Benchmarking DNA Sequence Models for Causal Regulatory Variant Prediction in Human Genetics

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Abstract
Machine learning holds immense promise in biology, particularly for the challenging task of identifying causal variants for Mendelian and complex traits. Two primary approaches have emerged for this task: supervised sequence-to-function models trained on functional genomics experimental data and self-supervised DNA language models that learn evolutionary constraints on sequences. However, the field currently lacks consistently curated datasets with accurate labels, especially for non-coding variants, that are necessary to comprehensively benchmark these models and advance the field. In this work, we present TraitGym, a curated dataset of regulatory genetic variants that are either known to be causal or are strong candidates across 113 Mendelian and 83 complex traits, along with carefully constructed control variants. We frame the causal variant prediction task as a binary classification problem and benchmark various models, including functional-genomics-supervised models, self-supervised models, models that combine machine learning predictions with curated annotation features, and ensembles of these. Our results provide insights into the capabilities and limitations of different approaches for predicting the functional consequences of non-coding genetic variants. We find that alignment-based models CADD and GPN-MSA compare favorably for Mendelian traits and complex disease traits, while functional-genomics-supervised models Enformer and Borzoi perform better for complex non-disease traits. Evo2 shows substantial performance gains with scale, but still lags somewhat behind alignment-based models, struggling particularly with enhancer variants. The benchmark, including a Google Colab notebook to evaluate a model in a few minutes, is available at https://huggingface.co/datasets/songlab/TraitGym.

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