Exploring 100 million years of mammalian evolution for the origins of exceptional traits

The Zoonomia Project, one of the largest comparative genomics initiatives ever undertaken, compared 240 mammalian species spanning over 100 million years of evolutionary history. This work revealed that at least 11% of the human genome is evolutionarily constrained, and that these constrained bases are more enriched for variants explaining common disease heritability than any other functional annotation. Yet nearly half of the most highly constrained bases remain unannotated in existing datasets, underscoring how much of the genome’s regulatory landscape remains unexplored. Building on this foundation, we are integrating the “common garden” framework from classical ecology with modern genomics to assay and compare cellular responses across diverse mammals. This effort includes RNA-seq and ATAC-seq profiling across 12 species and seven experimental states varying in temperature, oxygen, and glucose levels. We can identify molecular responses shared across mammals and those unique to species with remarkable physiological adaptations—such as camels that thrive in extreme heat, seals that dive deeply without suffering oxygen damage, and bats that tolerate extreme blood sugar fluctuations. Uncovering the genomic mechanisms that enable these exceptional traits may reveal new strategies for improving human health.