ArticleAmerican journal of human genetics2007
Most rare missense alleles are deleterious in humans: implications for complex disease and association studies.
Article in American journal of human genetics, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 355 papers, 2 of them syntheses that pooled it.
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Who cites it
355 citing papers in PubMed, 2 syntheses or guidelines pooled it, 604 citations in OpenAlex.
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- Evaluating confounding in rare variant genome wide association studies.Nature communications · 2026Article
- Leveraging ancestral recombination graphs for scalable mixed-model analysis of complex traits.Cell genomics · 2026Article
- Per-allele disease and complex trait effect sizes are predominantly African MAF-dependent in European populations.medRxiv : the preprint server for health sciences · 2026Article
- NovelFrontiers in medicine · 2026Article
- Whole-genome resequencing reveals genomic characteristics and candidate genomic regions potentially associated with local adaptation of Leiwuqi yak (Frontiers in veterinary science · 2026Article
- A gene-based model of fitness and its implications for genetic variation: linkage disequilibrium.Genetics · 2025Article
- De novo variant analysis of childhood-onset obsessive-compulsive disorder in the French-Canadian population.Translational psychiatry · 2025Article
- varCADD: large sets of standing genetic variation enable genome-wide pathogenicity prediction.Genome medicine · 2025Article
- A gene-based model of fitness and its implications for genetic variation: Linkage disequilibrium.bioRxiv : the preprint server for biology · 2025Article
- Mutational load and adaptive variation are shaped by climate and species range dynamics in Vitis arizonica.The New phytologist · 2025Article
- The structure and function of the ghrelin receptor coding for drug actions.Nature structural & molecular biology · 2025Article
- The influence of genetic polymorphisms on cytokine profiles in pediatric COVID-19: a pilot study.Frontiers in pediatrics · 2025Article
- Rare germline variants in cancer-relevant genes are associated with breast cancer risk in young women with high-risk family history.Breast cancer research and treatment · 2025Article
- Novel mutation leading to splice donor loss in a conserved site ofJournal of medical genetics · 2024Article
- The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease.International journal of molecular sciences · 2024Article
295 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The accumulation of mildly deleterious missense mutations in individual human genomes has been proposed to be a genetic basis for complex diseases. The plausibility of this hypothesis depends on quantitative estimates of the prevalence of mildly deleterious de novo mutations and polymorphic variants in humans and on the intensity of selective pressure against them. We combined analysis of mutations causing human Mendelian diseases, of human-chimpanzee divergence, and of systematic data on human genetic variation and found that ~20% of new missense mutations in humans result in a loss of function, whereas ~27% are effectively neutral. Thus, the remaining 53% of new missense mutations have mildly deleterious effects. These mutations give rise to many low-frequency deleterious allelic variants in the human population, as is evident from a new data set of 37 genes sequenced in >1,500 individual human chromosomes. Surprisingly, up to 70% of low-frequency missense alleles are mildly deleterious and are associated with a heterozygous fitness loss in the range 0.001-0.003. Thus, the low allele frequency of an amino acid variant can, by itself, serve as a predictor of its functional significance. Several recent studies have reported a significant excess of rare missense variants in candidate genes or pathways in individuals with extreme values of quantitative phenotypes. These studies would be unlikely to yield results if most rare variants were neutral or if rare variants were not a significant contributor to the genetic component of phenotypic inheritance. Our results provide a justification for these types of candidate-gene (pathway) association studies and imply that mutation-selection balance may be a feasible evolutionary mechanism underlying some common diseases.
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