ArticleProceedings of the National Academy of Sciences of the United States of America2019
Why haploinsufficiency persists.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers, 1 of them a synthesis that pooled it.
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Who cites it
62 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Rethinking 'rare'Journal of Parkinson's disease · 2025Pooled it
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- Determinants of functional burden pleiotropy and gene dosage responses across human traits.Nature communications · 2026Article
- Failed metabolic adaptation to stress contributes to epidermal cell adhesion defects in Darier disease.Science advances · 2026Article
- Exploring copy number alterations (CNAs) to gain new insight into SCLC heterogeneity.Molecular biology reports · 2026Review
- Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity.eLife · 2026Article
- AAV9-mediated targeting of natural antisense transcript as a novel treatment for Dravet syndrome.Molecular therapy. Nucleic acids · 2026Article
- New lens on congenital mild bone fragility: a novel Col1a1 knockout mouse model for osteogenesis imperfecta type 1.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2026Article
- Differential negative dominance by KCNA2 variants associated with global developmental delay suggests KCNA2 haploinsufficiency in humans.The Journal of physiology · 2026Article
- Decoding the germline genetic architecture of prostate cancer at a single cell resolution.PLoS genetics · 2025Article
- Internal ribosome entry sites enhance translation in trans in antisense non-coding SINEUP and circular RNAs.Nucleic acids research · 2025Article
- Retinoic Acid Induced 1 and Smith-Magenis Syndrome: From Genetics to Biology and Possible Therapeutic Strategies.International journal of molecular sciences · 2025Review
- Gene Dosage Sensitivity and Human Genetic Diseases.Journal of inherited metabolic disease · 2025Review
- A haploinsufficiency restoration strategy corrects neurobehavioral deficits in Nf1+/- mice.The Journal of clinical investigation · 2025Article
- Association of pituitary neuroendocrine tumors and neurofibromatosis type 1: assessing causation versus coincidence. Case report.Frontiers in endocrinology · 2025Article
- Therapeutic development approaches to treat haploinsufficiency diseases: restoring protein levels.Drug discovery today · 2024Review
- Quantitative perturbation-phenotype maps reveal nonlinear responses underlying robustness of PAR-dependent asymmetric cell division.PLoS biology · 2024Article
- Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model.Cell genomics · 2024Article
- Chromatin remodeling in tissue stem cell fate determination.Cell regeneration (London, England) · 2024Review
2 more citing papers are in PubMed but not listed here.
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Abstract
Haploinsufficiency describes the decrease in organismal fitness observed when a single copy of a gene is deleted in diploids. We investigated the origin of haploinsufficiency by creating a comprehensive dosage sensitivity data set for genes under their native promoters. We demonstrate that the expression of haploinsufficient genes is limited by the toxicity of their overexpression. We further show that the fitness penalty associated with excess gene copy number is not the only determinant of haploinsufficiency. Haploinsufficient genes represent a unique subset of genes sensitive to copy number increases, as they are also limiting for important cellular processes when present in one copy instead of two. The selective pressure to decrease gene expression due to the toxicity of overexpression, combined with the pressure to increase expression due to their fitness-limiting nature, has made haploinsufficient genes extremely sensitive to changes in gene expression. As a consequence, haploinsufficient genes are dosage stabilized, showing much more narrow ranges in cell-to-cell variability of expression compared with other genes in the genome. We propose a dosage-stabilizing hypothesis of haploinsufficiency to explain its persistence over evolutionary time.
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