{"doi":"10.1073/pnas.1900437116","title":"Why haploinsufficiency persists","abstract":"<jats:title>Significance</jats:title>\n                  <jats:p>For most genes, a single copy is enough to support normal growth and development of diploid organisms, but a small subset of genes known as haploinsufficient (HI) genes exhibit extreme sensitivity to decreased gene dosage. Given the relatively high frequency of gene-inactivating mutations over the lifespan of an organism, and cell-to-cell variability in gene expression, haploinsufficiency represents a significant barrier to organismal fitness. Why the expression of these genes has not been modulated over evolutionary time to eliminate their haploinsufficiency remains unexplained. We find that the limit of haploinsufficient genes on organismal fitness cannot be overcome by an increase in expression because haploinsufficient genes also confer a fitness disadvantage when encoded in extra copy, leaving these genes evolutionarily “stuck.”</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2019,"id":590589,"datarank":2.7886605761380783,"base_score":4.59511985013459,"endowment":4.59511985013459,"self_citation_contribution":0.6892679775201885,"citation_network_contribution":2.09939259861789,"self_endowment_contribution":0.6892679775201885,"citer_contribution":2.09939259861789,"corpus_percentile":null,"corpus_rank":null,"citation_count":98,"citer_count":93,"citers_with_citation_signal":76,"citers_with_endowment":76,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":14822,"name":"Angelika Amon","orcid":"0000-0001-9837-0314","position":1,"is_corresponding":false},{"id":1511071,"name":"Summer A. Morrill","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Why haploinsufficiency persists","abstract":"<jats:title>Significance</jats:title>\n                  <jats:p>For most genes, a single copy is enough to support normal growth and development of diploid organisms, but a small subset of genes known as haploinsufficient (HI) genes exhibit extreme sensitivity to decreased gene dosage. Given the relatively high frequency of gene-inactivating mutations over the lifespan of an organism, and cell-to-cell variability in gene expression, haploinsufficiency represents a significant barrier to organismal fitness. Why the expression of these genes has not been modulated over evolutionary time to eliminate their haploinsufficiency remains unexplained. We find that the limit of haploinsufficient genes on organismal fitness cannot be overcome by an increase in expression because haploinsufficient genes also confer a fitness disadvantage when encoded in extra copy, leaving these genes evolutionarily “stuck.”</jats:p>","is_dataset_classified":null,"base_score":4.59511985013459,"endowment":4.59511985013459,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31142641","pmcid":"PMC6575174","openalex_id":"https://openalex.org/W2946983779","authors":[],"funders":[{"funder_name":"HHS | National Institutes of Health","grant_id":"CA206157","title":null},{"funder_name":"HHS | National Institutes of Health","grant_id":"GM118066","title":null},{"funder_name":"National Science Foundation","grant_id":"1122374","title":"Graduate Research Fellowship Program"},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA206157","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R35 GM118066","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA014051","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM007287","title":null},{"funder_name":"Howard Hughes Medical Institute","grant_id":"","title":null}],"total_grants":8,"fwci":3.1103,"citation_percentile":0.92880647,"influential_citations":0,"citation_trend":[{"year":2019,"count":2},{"year":2020,"count":8},{"year":2021,"count":22},{"year":2022,"count":9},{"year":2023,"count":16},{"year":2024,"count":21},{"year":2025,"count":13},{"year":2026,"count":7}],"oa_status":"bronze","license":"https://www.pnas.org/site/aboutpnas/licenses.xhtml","oa_locations":[{"url":"https://www.pnas.org/content/pnas/116/24/11866.full.pdf","host_type":"journal"},{"url":"https://www.pnas.org/content/pnas/116/24/11866.full.pdf","host_type":"publisher"},{"url":"http://www.pnas.org/syndication/doi/10.1073/pnas.1900437116","host_type":"publisher"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.1900437116","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.1900437116","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31142641","host_type":"repository"},{"url":"https://hdl.handle.net/1721.1/126033","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6575174","host_type":"repository"},{"url":"https://dx.doi.org/10.1073/pnas.1900437116","host_type":""},{"url":"https://doi.org/https://doi.org/10.1073/pnas.1900437116","host_type":""}],"fields_of_study":["Ubiquitin and proteasome pathways","Chromosomal and Genetic Variations","Glycosylation and Glycoproteins Research","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Cell Survival","Promoter Regions, Genetic","Yeasts","Gene Expression","Genome","Gene Dosage","Haploinsufficiency"],"keywords":["Haploinsufficiency","Psychology","Genetics","Biology","Phenotype","gene dosage","Dosage Sensitivity","Genome","Cell Survival","Yeasts","Gene Expression","Promoter Regions, Genetic"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-25T03:14:33.988808Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}