ArticleeLife2023
Relating pathogenic loss-of-function mutations in humans to their evolutionary fitness costs.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Pooled it
- The landscape of gene loss and missense variation across the mammalian tree informs on gene essentiality.Nature genetics · 2026Article
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- Allele frequencies at recessive disease genes are mainly determined by pleiotropic effects in heterozygotes.Genetics · 2026Article
- Inference of elevated mutation rates and variant effects using 700k exomes.bioRxiv : the preprint server for biology · 2026Article
- LongAllele: a joint inference framework for allele-specific analysis on long-read bulk and single-cell RNA sequencing.bioRxiv : the preprint server for biology · 2026Article
- Sequence context and methylation interact to shape germline mutation rate variation at CpG sites.PLoS genetics · 2026Article
- Sequence context and methylation interact to shape germline mutation rate variation at CpG sites.bioRxiv : the preprint server for biology · 2026Article
- A framework to infer de novo exonic variants when parental genotypes are missing enhances association studies of autism.Bioinformatics (Oxford, England) · 2026Article
- Escape from X inactivation drives sex differences in gene expression.Molecular biology and evolution · 2026Article
- Allele Frequencies at Recessive Disease Genes are Mainly Determined by Pleiotropic Effects in Heterozygotes.bioRxiv : the preprint server for biology · 2025Article
- A DNA language model based on multispecies alignment predicts the effects of genome-wide variants.Nature biotechnology · 2025Article
- Rewiring the bone marrow: Evolution and the transcriptional architecture of trained immunity.eLife · 2025Review
- Estimation of demography and mutation rates from one million haploid genomes.American journal of human genetics · 2025Article
- Reproductive and cognitive phenotypes in carriers of recessive pathogenic variants.Nature human behaviour · 2025Article
- Multi-dimensional annotation of porcine variants using genomic and epigenomic features in pigs.BMC biology · 2025Article
- The distribution of highly deleterious variants across human ancestry groups.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A probabilistic graphical model for estimating selection coefficients of nonsynonymous variants from human population sequence data.Nature communications · 2025Article
- Article
- Context-adjusted proportion of singletons (CAPS): a novel metric for assessing negative selection in the human genome.NAR genomics and bioinformatics · 2024Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
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 to their evolutionary fitness effects. To this end, we first infer posterior distributions for the fitness costs of LOF mutations in 17,318 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 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, when sampled in the population, such highly deleterious mutations are typically only a couple of generations old. 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.