Abstract
Ultraconserved regions (UCRs) represent genomic elements with perfect sequence conservation across humans, rats, and mice. Though evolutionarily significant, most UCRs' functions remain elusive. Here, by leveraging current reference genomes from 34 species spanning diverse taxonomic groups, we refine the annotation, trace the evolutionary origins, and compile an updated catalog of UCRs. The updated UCRs are mostly 200-400 base pairs long, with lower GC content and SNP density but more deleterious mutations. They first emerge in fish, growing more abundant in vertebrates. Guided by genomic context and functional analyses, we classified them into three categories: type I (within protein-coding genes) mainly encodes brain development splicing regulators; type II (within non-coding genes) associates with lncRNAs linked to brain malignancies; type III (intergenic, 46% overlapping enhancer-like elements) regulates brain development genes. Our findings underscore UCRs' critical roles in human brain development and disorders, offering a framework for investigating their biological significance.