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Single-cell multi-ome regression models identify functional and disease-associated enhancers and enable chromatin potential analysis (vol 56, pg 627, 2024)

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NATURE GENETICS 2024年第6期56卷 1319-1319页

作者： Mitra, Sneha Malik, Rohan Wong, Wilfred Rahman, Afsana Hartemink, Alexander J. Pritykin, Yuri Dey, Kushal K. Leslie, Christina S. Computational and Systems Biology Program Memorial Sloan Kettering Cancer Center New York City NY USA Rye Country Day School Rye NY USA Tri-Institutional Training Program in Computational Biology and Medicine New York City NY USA Hunter College City University of New York New York City NY USA Department of Computer Science Duke University Durham NC USA Program in Computational Biology and Bioinformatics Duke University Durham NC USA Center for Genomic and Computational Biology Duke University Durham NC USA Department of Computer Science Princeton University Princeton NJ USA Lewis-Sigler Institute for Integrative Genomics Princeton University Princeton NJ USA

We present a gene-level regulatory model, single-cell ATAC + RNA linking (SCARlink), which predicts single-cell gene expression and links enhancers to target genes using multi-ome (scRNA-seq and scATAC–seq co-assay) sequencing data. The approach uses regularized Poisson regression on tile-level accessibility data to jointly model all regulatory effects at a gene locus, avoiding the limitations of pairwise gene–peak correlations and dependence on peak calling. SCARlink outperformed existing gene scoring methods for imputing gene expression from chromatin accessibility across high-coverage multi-ome datasets while giving comparable to improved performance on low-coverage datasets. Shapley value analysis on trained models identified cell-type-specific gene enhancers that are validated by promoter capture Hi-C and are 11× to 15× and 5× to 12× enriched in fine-mapped eQTLs and fine-mapped genome-wide association study (GWAS) variants, respectively. We further show that SCARlink-predicted and observed gene expression vectors provide a robust way to compute a chromatin potential vector field to enable developmental trajectory analysis.

关键词： Epigenetics Population genetics Software

Disentangling Interpretable Factors with Supervised Independent Subspace Principal Component Analysis

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arXiv 2024年

作者： Su, Jiayu Knowles, David A. Rabadan, Raul Program for Mathematical Genomics United States Department of Systems Biology Columbia University United States Department of Biomedical Informatics Columbia University United States Department of Computer Science Columbia University United States New York Genome Center United States

The success of machine learning models relies heavily on effectively representing high-dimensional data. However, ensuring data representations capture human-understandable concepts remains difficult, often requiring the incorporation of prior knowledge and decomposition of data into multiple subspaces. Traditional linear methods fall short in modeling more than one space, while more expressive deep learning approaches lack interpretability. Here, we introduce Supervised Independent Subspace Principal Component Analysis (sisPCA), a PCA extension designed for multi-subspace learning. Leveraging the Hilbert-Schmidt Independence Criterion (HSIC), sisPCA incorporates supervision and simultaneously ensures subspace disentanglement. We demonstrate sisPCA's connections with autoencoders and regularized linear regression and showcase its ability to identify and separate hidden data structures through extensive applications, including breast cancer diagnosis from image features, learning aging-associated DNA methylation changes, and single-cell analysis of malaria infection. Our results reveal distinct functional pathways associated with malaria colonization, underscoring the essentiality of explainable representation in high-dimensional data analysis. Copyright © 2024, The Authors. All rights reserved.

关键词： Self-supervised learning

Discovering molecular features of intrinsically disordered regions by using evolution for contrastive learning

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PLoS Computational biology 2022年第6期18卷 e1010238页

作者： Lu, Alex X. Lu, Amy X. Pritišanac, Iva Zarin, Taraneh Forman-Kay, Julie D. Moses, Alan M. Department of Computer Science University of Toronto Toronto Canada Department of Cell and Systems Biology University of Toronto Toronto Canada Program in Molecular Medicine Hospital for Sick Children Toronto Canada Department of Biochemistry University of Toronto Toronto Canada

A major challenge to the characterization of intrinsically disordered regions (IDRs), which are widespread in the proteome, but relatively poorly understood, is the identification of molecular features that mediate functions of these regions, such as short motifs, amino acid repeats and physicochemical properties. Here, we introduce a proteome-scale feature discovery approach for IDRs. Our approach, which we call "reverse homology", exploits the principle that important functional features are conserved over evolution. We use this as a contrastive learning signal for deep learning: given a set of homologous IDRs, the neural network has to correctly choose a held-out homolog from another set of IDRs sampled randomly from the proteome. We pair reverse homology with a simple architecture and standard interpretation techniques, and show that the network learns conserved features of IDRs that can be interpreted as motifs, repeats, or bulk features like charge or amino acid propensities. We also show that our model can be used to produce visualizations of what residues and regions are most important to IDR function, generating hypotheses for uncharacterized IDRs. Our results suggest that feature discovery using unsupervised neural networks is a promising avenue to gain systematic insight into poorly understood protein sequences. © 2022 Lu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

关键词： Amino acids

TERMinator: A Neural Framework for Structure-Based Protein Design using Tertiary Repeating Motifs

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arXiv 2022年

作者： Li, Alex J. Sundar, Vikram Grigoryan, Gevorg Keating, Amy E. Department of Chemistry Massachusetts Institute of Technology United States Computational and Systems Biology Program Massachusetts Institute of Technology United States Department of Computer Science Dartmouth College United States Departments of Biology and Biological Engineering Massachusetts Institute of Technology United States

Computational protein design has the potential to deliver novel molecular structures, binders, and catalysts for myriad applications. Recent neural graph-based models that use backbone coordinate-derived features show exceptional performance on native sequence recovery tasks and are promising frameworks for design. A statistical framework for modeling protein sequence landscapes using Tertiary Motifs (TERMs), compact units of recurring structure in proteins, has also demonstrated good performance on protein design tasks. In this work, we investigate the use of TERM-derived data as features in neural protein design frameworks. Our graph-based architecture, TERMinator, incorporates TERM-based and coordinate-based information and outputs a Potts model over sequence space. TERMinator outperforms state-of-the-art models on native sequence recovery tasks, suggesting that utilizing TERM-based and coordinate-based features together is beneficial for protein design. © 2022, CC BY.

关键词： Potts model

Trackable Agent-based Evolution Models at Wafer Scale

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arXiv 2024年

作者： Moreno, Matthew Andres Yang, Connor Dolson, Emily Zaman, Luis Department of Ecology and Evolutionary Biology University of Michigan Ann Arbor United States Center for the Study of Complex Systems University of Michigan Ann Arbor United States Michigan Institute for Data Science University of Michigan Ann Arbor United States Undergraduate Research Opportunities Program University of Michigan Ann Arbor United States Department of Computer Science and Engineering Michigan State University East Lansing United States Program in Ecology Evolution and Behavior Michigan State University East Lansing United States

Continuing improvements in computing hardware are poised to transform capabilities for in silico modeling of cross-scale phenomena underlying major open questions in evolutionary biology and artificial life, such as transitions in individuality, eco-evolutionary dynamics, and rare evolutionary events. Emerging ML/AI-oriented hardware accelerators, like the 850,000 processor Cerebras Wafer Scale Engine (WSE), hold particular promise. However, many practical challenges remain in conducting informative evolution experiments that efficiently utilize these platforms’ large processor counts. Here, we focus on the problem of extracting phylogenetic information from agent-based evolution on the WSE platform. This goal drove significant refinements to decentralized in silico phylogenetic tracking, reported here. These improvements yield order-of-magnitude performance improvements. We also present an asynchronous island-based genetic algorithm (GA) framework for WSE hardware. Emulated and on-hardware GA benchmarks with a simple tracking-enabled agent model clock upwards of 1 million generations a minute for population sizes reaching 16 million agents. This pace enables quadrillions of agent replication events a day. We validate phylogenetic reconstructions from these trials and demonstrate their suitability for inference of underlying evolutionary conditions. In particular, we demonstrate extraction, from wafer-scale simulation, of clear phylometric signals that differentiate runs with adaptive dynamics enabled versus disabled. Together, these benchmark and validation trials reflect strong potential for highly scalable agent-based evolution simulation that is both efficient and observable. Developed capabilities will bring entirely new classes of previously intractable research questions within reach, benefiting further explorations within the evolutionary biology and artificial life communities across a variety of emerging high-performance computing platforms. Copyright © 20

关键词： Genetic algorithms

Ecology, Spatial Structure, and Selection Pressure Induce Strong Signatures in Phylogenetic Structure

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arXiv 2024年

作者： Moreno, Matthew Andres Rodriguez-Papa, Santiago Dolson, Emily Department of Ecology and Evolutionary Biology University of Michigan Ann Arbor United States Center for the Study of Complex Systems University of Michigan Ann Arbor United States Michigan Institute for Data Science University of Michigan Ann Arbor United States Department of Computer Science and Engineering Michigan State University East Lansing United States Program in Ecology Evolution and Behavior Michigan State University East Lansing United States

Evolutionary dynamics are shaped by a variety of fundamental, generic drivers, including spatial structure, ecology, and selection pressure. These drivers impact the trajectory of evolution, and have been hypothesized to influence phylogenetic structure. For instance, they can help explain natural history, steer behavior of contemporary evolving populations, and influence efficacy of application-oriented evolutionary optimization. Likewise, in inquiry-oriented artificial life systems, these drivers constitute key building blocks for open-ended evolution. Here, we set out to assess (1) if spatial structure, ecology, and selection pressure leave detectable signatures in phylogenetic structure, (2) the extent, in particular, to which ecology can be detected and discerned in the presence of spatial structure, and (3) the extent to which these phylogenetic signatures generalize across evolutionary systems. To this end, we analyze phylogenies generated by manipulating spatial structure, ecology, and selection pressure within three computational models of varied scope and sophistication. We find that selection pressure, spatial structure, and ecology have characteristic effects on phylogenetic metrics, although these effects are complex and not always intuitive. Signatures have some consistency across systems when using equivalent taxonomic unit definitions (e.g., individual, genotype, species). Further, we find that sufficiently strong ecology can be detected in the presence of spatial structure. We also find that, while low-resolution phylogenetic reconstructions can bias some phylogenetic metrics, high-resolution reconstructions recapitulate them faithfully. Although our results suggest potential for evolutionary inference of spatial structure, ecology, and selection pressure through phylogenetic analysis, further methods development is needed to distinguish these drivers' phylometric signatures from each other and to appropriately normalize phylogenetic metrics. With s

关键词： Abiotic

A Multi-phase Deep Learning Approach for Predicting HCC Response to TACE using Complete Computed Tomography

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A Multi-phase Deep Learning Approach for Predicting HCC Resp...

Data science and Engineering in Healthcare, Medicine and biology, IEEE EMBS Special Topic Conference on

作者： Shun Cheng Chang Chien Fu Liu Marta Misztal Yi Hsien Hsieh Che Lin Graduate Institute of Communication Engineering National Taiwan University (NTU) Taiwan School of Electronic Engineering and Computer Science Queen Mary University of London UK Department of Electrical Engineering NTU Taiwan Center for Computational and Systems Biology and Center for Biotechnology NTU Taiwan Smart Medicine and Health Informatics Program NTU Taiwan

In this research study, we compare the predictive performance of two advanced deep learning-based models in order to provide a solution to TACE (Transarterial Chemoembolization) response prediction in HCC (Hepatocellular Carcinoma) patients. Using entire abdominal CT scans enabled a broader perspective available for the model, eliminating the need for segmentation during the preprocessing. Making use of both single-phase and multi-phase CT imaging, we have used DenseNet121 and have obtained an accuracy of 80% for the multi-phase *** Relevance: The ability to predict the effectiveness of TACE treatment prior to its administration makes it possible to provide a better decision-making aid for physicians and patients.

关键词：

Testing the Inference Accuracy of Accelerator-Friendly Approximate Phylogeny Tracking

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Testing the Inference Accuracy of Accelerator-Friendly Appro...

Computational Intelligence in Artificial Life and Cooperative Intelligent systems (ALIFE-CIS), IEEE Symposium on

作者： Matthew Andres Moreno Anika Ranjan Emily Dolson Luis Zaman Department of Ecology and Evolutionary Biology University of Michigan Ann Arbor United States Center for the Study of Complex Systems University of Michigan Ann Arbor United States Michigan Institute for Data and AI in Society University of Michigan Ann Arbor United States Undergraduate Research Opportunities Program University of Michigan Ann Arbor United States Department of Computer Science and Engineering Michigan State University East Lansing United States Program in Ecology Evolution and Behavior Michigan State University East Lansing United States

ISBN: (数字)9798331508371

ISBN: (纸本)9798331508388

computer simulations are an important tool for studying the mechanics of biological evolution. In particular, agent-based approaches provide an opportunity to collect high-quality records of ancestry relationships. Such phylogenies can provide insight into evolutionary dynamics within these simulations. Previous work generally tracks lineages directly, yielding an exact phylogenetic record of evolutionary history. However, challenges exist in scaling direct ancestrytracking approaches to highly-distributed, many-processor evolution in silico. An alternative approach is to estimate phylogenetic history via noncoding annotations on digital genomes, akin to how bioinformaticians build phylogenies by assessing genetic similarities between organisms. Recent work has extended this “hereditary stratigraphy” approach to support powerful hardware accelerator platforms, such as the Cerebras Wafer-Scale Engine. Although these second-generation “surface”-based hereditary stratigraphy algorithms have demonstrated order-ofmagnitude speedups over first-generation “column”-based algorithms, it remains unknown how they impact the accuracy of reconstructed phylogenies. To address this question, we assessed reconstruction accuracy under alternative configurations across a matrix of evolutionary conditions varying in selection pressure, spatial structure, and ecological dynamics. Encouragingly, we find that the second-generation approaches provide higher reconstruction quality across most surveyed conditions.

关键词： Surface reconstruction Accuracy Annotations Heuristic algorithms Computational modeling Biological system modeling Stratigraphy Phylogeny History Bars

Testing the Inference Accuracy of Accelerator-Friendly Approximate Phylogeny Tracking

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Testing the Inference Accuracy of Accelerator-Friendly Appro...

2025 IEEE Symposium on Computational Intelligence in Artificial Life and Cooperative Intelligent systems, ALIFE-CIS 2025

作者： Moreno, Matthew Andres Ranjan, Anika Dolson, Emily Zaman, Luis University of Michigan Department of Ecology and Evolutionary Biology Ann Arbor United States Center for the Study of Complex Systems University of Michigan Ann Arbor United States Michigan Institute for Data and Ai in Society University of Michigan Ann Arbor United States Undergraduate Research Opportunities Program University of Michigan Ann Arbor United States Michigan State University Department of Computer Science and Engineering East Lansing United States Program in Ecology Evolution and Behavior Michigan State University East Lansing United States

ISBN: (纸本)9798331508371

computer simulations are an important tool for studying the mechanics of biological evolution. In particular, agent-based approaches provide an opportunity to collect high-quality records of ancestry relationships. Such phylogenies can provide insight into evolutionary dynamics within these simulations. Previous work generally tracks lineages directly, yielding an exact phylogenetic record of evolutionary history. However, challenges exist in scaling direct ancestrytracking approaches to highly-distributed, many-processor evolution in silico. An alternative approach is to estimate phylogenetic history via noncoding annotations on digital genomes, akin to how bioinformaticians build phylogenies by assessing genetic similarities between organisms. Recent work has extended this 'hereditary stratigraphy' approach to support powerful hardware accelerator platforms, such as the Cerebras Wafer-Scale Engine. Although these second-generation 'surface'-based hereditary stratigraphy algorithms have demonstrated order-ofmagnitude speedups over first-generation 'column'-based algorithms, it remains unknown how they impact the accuracy of reconstructed phylogenies. To address this question, we assessed reconstruction accuracy under alternative configurations across a matrix of evolutionary conditions varying in selection pressure, spatial structure, and ecological dynamics. Encouragingly, we find that the second-generation approaches provide higher reconstruction quality across most surveyed conditions. © 2025 IEEE.

关键词： Biostratigraphy