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The degree of gene and sequence preservation across species provides valuable insights into the relative necessity of genes from the perspective of natural selection. Here, we developed novel interspecies metrics across 462 mammalian species, GISMO (Gene identity score of mammalian orthologs) and GISMO-mis (GISMO-missense), to quantify gene loss traversing millions of years of evolution. GISMO is a measure of gene loss across mammals weighed by evolutionary distance relative to humans, whereas GISMO-mis quantifies the ratio of missense to synonymous variants across mammalian species for a given gene. Despite large sample sizes, current human constraint metrics are still not well calibrated for short genes. Traversing over 100 million years of evolution across hundreds of mammals can identify the most essential genes and improve gene-disease association. Beyond human genetics, these metrics provide measures of gene constraint to further enable mammalian genetics research. Our analyses showed that both metrics are strongly correlated with measures of human gene constraint for loss-of-function, missense, and copy number dosage derived from upwards of a million human samples, which highlight the power of interspecies constraint. Importantly, neither GISMO nor GISMO-mis are strongly correlated with coding sequence length. Therefore both metrics can identify novel constrained genes that were too small for existing human constraint metrics to capture. We also found that GISMO scores capture rare variant association signals across a range of phenotypes associated with …