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• W4291475492 abstract "Abstract Causal loss-of-function (LOF) variants for Mendelian and severe complex diseases are enriched in “mutation intolerant” genes. We show how such observations can be interpreted in light of a model of mutation-selection balance, and use the model to relate the pathogenic consequences of LOF mutations at present-day to their evolutionary fitness effects. To this end, we first infer posterior distributions for the fitness costs of LOF mutations in 17,322 autosomal and 679 X-linked genes from exome sequences in 56,855 individuals. Estimated fitness costs for the loss of a gene copy are typically above 1%; they tend to be largest for X-linked genes, whether or not they have a Y homolog, followed by autosomal genes and genes in the pseudoautosomal region. We then compare inferred fitness effects for all possible de novo LOF mutations to those of de novo mutations identified in individuals diagnosed with one of six severe, complex diseases or developmental disorders. Probands carry an excess of mutations with estimated fitness effects above 10%; as we show by simulation, such highly deleterious mutations are typically only a couple of generations old when sampled in the population. Moreover, the proportion of highly deleterious mutations carried by probands reflects the typical age of onset of the disease. The study design also has a discernible influence: a greater proportion of highly deleterious mutations is detected in pedigree than case-control studies, and for autism, in simplex than multiplex families and in female versus male probands. Thus, anchoring observations in human genetics to a population genetic model allows us to learn about the fitness effects of mutations identified by different mapping strategies and for different traits." @default.
• W4291475492 created "2022-08-15" @default.
• W4291475492 creator A5039579959 @default.
• W4291475492 creator A5052165531 @default.
• W4291475492 creator A5070438115 @default.
• W4291475492 creator A5088220823 @default.
• W4291475492 date "2022-08-12" @default.
• W4291475492 modified "2023-09-29" @default.
• W4291475492 title "Relating pathogenic loss-of function mutations in humans to their evolutionary fitness costs" @default.
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• W4291475492 doi "https://doi.org/10.1101/2022.08.11.503594" @default.
• W4291475492 hasPublicationYear "2022" @default.
• W4291475492 type Work @default.

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