Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans

Gibbons, John G.; Branco, Alan T.; Yu, Shui; Lemos, Bernardo

doi:10.1038/ncomms5850

Cited by 141 publications

(220 citation statements)

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“…By using this method, our CN estimates for a panel of CN variable genes are in close agreement with a previous study (19,35). We observed more than 10-fold variation in rDNA CN within humans and mice, with remarkable congruence in the lower and upper bounds of variation in 5S (human, minimum 16 and maximum 210; mouse, minimum 32 and maximum 224) and 45S elements (human, minimum 14 and maximum 410; mouse, minimum 31 and maximum 289; Fig.…”

Section: Resultssupporting

confidence: 77%

“…First, we developed a computational approach to determine rDNA CN across human and mouse genomes by using wholegenome DNA sequencing (DNA-seq) data (19). By using this method, our CN estimates for a panel of CN variable genes are in close agreement with a previous study (19,35).…”

Section: Resultssupporting

confidence: 63%

“…Second, we examined the robustness of the association with the data stratified by population and sex (Table S1). Third, correcting the estimates of CN to mitigate confounding factors caused by pseudogenes had a minor effect on individual estimates (Materials and Methods) (19) (Fig. S3) and did not change our estimates of the strength of cCNV.…”

Section: Resultsmentioning

confidence: 99%

“…The variation is functionally relevant with rDNA CN polymorphism modifying chromatin states and gene expression across the genome in humans and flies (17)(18)(19). In mammals, the rDNA arrays are dispersed across several chromosomes, and encode the four rRNAs that account for more than 60% of all transcription in the cell (20,21).…”

mentioning

confidence: 99%

“…CN variation in the 5S and 45S DNA elements was ascertained with short-read whole-genome sequence data (19). We applied the methodology to samples from 78 and 90 individuals with African (YRI) and European (CEU) ancestry, respectively (32), and 17 inbred laboratory strains of mice and 10 wild Mus musculus castaneus isolates (33,34).…”

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confidence: 99%

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

Gibbons

Branco

Godinho

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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177

176

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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.nucleolus | ribosome | gene dosage balance | concerted evolution | bisphenol A R epeated gene arrays have provided unique challenges to genetic and genome analyses, and have remained among the most elusive components of eukaryotic genomes (1, 2). Tandemly repeated loci of high copy number (CN) are labile, evolutionary dynamic, often subjected to concerted evolution of DNA sequences, and display abundant CN variation that emerges from high rates of repeat expansion and contraction (1). Moreover, natural selection contributes to the determination of gene CN, shaping rapid gene amplification in cancer, balanced gene loss after whole genome duplication, and optimal gene CN in locally adapted populations (3-5). For example, higher CN of the amylase gene is present in populations with starch-rich diets across organisms as diverse as humans, dogs, and fungi (3, 6, 7). Remarkably, gene CN may also be developmentally amplified in specific tissues to ensure rates of transcription in genes with high transcriptional demands (8,9). This is the case, for instance, of the chorion genes in Drosophila, which are amplified up to 80 fold in ovarian cells (10).The ribosomal DNA (rDNA) arrays display substantial CN variation within and between species (2, 11-16). The variation is functionally relevant with rDNA CN polymorphism modifying chromatin states and gene expression across the genome in humans and flies (17)(18)(19). In mammals, the rDNA arrays are dispersed across several chromosomes, and encode the four rRNAs that account for more than 60% of all transcription in the cell (20,21). Transcription of rDNA loci varies with cell and tissue type and is epigenetically regulated with allelic specificity (22, 23). The four rRNAs are indispensable structural and catalyti...

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Section: Resultssupporting

confidence: 77%

Section: Resultssupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Gibbons

Branco

Godinho

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

177

176

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18S rRNA V9 metabarcoding for diet characterization: a critical evaluation with two sympatric zooplanktivorous fish species

Albaina

Aguirre

Abad

et al. 2016

Ecology and Evolution

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The potential of the 18S rRNA V9 metabarcoding approach for diet assessment was explored using MiSeq paired‐end (PE; 2 × 150 bp) technology. To critically evaluate the method′s performance with degraded/digested DNA, the diets of two zooplanktivorous fish species from the Bay of Biscay, European sardine (Sardina pilchardus) and European sprat (Sprattus sprattus), were analysed. The taxonomic resolution and quantitative potential of the 18S V9 metabarcoding was first assessed both in silico and with mock and field plankton samples. Our method was capable of discriminating species within the reference database in a reliable way providing there was at least one variable position in the 18S V9 region. Furthermore, it successfully discriminated diet between both fish species, including habitat and diel differences among sardines, overcoming some of the limitations of traditional visual‐based diet analysis methods. The high sensitivity and semi‐quantitative nature of the 18S V9 metabarcoding approach was supported by both visual microscopy and qPCR‐based results. This molecular approach provides an alternative cost and time effective tool for food‐web analysis.

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Expansion of rDNA and pericentromere satellite repeats in the genomes of bank voles Myodes glareolus exposed to environmental radionuclides

Jernfors

Danforth

Kesäniemi

et al. 2021

Ecology and Evolution

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Altered copy number of certain highly repetitive regions of the genome, such as satellite DNA within heterochromatin and ribosomal RNA loci (rDNA), is hypothesized to help safeguard the genome against damage derived from external stressors. We quantified copy number of the 18S rDNA and a pericentromeric satellite DNA (Msat‐160) in bank voles ( Myodes glareolus ) inhabiting the Chernobyl Exclusion Zone (CEZ), an area that is contaminated by radionuclides and where organisms are exposed to elevated levels of ionizing radiation. We found a significant increase in 18S rDNA and Msat‐160 content in the genomes of bank voles from contaminated locations within the CEZ compared with animals from uncontaminated locations. Moreover, 18S rDNA and Msat‐160 copy number were positively correlated in the genomes of bank voles from uncontaminated, but not in the genomes of animals inhabiting contaminated, areas. These results show the capacity for local‐scale geographic variation in genome architecture and are consistent with the genomic safeguard hypothesis. Disruption of cellular processes related to genomic stability appears to be a hallmark effect in bank voles inhabiting areas contaminated by radionuclides.

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Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans

Cited by 141 publications

References 65 publications

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

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

18S rRNA V9 metabarcoding for diet characterization: a critical evaluation with two sympatric zooplanktivorous fish species

Expansion of rDNA and pericentromere satellite repeats in the genomes of bank voles Myodes glareolus exposed to environmental radionuclides

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