Evolutionary constraint metrics across 462 mammals sharpen human disease gene prioritization

Researchers have built two metrics of evolutionary constraint, GISMO and GISMO-mis, using gene loss and missense variation mapped across 462 mammalian species. Together the measures offer complementary assessments of gene essentiality: when a gene is rarely lost or rarely accumulates missense changes across the mammalian tree, it is more likely to be essential. Applied to human data, the metrics improve prioritization of candidate human disease genes, giving clinicians and researchers a way to rank genes underlying both rare and common conditions. The work was published in Nature Genetics on 20 October 2026. Open questions include how the metrics perform for genes with weak evolutionary signal and how they will be integrated into existing variant-interpretation pipelines in clinical genetics.

Written by a model from the reports · updated 4 hours ago