{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T03:27:22Z","timestamp":1775964442394,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010295","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000}}],"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T00:00:00Z","timestamp":1657670400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35 GM119850"],"award-info":[{"award-number":["R35 GM119850"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"crossref","award":["NNF10CC1016517, NNF20SA0066621"],"award-info":[{"award-number":["NNF10CC1016517, NNF20SA0066621"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Lilly Innovation Fellows Award"},{"DOI":"10.13039\/100000888","name":"W. M. Keck Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000888","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    The concept of \u201chousekeeping gene\u201d has been used for four decades but remains loosely defined. Housekeeping genes are commonly described as \u201cessential for cellular existence regardless of their specific function in the tissue or organism\u201d, and \u201cstably expressed irrespective of tissue type, developmental stage, cell cycle state, or external signal\u201d. However, experimental support for the tenet that gene essentiality is linked to stable expression across cell types, conditions, and organisms has been limited. Here we use genome-scale functional genomic screens together with bulk and single-cell sequencing technologies to test this link and optimize a quantitative and experimentally validated definition of housekeeping gene. Using the optimized definition, we identify, characterize, and provide as resources, housekeeping gene lists extracted from several human datasets, and 10 other animal species that include primates, chicken, and\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    . We find that stably expressed genes are not necessarily essential, and that the individual genes that are essential and stably expressed can considerably differ across organisms; yet the pathways enriched among these genes are conserved. Further, the level of conservation of housekeeping genes across the analyzed organisms captures their taxonomic groups, showing evolutionary relevance for our definition. Therefore, we present a quantitative and experimentally supported definition of housekeeping genes that can contribute to better understanding of their unique biological and evolutionary characteristics.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1010295","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T13:43:43Z","timestamp":1657719823000},"page":"e1010295","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":139,"title":["What are housekeeping genes?"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9339-2511","authenticated-orcid":true,"given":"Chintan J.","family":"Joshi","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7047-5445","authenticated-orcid":true,"given":"Wenfan","family":"Ke","sequence":"additional","affiliation":[]},{"given":"Anna","family":"Drangowska-Way","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0503-4181","authenticated-orcid":true,"given":"Eyleen J.","family":"O\u2019Rourke","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7700-3654","authenticated-orcid":true,"given":"Nathan E.","family":"Lewis","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,7,13]]},"reference":[{"key":"pcbi.1010295.ref001","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.tig.2013.05.010","article-title":"Human housekeeping genes, revisited","volume":"29","author":"E Eisenberg","year":"2013","journal-title":"Trends Genet"},{"key":"pcbi.1010295.ref002","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1471-2164-7-31","article-title":"Further understanding human disease genes by comparing with housekeeping genes and other genes","volume":"7","author":"Z Tu","year":"2006","journal-title":"BMC Genomics"},{"key":"pcbi.1010295.ref003","article-title":"Further defining housekeeping, or \u201cmaintenance,\u201d genes Focus on \u201cA compendium of gene expression in normal human tissues\u201d","author":"AJ Butte","year":"2001","journal-title":"Physiol Genomics"},{"key":"pcbi.1010295.ref004","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.tig.2008.08.004","article-title":"On the nature of human housekeeping genes","volume":"24","author":"J Zhu","year":"2008","journal-title":"Trends Genet"},{"key":"pcbi.1010295.ref005","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1152\/physiolgenomics.2000.2.3.143","article-title":"Comparison of human adult and fetal expression and identification of 535 housekeeping\/maintenance genes","volume":"2000","author":"JA Warrington","year":"2000","journal-title":"Physiol Genomics"},{"key":"pcbi.1010295.ref006","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S0168-1656(99)00163-7","article-title":"Housekeeping genes as internal standards: Use and limits","volume":"75","author":"O Thellin","year":"1999","journal-title":"J Biotechnol"},{"key":"pcbi.1010295.ref007","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nrg2398","article-title":"Tuning gene expression to changing environments: From rapid responses to evolutionary adaptation","author":"L L\u00f3pez-Maury","year":"2008","journal-title":"Nature Reviews Genetics"},{"key":"pcbi.1010295.ref008","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1093\/molbev\/msh010","article-title":"Mammalian Housekeeping Genes Evolve More Slowly than Tissue-Specific Genes","volume":"21","author":"L Zhang","year":"2004","journal-title":"Mol Biol Evol"},{"key":"pcbi.1010295.ref009","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev.genom.1.1.99","article-title":"How many genes can make a cell: The minimal-gene-set concept","volume":"1","author":"V. 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