Evolution of 3D Genome Organization: Mechanisms, Regulation, and Comparative Genomics

How 3D genome architecture varies across species, how it is encoded by molecular mechanisms and genomic sequence, and how it shapes animal evolution are questions that have become tractable only recently. Rapidly expanding chromatin-conformation data sets, chromosome-scale genome assemblies, and advances in computational modeling now enable comparative 3D genomics across broad phylogenetic scales. Here we review recent progress in 3D genome evolution, tracing how chromosome territories, polarized chromosome arrangements, compartments, and topologically associating domains have diversified across lineages. We examine the molecular and sequence determinants of this diversification, including condensin II, CCCTC-binding factor, alternative insulators, repetitive sequences, and large-scale chromosome rearrangements, and consider how architectural change may influence gene regulation, phenotypic divergence, and speciation. Finally, we discuss phylogeny-aware statistical models, sequence-to-contact map predictors, and emerging multimodal foundation models as complementary computational frameworks for identifying conserved and lineage-specific folding patterns, prioritizing sequence changes with predicted architectural effects, and generating testable evolutionary hypotheses.