Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes

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. Significance Ribosomes are essential intracellular machines composed of proteins and RNA molecules. The DNA sequences [i.e., ribosomal DNA (rDNA)] encoding rRNAs are tandemly repeated and give rise to the nucleolus. The rRNAs are transcribed from two array kinds (the 5S and the 45S arrays). Here we show that variation in the 5S and 45S rDNA arrays is tightly coupled, despite their location on different chromosomes. Our observations suggest that natural selection contributes to maintain balanced rDNA dosage across unlinked rDNA arrays. Finally, we show that bisphenol A can induce parallel loss of rDNA units in 5S and 45S arrays. These observations raise the prospect that human diseases might be traced to disrupted rDNA dosage balance in the genome.