A 5' UTR Language Model for Decoding Untranslated Regions of mRNA and Function Predictions

The 5' UTR, a regulatory region at the beginning of an mRNA molecule, plays a crucial role in regulating the translation process and impacts the protein expression level. Language models have showcased their effectiveness in decoding the functions of protein and genome sequences. Here, we introduced a language model for 5' UTR, which we refer to as the UTR-LM. The UTR-LM is pre-trained on endogenous 5' UTRs from multiple species and is further augmented with supervised information including secondary structure and minimum free energy. We fine-tuned the UTR-LM in a variety of downstream tasks. The model outperformed the best-known benchmark by up to 42% for predicting the Mean Ribosome Loading, and by up to 60% for predicting the Translation Efficiency and the mRNA Expression Level. The model also applies to identifying unannotated Internal Ribosome Entry Sites within the untranslated region and improves the AUPR from 0.37 to 0.52 compared to the best baseline. Further, we designed a library of 211 novel 5' UTRs with high predicted values of translation efficiency and evaluated them via a wet-lab assay. Experiment results confirmed that our top designs achieved a 32.5% increase in protein production level relative to well-established 5' UTR optimized for therapeutics.

Bandit Theory and Thompson Sampling-Guided Directed Evolution for Sequence Optimization

Directed Evolution (DE), a landmark wet-lab method originated in 1960s, enables discovery of novel protein designs via evolving a population of candidate sequences. Recent advances in biotechnology has made it possible to collect high-throughput data, allowing the use of machine learning to map out a protein's sequence-to-function relation. There is a growing interest in machine learning-assisted DE for accelerating protein optimization. Yet the theoretical understanding of DE, as well as the use of machine learning in DE, remains limited. In this paper, we connect DE with the bandit learning theory and make a first attempt to study regret minimization in DE. We propose a Thompson Sampling-guided Directed Evolution (TS-DE) framework for sequence optimization, where the sequence-to-function mapping is unknown and querying a single value is subject to costly and noisy measurements. TS-DE updates a posterior of the function based on collected measurements. It uses a posterior-sampled function estimate to guide the crossover recombination and mutation steps in DE. In the case of a linear model, we show that TS-DE enjoys a Bayesian regret of order $\tilde O(d^{2}\sqrt{MT})$, where $d$ is feature dimension, $M$ is population size and $T$ is number of rounds. This regret bound is nearly optimal, confirming that bandit learning can provably accelerate DE. It may have implications for more general sequence optimization and evolutionary algorithms.