods, while iterative accumulation provides convergence guarantees via the law of large numbers. On COVID-19 miRNA data (GSE240888, 332 features) and three Alzheimer's disease classification tasks (GSE84422, 13237 genes; Normal vs.\ Possible, Probable, and Definite AD), StackFeat-RL achieves the highest predictive accuracy among all evaluated methods, including ElasticNet, Boruta, mRMR, and stability selection, while requiring 3--4

\times

fewer features. Keywords: feature selection, reinforcement learning, REINFORCE, elastic net, biomarker discovery, Alzheimer's disease, dual-criterion selection, protein interaction networks

A. Yermekov, D. A. Herrera-Martí

PAfoS.AI, Almaty, Kazakhstan · CEA List, Université Grenoble Alpes, France

Scientific Discovery Feature Selection Genomics

Apr 23, 2026cs.LG

Evaluating Post-hoc Explanations of the Transformer-based Genome Language Model DNABERT-2

Explaining deep neural network predictions on genome sequences enables biological insight and hypothesis generation-often of greater interest than predictive performance alone. While explanations of convolutional neural networks (CNNs) have been shown to capture relevant patterns in genome sequences, it is unclear whether this transfers to more expressive Transformer-based genome language models (gLMs). To answer this question, we adapt AttnLRP, an extension of layer-wise relevance propagation to the attention mechanism, and apply it to the state-of-the-art gLM DNABERT-2. Thereby, we propose strategies to transfer explanations from token and nucleotide level. We evaluate the adaption of AttnLRP on genomic datasets using multiple metrics. Further, we provide an extensive comparison between the explanations of DNABERT-2 and a baseline CNN. Our results demonstrate that AttnLRP yields reliable explanations corresponding to known biological patterns. Hence, like CNNs, gLMs can also help derive biological insights. This work contributes to the explainability of gLMs and addresses the comparability of relevance attributions across different architectures.

Isabel Kurth, Paulo Yanez Sarmiento, Bernhard Y. Renard

Hasso Plattner Institute University of Potsdam

Transformer Interpretability Attention Mechanisms Genomics Layer-Wise Relevance Propagation

Mar 2, 2026cs.LG

Partial Causal Structure Learning for Valid Selective Conformal Inference under Interventions

Selective conformal prediction can yield substantially tighter uncertainty sets when we can identify calibration examples that are exchangeable with the test example. In interventional settings, such as perturbation experiments in genomics, exchangeability often holds only within subsets of interventions that leave a target variable "unaffected" (e.g., non-descendants of an intervened node in a causal graph). We study the practical regime where this invariance structure is unknown and must be estimated from data. Our main result quantifies how coverage degrades when the estimated safe calibration set accidentally includes interventions that affect the target, and gives a conservative correction when an upper bound on this error is available. Rather than learning a full causal graph, we learn only the intervention-target relationships needed to choose calibration interventions. We give algorithms for this partial learning task and evaluate them on synthetic structural equation models and Replogle K562 CRISPR-interference data, where the experiments illustrate synthetic gains from selective calibration and finite-sample tradeoffs on real perturbation screens.

Amir Asiaee, Kavey Aryan, James P. Long

Department of Biostatistics, Vanderbilt University Medical Center, TN 37203, USA · Department of Informatics, King’s College London, London, UK · Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA

Selective Inference Causal Structure Learning Conformal Prediction Genomics Causal Intervention

Feb 9, 2026cs.LG

Central Dogma Transformer II: An AI Microscope for Understanding Cellular Regulatory Mechanisms

Motivation: Interpretability is not optional in biology: understanding gene regulation requires models whose learned structure can be directly interrogated, not merely accurate predictors whose internals resist mapping onto regulatory relationships. We ask whether an architecture mirroring the central dogma yields attention and gradient maps that recover known regulatory elements and networks in inspectable form. Results: Central Dogma Transformer II (CDT-II) mirrors the central dogma in its architecture -- DNA self-attention, RNA self-attention, and DNA-to-RNA cross-attention -- requiring only genomic embeddings and raw per-cell expression. On K562 CRISPR interference (CRISPRi) data with five genes held out entirely, CDT-II predicts perturbation effects (per-gene mean r = 0.84), recovers the GFI1B regulatory network (6.6-fold enrichment, P = 3.5 x 10^-17), and concentrates cross-attention on ENCODE regulatory elements including CTCF sites (mean 7.67x across 28 target genes, P < 0.001). Gradient attribution predicts consequences of perturbing therapeutic targets (mean r = 0.82). For TFRC, target of the anti-TfR1 antibody PPMX-T003, it identifies erythrocyte-structure, iron-dependent DNA-synthesis and oxidative-stress genes, matching anemia and ferroptosis reported clinically and preclinically -- without clinical data as input. CDT-II acts as an AI microscope, surfacing clinically relevant regulatory structure from perturbation experiments alone. Availability: Source code is available at https://github.com/nobusama/CDT2. Pre-computed embeddings, training data, and model weights are available at https://huggingface.co/datasets/nobusama17/CDT2-data.

Nobuyuki Ota

Independent Researcher, Burlingame, CA, USA

Transformer Interpretability Single-Cell Perturbation Modeling Transformer Attention Gene Regulatory Network Inference Genomics

Jun 2, 2025cs.CL

Leveraging Natural Language Processing to Unravel the Mystery of Life: A Review of NLP Approaches in Genomics, Transcriptomics, and Proteomics

Natural Language Processing (NLP) has transformed various fields beyond linguistics by applying techniques originally developed for human language to the analysis of biological sequences. This review explores the application of NLP methods to biological sequence data, focusing on genomics, transcriptomics, and proteomics. We examine how various NLP methods, from classic approaches like word2vec to advanced models employing transformers and hyena operators, are being adapted to analyze DNA, RNA, protein sequences, and entire genomes. The review also examines tokenization strategies and model architectures, evaluating their strengths, limitations, and suitability for different biological tasks. We further cover recent advances in NLP applications for biological data, such as structure prediction, gene expression, and evolutionary analysis, highlighting the potential of these methods for extracting meaningful insights from large-scale genomic data. As language models continue to advance, their integration into bioinformatics holds immense promise for advancing our understanding of biological processes in all domains of life.

Ella Rannon, David Burstein

The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel

Protein Language Models Genomics Sequence Modeling