Abstract
Recent advances in single-cell omics technology have transformed the landscape of cellular and molecular research, enriching the scope and intricacy of cellular characterisation. Perturbation modelling seeks to comprehensively grasp the effects of external influences like disease onset or molecular knock-outs or external stimulants on cellular physiology, specifically on transcription factors, signal transducers, biological pathways, and dynamic cell states. Machine and deep learning tools transform complex perturbational phenomena in algorithmically tractable tasks to formulate predictions based on various types of single-cell datasets. However, the recent surge in tools and datasets makes it challenging for experimental biologists and computational scientists to keep track of the recent advances in this rapidly expanding filed of single-cell modelling. Here, we recapitulate the main objectives of perturbation modelling and summarise novel single-cell perturbation technologies based on genetic manipulation like CRISPR or compounds, spanning across omic modalities. We then concisely review a burgeoning group of computational methods extending from classical statistical inference methodologies to various machine and deep learning architectures like shallow models or autoencoders, to biologically informed approaches based on gene regulatory networks, and to combinatorial efforts reminiscent of ensemble learning. We also discuss the rising trend of large foundational models in single-cell perturbation modelling inspired by large language models. Lastly, we critically assess the challenges that underline single-cell perturbation modelling while pointing towards relevant future perspectives like perturbation atlases, multi-omics and spatial datasets, causal machine learning for interpretability, multi-task learning for performance and explainability as well as prospects for solving interoperability and benchmarking pitfalls.