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Study Follows Evolutionary Fitness Effects of Loss-of-Function Mutations

For a paper in eLife, a Columbia University and University of Oxford team explores the evolutionary fitness consequences of loss-of-function (LOF) mutations behind Mendelian conditions or severe complex disease. Using exome sequence data for nearly 55,900 non-Finnish European individuals in gnomAD and variant segregation data in UK Biobank exomes, the researchers used computational modeling and forward population genetic simulation approaches to systematically estimate the fitness costs associated with LOF alleles affecting one copy each of the more than 17,300 autosomal genes and 679 X-linked genes considered. Those estimates, in turn, helped them gauge the fitness consequences of de novo LOF mutations found in individuals with half a dozen developmental or neuropsychiatric conditions. In general, the estimates "suggest stronger selection on the loss of a gene copy on the X [chromosome] than the autosomes, other than in the pseudo-autosomal region," the authors report. "They are on average higher for de novo mutations and very rare segregating variants than variants at high allele frequencies in the population. And they reveal an enrichment of strongly deleterious mutations in cases for five early onset disorders, in rough accordance with their severity."