The landscape of gene loss and missense variation across the mammalian tree informs on gene essentiality.

Patterns of gene and sequence preservation across species provide insight into gene essentiality under natural selection. Here we developed two interspecies constraint metrics across 462 mammalian species: Gene Identity Score of Mammalian Orthologs (GISMO), which quantifies gene loss weighted by evolutionary distance to humans, and GISMO-mis, which measures missense constraint using the ratio of missense to synonymous variation across mammals. Both metrics are strongly correlated with human loss of function, missense and dosage constraint derived from large-scale sequencing studies, yet are largely independent of coding sequence length. GISMO and GISMO-mis identify essential genes missed by existing human-only metrics, particularly short genes. Genes in the most constrained deciles are enriched for rare variant associations in disorders linked to reduced fecundity, including schizophrenia, autism and neurodevelopmental disorders, and show strong enrichment for common variant heritability. These deciles also exhibit reduced copy number variation, consistent with dosage sensitivity. In addition, GISMO improves prioritization of recessive disease genes and captures signatures of homozygous selection across the mammalian tree. Taken together, GISMO and GISMO-mis leverage deep mammalian evolution to provide complementary, length-robust measures of gene essentiality that strengthen disease-gene prioritization and illuminate the selective forces shaping human biology.