Genome language modeling (GLM): a beginner’s cheat sheet

Integrating genomics with diverse data modalities has the potential to revolutionize personalized medicine. However, this integration poses significant challenges due to the fundamental differences in data types and structures. The vast size of the genome necessitates transformation into a condensed representation containing key biomarkers and relevant features to ensure interoperability with other modalities. This commentary explores both conventional and state-of-the-art approaches to genome language modeling (GLM), with a focus on representing and extracting meaningful features from genomic sequences. We focus on the latest trends of applying language modeling techniques on genomics sequence data, treating it as a text modality. Effective feature extraction is essential in enabling machine learning models to effectively analyze large genomic datasets, particularly within multimodal frameworks. We first provide a step-by-step guide to various genomic sequence preprocessing and tokenization techniques. Then we explore feature extraction methods for the transformation of tokens using frequency, embedding, and neural network-based approaches. In the end, we discuss machine learning (ML) applications in genomics, focusing on classification, regression, language processing algorithms, and multimodal integration. Additionally, we explore the role of GLM in functional annotation, emphasizing how advanced ML models, such as Bidirectional encoder representations from transformers, enhance the interpretation of genomic data. To the best of our knowledge, we compile the first end-to-end analytic guide to convert complex genomic data into biologically interpretable information using GLM, thereby facilitating the development of novel data-driven hypotheses.