No abstract

The integrative analysis of high‐throughput reporter assays, machine learning, and profiles of epigenomic chromatin state in a broad array of cells and tissues has the potential to significantly improve our understanding of noncoding regulatory element function and its contribution to human disease. Here, we report results from the CAGI 5 regulation saturation challenge where participants were asked to predict the impact of nucleotide substitution at every base pair within five disease‐associated human enhancers and nine disease‐associated promoters. A library of mutations covering all bases was generated by saturation mutagenesis and altered activity was assessed in a massively parallel reporter assay (MPRA) in relevant cell lines. Reporter expression was measured relative to plasmid DNA to determine the impact of variants. The challenge was to predict the functional effects of variants on reporter expression. Comparative analysis of the full range of submitted prediction results identifies the most successful models of transcription factor binding sites, machine learning algorithms, and ways to choose among or incorporate diverse datatypes and cell‐types for training computational models. These results have the potential to improve the design of future studies on more diverse sets of regulatory elements and aid the interpretation of disease‐associated genetic variation.

Deciphering the potential of noncoding loci to influence gene regulation has been the subject of intense research, with important implications in understanding genetic underpinnings of human diseases. Massively parallel reporter assays (MPRAs) can measure regulatory activity of thousands of DNA sequences and their variants in a single experiment. With increasing number of publically available MPRA data sets, one can now develop data‐driven models which, given a DNA sequence, predict its regulatory activity. Here, we performed a comprehensive meta‐analysis of several MPRA data sets in a variety of cellular contexts. We first applied an ensemble of methods to predict MPRA output in each context and observed that the most predictive features are consistent across data sets. We then demonstrate that predictive models trained in one cellular context can be used to predict MPRA output in another, with loss of accuracy attributed to cell‐type‐specific features. Finally, we show that our approach achieves top performance in the Fifth Critical Assessment of Genome Interpretation “Regulation Saturation” Challenge for predicting effects of single‐nucleotide variants. Overall, our analysis provides insights into how MPRA data can be leveraged to highlight functional regulatory regions throughout the genome and can guide effective design of future experiments by better prioritizing regions of interest.

We propose a model-free reinforcement learning method for controlling mixed autonomy traffic in simulated traffic networks with through-traffic-only two-way and fourway intersections. Our method utilizes multi-agent policy decomposition which allows decentralized control based on local observations for an arbitrary number of controlled vehicles. We demonstrate that, even without reward shaping, reinforcement learning learns to coordinate the vehicles to exhibit traffic signal-like behaviors, achieving near-optimal throughput with 33-50% controlled vehicles. With the help of multi-task learning and transfer learning, we show that this behavior generalizes across inflow rates and size of the traffic network. Our code, models, and videos of results are available at https://github.com/ZhongxiaYan/mixed autonomy intersections.

systems considered in this article, the presented methodology emphasizes ease of application within any simulated vehicular system while minimizing manual efforts by the practitioner. The control inputs consist of local information around each automated vehicle, while the control outputs are commands for longitudinal acceleration and lateral lane change. Experimental results are presented for relatively small simulated traffic systems, though the methodology can be adapted to larger vehicular systems with minor modifications. Experimentally optimized behaviors provide insights to the practitioner which may assist in designing simplified and interpretable control strategies. Implementation in real-world systems depends on two requirements: 1) a reliable fallback mechanism for ensuring safety of vehicles, and 2) sufficient fidelity of the simulator for simulated behaviors to transfer. These requirements are under active research for traffic systems and may be practical in some robotic settings. To facilitate robust transfer of policies from simulated to real-world systems, future extensions of this work may inject additional randomization into simulation while reducing the unmodeled stochasticity of targeted real-world systems as much as possible.