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

GISMO and GISMO-mis, two mammalian constraint metrics, strongly correlate with human gene essentiality and identify critical genes missed by existing methods, especially short genes.

• Why it matters: Understanding gene essentiality is vital for disease gene discovery and interpreting genetic variation, but current human-only metrics overlook many essential genes, limiting insights into disease mechanisms.
• What they did: Researchers developed two metrics across 462 mammalian species: GISMO, which measures gene loss weighted by evolutionary distance, and GISMO-mis, which assesses missense constraint via variation ratios, demonstrating their independence from coding sequence length.
• The result: Genes in the most constrained deciles are enriched for rare variants linked to disorders like schizophrenia and autism, show strong heritability enrichment, and exhibit reduced copy number variation, enhancing disease-gene prioritization and understanding of evolutionary pressures.