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However, changes affecting gene dosage from the chromosome down to the individual gene level possess a significant pathological potential and can lead to developmental disorders (DDs). This indicates that expression from a balanced gene complement is highly relevant for proper cellular and organismal function in eukaryotes. Paradoxically, gene and whole chromosome duplications are a principal driver of evolution, while heteromorphic sex chromosomes (XY and ZW) are naturally occurring aneuploidies important for sex determination. Here, we provide an overview of the biology of gene dosage at the crossroads between evolutionary benefit and pathogenicity during disease. We describe the buffering mechanisms and cellular responses to alterations, which could provide a common ground for the understanding of DDs caused by copy number alterations.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009906","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T18:26:39Z","timestamp":1639074399000},"page":"e1009906","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["The good, the bad, and the ugly: Evolutionary and pathological aspects of gene dosage alterations"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1111-9459","authenticated-orcid":true,"given":"M. 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Dawes","year":"1999","journal-title":"Science"},{"key":"pgen.1009906.ref029","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/genetics\/96.1.165","article-title":"Male-specific lethal mutations of Drosophila melanogaster","volume":"96","author":"JM Belote","year":"1980","journal-title":"Genetics"},{"key":"pgen.1009906.ref030","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1101\/gad.11.2.156","article-title":"Xist-deficient mice are defective in dosage compensation but not spermatogenesis","volume":"11","author":"Y Marahrens","year":"1997","journal-title":"Genes Dev"},{"key":"pgen.1009906.ref031","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1101\/gad.281162.116","article-title":"Female mice lacking Xist RNA show partial dosage compensation and survive to term","volume":"30","author":"L Yang","year":"2016","journal-title":"Genes 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Biol."},{"key":"pgen.1009906.ref058","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature09529","article-title":"Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast","volume":"468","author":"N Pavelka","year":"2010","journal-title":"Nature"},{"key":"pgen.1009906.ref059","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1038\/s41598-018-19782-4","article-title":"Widespread modulation of gene expression by copy number variation in skeletal muscle","volume":"8","author":"L Geistlinger","year":"2018","journal-title":"Sci Rep"},{"key":"pgen.1009906.ref060","doi-asserted-by":"crossref","first-page":"r28","DOI":"10.1186\/gb-2012-13-4-r28","article-title":"Mediation of Drosophila autosomal dosage effects and compensation by network interactions","volume":"13","author":"JH Malone","year":"2012","journal-title":"Genome Biol"},{"key":"pgen.1009906.ref061","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1093\/genetics\/97.3-4.639","article-title":"The molecular basis of dominance","volume":"97","author":"H Kacser","year":"1981","journal-title":"Genetics"},{"key":"pgen.1009906.ref062","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41586-020-2287-8","article-title":"A structural variation reference for medical and population genetics2020","volume":"581","author":"RL Collins","journal-title":"Nature"},{"key":"pgen.1009906.ref063","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.gde.2016.08.001","article-title":"Human adaptation and evolution by segmental duplication","volume":"41","author":"MY Dennis","year":"2016","journal-title":"Curr Opin Genet Dev"},{"key":"pgen.1009906.ref064","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-642-86659-3","volume-title":"Evolution by Gene Duplication.","author":"S Ohno","year":"1970"},{"key":"pgen.1009906.ref065","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1093\/genetics\/141.3.1037","article-title":"The Triplo-lethal locus of Drosophila: reexamination of mutants and discovery of a second-site suppressor","volume":"141","author":"DR Dorer","year":"1995","journal-title":"Genetics"},{"key":"pgen.1009906.ref066","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/cge.12499","article-title":"Cornelia de Lange syndrome","volume":"88","author":"MI Boyle","year":"2015","journal-title":"Clin Genet"},{"key":"pgen.1009906.ref067","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1136\/jmg.2008.062471","article-title":"Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange","volume":"46","author":"J Yan","year":"2009","journal-title":"J Med Genet"},{"key":"pgen.1009906.ref068","article-title":"A cross-disorder dosage sensitivity map of the human genome","author":"RL Collins","year":"2021","journal-title":"bioRxiv. medRxiv"},{"key":"pgen.1009906.ref069","first-page":"s165","article-title":"Minor viability mutants in Drosophila","volume":"92","author":"JF Crow","year":"1979","journal-title":"Genetics"},{"key":"pgen.1009906.ref070","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1534\/genetics.104.036871","article-title":"Mechanisms of haploinsufficiency revealed by genome-wide profiling in yeast","volume":"169","author":"AM Deutschbauer","year":"2005","journal-title":"Genetics"},{"key":"pgen.1009906.ref071","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/ng.2007.49","article-title":"Identification and characterization of high-flux-control genes of yeast through competition analyses in continuous cultures","volume":"40","author":"D Delneri","year":"2008","journal-title":"Nat Genet"},{"key":"pgen.1009906.ref072","doi-asserted-by":"crossref","first-page":"e2005130","DOI":"10.1371\/journal.pbio.2005130","article-title":"High-dimensional single-cell phenotyping reveals extensive haploinsufficiency","volume":"16","author":"S Ohnuki","year":"2018","journal-title":"PLoS Biol"},{"key":"pgen.1009906.ref073","doi-asserted-by":"crossref","first-page":"15641","DOI":"10.1073\/pnas.95.26.15641","article-title":"Modeling stochastic gene expression: implications for haploinsufficiency","volume":"95","author":"DL Cook","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1009906.ref074","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1534\/g3.117.300400","article-title":"Dosage-Dependent Expression Variation Suppressed on the Drosophila Male X Chromosome","volume":"8","author":"H Lee","year":"2018","journal-title":"G3"},{"key":"pgen.1009906.ref075","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1002\/bies.10023","article-title":"Exploring the etiology of haploinsufficiency","volume":"24","author":"RA Veitia","year":"2002","journal-title":"Bioessays"},{"key":"pgen.1009906.ref076","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0168-9525(93)90050-R","article-title":"Fluxes, doses and poisons: molecular perspectives on dominance","volume":"9","author":"J Hodgkin","year":"1993","journal-title":"Trends Genet"},{"key":"pgen.1009906.ref077","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/nature01771","article-title":"Dosage sensitivity and the evolution of gene families in yeast","volume":"424","author":"B Papp","year":"2003","journal-title":"Nature"},{"key":"pgen.1009906.ref078","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0065-2660(08)60142-X","article-title":"The minute genes in Drosophila and their 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Matharu","year":"2019","journal-title":"Science"},{"key":"pgen.1009906.ref082","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/2042-6410-5-5","article-title":"Transcriptional effects of gene dose reduction","volume":"5","author":"Z-X Chen","year":"2014","journal-title":"Biol Sex Differ"},{"key":"pgen.1009906.ref083","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/nbt.3514","article-title":"Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases","volume":"34","author":"R Chen","year":"2016","journal-title":"Nat Biotechnol"},{"key":"pgen.1009906.ref084","doi-asserted-by":"crossref","first-page":"e1000650","DOI":"10.1371\/journal.pgen.1000650","article-title":"Multiple organ system defects and transcriptional dysregulation in the Nipbl(+\/-) mouse, a model of Cornelia de Lange Syndrome","volume":"5","author":"S Kawauchi","year":"2009","journal-title":"PLoS 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Xp22.31 gene dosage to Turner and Klinefelter syndromes and sex-biased phenotypes","volume":"64","author":"W Davies","year":"2021","journal-title":"Eur J Med Genet"},{"key":"pgen.1009906.ref099","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1101\/gr.262774.120","article-title":"Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism","volume":"30","author":"MR Starostik","year":"2020","journal-title":"Genome Res"},{"key":"pgen.1009906.ref100","doi-asserted-by":"crossref","first-page":"3987","DOI":"10.1038\/s41467-020-17764-7","article-title":"Developmental potential of aneuploid human embryos cultured beyond implantation","volume":"11","author":"MN Shahbazi","year":"2020","journal-title":"Nat Commun."},{"key":"pgen.1009906.ref101","doi-asserted-by":"crossref","first-page":"11165","DOI":"10.1038\/ncomms11165","article-title":"Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential","volume":"7","author":"H Bolton","year":"2016","journal-title":"Nat Commun"},{"key":"pgen.1009906.ref102","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1086\/514346","article-title":"Mendelian Inheritance in Man and its online version, OMIM","volume":"80","author":"VA McKusick","year":"2007","journal-title":"Am J Hum Genet"},{"key":"pgen.1009906.ref103","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1126\/science.aar6731","article-title":"Quantifying the contribution of recessive coding variation to developmental disorders","volume":"362","author":"HC Martin","year":"2018","journal-title":"Science"},{"key":"pgen.1009906.ref104","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/S0140-6736(14)61705-0","article-title":"Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data","volume":"385","author":"CF Wright","year":"2015","journal-title":"Lancet"},{"key":"pgen.1009906.ref105","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nature12517","article-title":"Cerebral organoids model human brain development and microcephaly","volume":"501","author":"MA Lancaster","year":"2013","journal-title":"Nature"},{"key":"pgen.1009906.ref106","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1146\/annurev.genom.7.080505.115618","article-title":"Structural variation of the human genome","volume":"7","author":"AJ Sharp","year":"2006","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"pgen.1009906.ref107","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/B978-0-12-803685-3.00018-5","volume-title":"Spinal Muscular Atrophy.","author":"Y Hua","year":"2017"},{"key":"pgen.1009906.ref108","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1038\/s41559-019-1009-9","article-title":"Massive gene amplification on a recently formed Drosophila Y chromosome","volume":"3","author":"D Bachtrog","year":"2019","journal-title":"Nat Ecol Evol"},{"key":"pgen.1009906.ref109","first-page":"440","article-title":"Self-imposed silence: parental antagonism and the evolution of X-chromosome inactivation","volume":"60","author":"D Haig","year":"2006","journal-title":"Evolution"},{"key":"pgen.1009906.ref110","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/s41594-019-0306-y","article-title":"X-chromosome upregulation is driven by increased burst frequency","volume":"26","author":"AJM Larsson","year":"2019","journal-title":"Nat Struct Mol Biol"},{"key":"pgen.1009906.ref111","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1038\/ng.948","article-title":"Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster","volume":"43","author":"X Deng","year":"2011","journal-title":"Nat 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protein complexes in aneuploid cells","volume":"33","author":"CM Brennan","year":"2019","journal-title":"Genes Dev"},{"key":"pgen.1009906.ref116","doi-asserted-by":"crossref","DOI":"10.3390\/genes11091046","article-title":"An Overview of Duplicated Gene Detection Methods: Why the Duplication Mechanism Has to Be Accounted for in Their Choice.","volume":"11","author":"T Lallemand","year":"2020","journal-title":"Genes"},{"key":"pgen.1009906.ref117","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nature02424","article-title":"Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae","volume":"428","author":"M Kellis","year":"2004","journal-title":"Nature"},{"key":"pgen.1009906.ref118","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.cell.2012.03.033","article-title":"Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication","volume":"149","author":"MY 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Magklara","year":"2011","journal-title":"Cell"},{"key":"pgen.1009906.ref125","doi-asserted-by":"crossref","first-page":"R10","DOI":"10.1186\/gb-2012-13-2-r10","article-title":"Autosomal monoallelic expression in the mouse","volume":"13","author":"LM Zwemer","year":"2012","journal-title":"Genome Biol"},{"key":"pgen.1009906.ref126","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1126\/science.1245316","article-title":"Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells","volume":"343","author":"Q Deng","year":"2014","journal-title":"Science"},{"key":"pgen.1009906.ref127","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nrg3888","article-title":"Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation","volume":"16","author":"B Reinius","year":"2015","journal-title":"Nat Rev 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