skip to main content


Title: UFold: fast and accurate RNA secondary structure prediction with deep learning
Abstract

For many RNA molecules, the secondary structure is essential for the correct function of the RNA. Predicting RNA secondary structure from nucleotide sequences is a long-standing problem in genomics, but the prediction performance has reached a plateau over time. Traditional RNA secondary structure prediction algorithms are primarily based on thermodynamic models through free energy minimization, which imposes strong prior assumptions and is slow to run. Here, we propose a deep learning-based method, called UFold, for RNA secondary structure prediction, trained directly on annotated data and base-pairing rules. UFold proposes a novel image-like representation of RNA sequences, which can be efficiently processed by Fully Convolutional Networks (FCNs). We benchmark the performance of UFold on both within- and cross-family RNA datasets. It significantly outperforms previous methods on within-family datasets, while achieving a similar performance as the traditional methods when trained and tested on distinct RNA families. UFold is also able to predict pseudoknots accurately. Its prediction is fast with an inference time of about 160 ms per sequence up to 1500 bp in length. An online web server running UFold is available at https://ufold.ics.uci.edu. Code is available at https://github.com/uci-cbcl/UFold.

 
more » « less
Award ID(s):
1715017 1763272
NSF-PAR ID:
10306125
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  
Publisher / Repository:
Oxford University Press
Date Published:
Journal Name:
Nucleic Acids Research
Volume:
50
Issue:
3
ISSN:
0305-1048
Page Range / eLocation ID:
p. e14-e14
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract

    Protein language models (pLMs) trained on a large corpus of protein sequences have shown unprecedented scalability and broad generalizability in a wide range of predictive modeling tasks, but their power has not yet been harnessed for predicting protein–nucleic acid binding sites, critical for characterizing the interactions between proteins and nucleic acids. Here, we present EquiPNAS, a new pLM-informed E(3) equivariant deep graph neural network framework for improved protein–nucleic acid binding site prediction. By combining the strengths of pLM and symmetry-aware deep graph learning, EquiPNAS consistently outperforms the state-of-the-art methods for both protein–DNA and protein–RNA binding site prediction on multiple datasets across a diverse set of predictive modeling scenarios ranging from using experimental input to AlphaFold2 predictions. Our ablation study reveals that the pLM embeddings used in EquiPNAS are sufficiently powerful to dramatically reduce the dependence on the availability of evolutionary information without compromising on accuracy, and that the symmetry-aware nature of the E(3) equivariant graph-based neural architecture offers remarkable robustness and performance resilience. EquiPNAS is freely available at https://github.com/Bhattacharya-Lab/EquiPNAS.

     
    more » « less
  2. Abstract The problem of determining which nucleotides of an RNA sequence are paired or unpaired in the secondary structure of an RNA, which we call RNA state inference, can be studied by different machine learning techniques. Successful state inference of RNA sequences can be used to generate auxiliary information for data-directed RNA secondary structure prediction. Typical tools for state inference, such as hidden Markov models, exhibit poor performance in RNA state inference, owing in part to their inability to recognize nonlocal dependencies. Bidirectional long short-term memory (LSTM) neural networks have emerged as a powerful tool that can model global nonlinear sequence dependencies and have achieved state-of-the-art performances on many different classification problems. This paper presents a practical approach to RNA secondary structure inference centered around a deep learning method for state inference. State predictions from a deep bidirectional LSTM are used to generate synthetic SHAPE data that can be incorporated into RNA secondary structure prediction via the Nearest Neighbor Thermodynamic Model (NNTM). This method produces predicted secondary structures for a diverse test set of 16S ribosomal RNA that are, on average, 25 percentage points more accurate than undirected MFE structures. Accuracy is highly dependent on the success of our state inference method, and investigating the global features of our state predictions reveals that accuracy of both our state inference and structure inference methods are highly dependent on the similarity of pairing patterns of the sequence to the training dataset. Availability of a large training dataset is critical to the success of this approach. Code available at https://github.com/dwillmott/rna-state-inf . 
    more » « less
  3. Abstract Motivation

    The human microbiome, which is linked to various diseases by growing evidence, has a profound impact on human health. Since changes in the composition of the microbiome across time are associated with disease and clinical outcomes, microbiome analysis should be performed in a longitudinal study. However, due to limited sample sizes and differing numbers of timepoints for different subjects, a significant amount of data cannot be utilized, directly affecting the quality of analysis results. Deep generative models have been proposed to address this lack of data issue. Specifically, a generative adversarial network (GAN) has been successfully utilized for data augmentation to improve prediction tasks. Recent studies have also shown improved performance of GAN-based models for missing value imputation in a multivariate time series dataset compared with traditional imputation methods.

    Results

    This work proposes DeepMicroGen, a bidirectional recurrent neural network-based GAN model, trained on the temporal relationship between the observations, to impute the missing microbiome samples in longitudinal studies. DeepMicroGen outperforms standard baseline imputation methods, showing the lowest mean absolute error for both simulated and real datasets. Finally, the proposed model improved the predicted clinical outcome for allergies, by providing imputation for an incomplete longitudinal dataset used to train the classifier.

    Availability and implementation

    DeepMicroGen is publicly available at https://github.com/joungmin-choi/DeepMicroGen.

     
    more » « less
  4. Abstract

    Advances in visual perceptual tasks have been mainly driven by the amount, and types, of annotations of large-scale datasets. Researchers have focused on fully-supervised settings to train models using offline epoch-based schemes. Despite the evident advancements, limitations and cost of manually annotated datasets have hindered further development for event perceptual tasks, such as detection and localization of objects and events in videos. The problem is more apparent in zoological applications due to the scarcity of annotations and length of videos-most videos are at most ten minutes long. Inspired by cognitive theories, we present a self-supervised perceptual prediction framework to tackle the problem of temporal event segmentation by building a stable representation of event-related objects. The approach is simple but effective. We rely on LSTM predictions of high-level features computed by a standard deep learning backbone. For spatial segmentation, the stable representation of the object is used by an attention mechanism to filter the input features before the prediction step. The self-learned attention maps effectively localize the object as a side effect of perceptual prediction. We demonstrate our approach on long videos from continuous wildlife video monitoring, spanning multiple days at 25 FPS. We aim to facilitate automated ethogramming by detecting and localizing events without the need for labels. Our approach is trained in an online manner on streaming input and requires only a single pass through the video, with no separate training set. Given the lack of long and realistic (includes real-world challenges) datasets, we introduce a new wildlife video dataset–nest monitoring of the Kagu (a flightless bird from New Caledonia)–to benchmark our approach. Our dataset features a video from 10 days (over 23 million frames) of continuous monitoring of the Kagu in its natural habitat. We annotate every frame with bounding boxes and event labels. Additionally, each frame is annotated with time-of-day and illumination conditions. We will make the dataset, which is the first of its kind, and the code available to the research community. We find that the approach significantly outperforms other self-supervised, traditional (e.g., Optical Flow, Background Subtraction) and NN-based (e.g., PA-DPC, DINO, iBOT), baselines and performs on par with supervised boundary detection approaches (i.e., PC). At a recall rate of 80%, our best performing model detects one false positive activity every 50 min of training. On average, we at least double the performance of self-supervised approaches for spatial segmentation. Additionally, we show that our approach is robust to various environmental conditions (e.g., moving shadows). We also benchmark the framework on other datasets (i.e., Kinetics-GEBD, TAPOS) from different domains to demonstrate its generalizability. The data and code are available on our project page:https://aix.eng.usf.edu/research_automated_ethogramming.html

     
    more » « less
  5. Abstract

    Noncoding RNAs (ncRNAs) have recently attracted considerable attention due to their key roles in biology. The ncRNA–proteins interaction (NPI) is often explored to reveal some biological activities that ncRNA may affect, such as biological traits, diseases, etc. Traditional experimental methods can accomplish this work but are often labor-intensive and expensive. Machine learning and deep learning methods have achieved great success by exploiting sufficient sequence or structure information. Graph Neural Network (GNN)-based methods consider the topology in ncRNA–protein graphs and perform well on tasks like NPI prediction. Based on GNN, some pairwise constraint methods have been developed to apply on homogeneous networks, but not used for NPI prediction on heterogeneous networks. In this paper, we construct a pairwise constrained NPI predictor based on dual Graph Convolutional Network (GCN) called NPI-DGCN. To our knowledge, our method is the first to train a heterogeneous graph-based model using a pairwise learning strategy. Instead of binary classification, we use a rank layer to calculate the score of an ncRNA–protein pair. Moreover, our model is the first to predict NPIs on the ncRNA–protein bipartite graph rather than the homogeneous graph. We transform the original ncRNA–protein bipartite graph into two homogenous graphs on which to explore second-order implicit relationships. At the same time, we model direct interactions between two homogenous graphs to explore explicit relationships. Experimental results on the four standard datasets indicate that our method achieves competitive performance with other state-of-the-art methods. And the model is available at https://github.com/zhuoninnin1992/NPIPredict

     
    more » « less