Genetic variation at mouse and human ribosomal DNA influences associated epigenetic states

Francisco Rodriguez-Algarra, Robert A.E. Seaborne, Amy F. Danson, Selin Yildizoglu, Harunori Yoshikawa, Pui Pik Law, Zakaryya Ahmad, Victoria A. Maudsley, Ama Brew, Nadine Holmes, Mateus Ochôa, Alan Hodgkinson, Sarah J. Marzi, Madapura M. Pradeepa, Matthew Loose, Michelle L. Holland, Vardhman K. Rakyan

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


BACKGROUND: Ribosomal DNA (rDNA) displays substantial inter-individual genetic variation in human and mouse. A systematic analysis of how this variation impacts epigenetic states and expression of the rDNA has thus far not been performed. RESULTS: Using a combination of long- and short-read sequencing, we establish that 45S rDNA units in the C57BL/6J mouse strain exist as distinct genetic haplotypes that influence the epigenetic state and transcriptional output of any given unit. DNA methylation dynamics at these haplotypes are dichotomous and life-stage specific: at one haplotype, the DNA methylation state is sensitive to the in utero environment, but refractory to post-weaning influences, whereas other haplotypes entropically gain DNA methylation during aging only. On the other hand, individual rDNA units in human show limited evidence of genetic haplotypes, and hence little discernible correlation between genetic and epigenetic states. However, in both species, adjacent units show similar epigenetic profiles, and the overall epigenetic state at rDNA is strongly positively correlated with the total rDNA copy number. Analysis of different mouse inbred strains reveals that in some strains, such as 129S1/SvImJ, the rDNA copy number is only approximately 150 copies per diploid genome and DNA methylation levels are < 5%. CONCLUSIONS: Our work demonstrates that rDNA-associated genetic variation has a considerable influence on rDNA epigenetic state and consequently rRNA expression outcomes. In the future, it will be important to consider the impact of inter-individual rDNA (epi)genetic variation on mammalian phenotypes and diseases.

Original languageEnglish
Article number54
Pages (from-to)54
Number of pages1
JournalGenome Biology
Issue number1
Publication statusPublished - 14 Feb 2022


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