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Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth’s vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.

INTRODUCTION: Deciphering the molecular and genetic changes that differentiate humans from our closest primate relatives is critical for understanding our origins. Although earlier studies have prioritized how newly gained genetic sequences or variations have contributed to evolutionary innovation, the role of sequence loss has been less appreciated. Alterations in evolutionary conserved regions that are enriched for biological function could be particularly more likely to have phenotypic effects. We thus sought to identify and characterize sequences that have been conserved across evolution, but are then surprisingly lost in all humans. These human-specific deletions in conserved regions (hCONDELs) may play an important role in uniquely human traits. RATIONALE: Sequencing advancements have identified millions of genetic changes between chimpanzee and human genomes; however, the functional impacts of the ~1 to 5% difference between our species is largely unknown. hCONDELs are one class of these predominantly noncoding sequence changes. Although large hCONDELs (>1 kb) have been previously identified, the vast majority of all hCONDELs (95.7%) are small (