title: Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans.
abstract: Ribosomes are essential intracellular machines composed of proteins and RNA molecules. The DNA sequences (rDNA) encoding ribosomal RNAs (rRNAs) are tandemly repeated and give origin to the nucleolus. Here we develop a computational method for estimating rDNA dosage (copy number) and mitochondrial DNA abundance using whole-genome short-read DNA sequencing. We estimate these attributes across hundreds of human genomes and their association with global gene expression. The analyses uncover abundant variation in rDNA dosage that is coupled with the expression of hundreds of functionally coherent gene sets. These include associations with genes coding for chromatin components that target the nucleolus, including CTCF and HP1β. Finally, the data show an inverse association between rDNA dosage and mitochondrial DNA abundance that is manifested across genotypes. Our findings uncover a novel and cryptic source of hypervariable genomic diversity with global regulatory consequences (ribosomal eQTL) in humans. The variation provides a mechanism for cellular homeostasis and for rapid and reversible adaptation.
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Building 2, Room 219, Boston, Massachusetts 02115, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Gibbons
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Building 2, Room 219, Boston, Massachusetts 02115, USA.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Branco
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Building 2, Room 219, Boston, Massachusetts 02115, USA.
authors.forename: Shoukai
authors.initials: S
authors.lastname: Yu
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Building 2, Room 219, Boston, Massachusetts 02115, USA.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Lemos
mesh_terms: D002466:Cell Nucleolus / Q000378:metabolism*; D000090266:Chromobox Protein Homolog 5; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004275:DNA, Ribosomal / Q000235:genetics* / Q000378:metabolism; D004303:Dosage Compensation, Genetic; D015870:Gene Expression; D015894:Genome, Human; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D040641:Quantitative Trait Loci
chemical_list: C000715593:CBX1 protein, human; D004272:DNA, Mitochondrial; D004275:DNA, Ribosomal; D000090266:Chromobox Protein Homolog 5