AlphaGenome Enhances Personal Gene Expression Prediction but Retains Key Limitations

In recent years, numerous genome AI models have been developed to elucidate the relationship between DNA sequence and gene expression. However, these models have faced criticism for their limited accuracy in predicting individual-specific gene expression. AlphaGenome, the current state-of-the-art in genome AI, achieves exceptional performance across a range of sequence-based predictive tasks, but its utility for personal expression prediction has not yet been assessed. In this study, we evaluate AlphaGenome's ability to predict personal gene expression and find that it significantly outperforms its predecessor. Using GTEx data, AlphaGenome improves the prediction of expression direction over Enformer, achieving an odds ratio of 3.0. In some cases, it even reverses previously observed negative correlations into positive ones. Moreover, AlphaGenome demonstrates improved performance for genes with known nonlinear sequence-expression relationships, though it uncovers mechanisms distinct from those identified by tree-based models.