title: Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes.
abstract: Tandemly repeated ribosomal DNA (rDNA) arrays are among the most evolutionary dynamic loci of eukaryotic genomes. The loci code for essential cellular components, yet exhibit extensive copy number (CN) variation within and between species. CN might be partly determined by the requirement of dosage balance between the 5S and 45S rDNA arrays. The arrays are nonhomologous, physically unlinked in mammals, and encode functionally interdependent RNA components of the ribosome. Here we show that the 5S and 45S rDNA arrays exhibit concerted CN variation (cCNV). Despite 5S and 45S rDNA elements residing on different chromosomes and lacking sequence similarity, cCNV between these loci is strong, evolutionarily conserved in humans and mice, and manifested across individual genotypes in natural populations and pedigrees. Finally, we observe that bisphenol A induces rapid and parallel modulation of 5S and 45S rDNA CN. Our observations reveal a novel mode of genome variation, indicate that natural selection contributed to the evolution and conservation of cCNV, and support the hypothesis that 5S CN is partly determined by the requirement of dosage balance with the 45S rDNA array. We suggest that human disease variation might be traced to disrupted rDNA dosage balance in the genome.
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard University T. H. Chan School of Public Health, Boston, MA 02115; and.
authors.forename: John G
authors.initials: JG
authors.lastname: Gibbons
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard University T. H. Chan School of Public Health, Boston, MA 02115; and.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Branco
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Susana A
authors.initials: SA
authors.lastname: Godinho
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard University T. H. Chan School of Public Health, Boston, MA 02115; and.
authors.forename: Shoukai
authors.initials: S
authors.lastname: Yu
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard University T. H. Chan School of Public Health, Boston, MA 02115; and blemos@hsph.harvard.edu.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Lemos
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000187:drug effects / Q000235:genetics*; D004275:DNA, Ribosomal / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D016678:Genome / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D010375:Pedigree; D010636:Phenols / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics; D012341:RNA, Ribosomal, 5S / Q000235:genetics; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004275:DNA, Ribosomal; D010636:Phenols; D012335:RNA, Ribosomal; D012341:RNA, Ribosomal, 5S; C088179:RNA, ribosomal, 45S; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: bisphenol A; concerted evolution; gene dosage balance; nucleolus; ribosome