Evolution of comparative transcriptomics: biological scales, phylogenetic spans, and modeling frameworks

Comparative transcriptomic studies are key to understanding how molecular evolution drives phenotypic divergence across the tree of life. Here, we discuss three major directions in which the field of comparative transcriptomics is evolving. The first one is enabled by advances in sequencing technologies. Bulk RNA sequencing emerged two decades ago as a key tool to characterize transcriptomic states, enabling evolutionary comparisons at the tissue and organ levels. However, single-cell and spatial transcriptomics are now driving a shift toward a paradigm centered around cell types. Second, while comparative transcriptomic studies have historically focused on a few key model organisms and on species closely related to humans, recent trends have shifted toward both broader phylogenetic coverage and deeper sampling within clades. In parallel, the growing amount of transcriptomic data, together with the advent of machine learning approaches, are leading to the development of new modeling frameworks. These frameworks range from reconstruction of cell type phylogenies to prediction of RNA coverage from genomic sequence alone and have propelled significant progress in evolutionary biology and its biomedical applications.