Ribosomal DNA copy number variation shapes human physiology and disease risk

Abstract

1Variation in ribosomal DNA (rDNA) copy number influences diverse physiological traits in model organisms, yet its consequences for human health remain poorly characterized. Here, we provide the largest analysis of 45S rDNA copy number to date and the first population-scale characterization of 5S using whole-genome sequencing from 490,383 UK Biobank participants. Despite encoding components of the same molecular machine, these arrays vary independently and associate with divergent phenotypes. Higher 45S copy number associates with common metabolic diseases, increased adiposity, and hematologi-cal signatures reminiscent of ribosomopathies. Molecular characterization reveals a coher-ent through line: elevated secretory cell-derived proteins in plasma, altered proteostasis and translation gene programs across tissues, and increased glucose-stimulated insulin secretion in primary human pancreatic islets. In contrast, 5S copy number shows no dis-ease associations but instead correlates with proportional organismal growth: increased lean mass and organ volumes. Here too, molecular signatures aligns with population-level findings, as tissue transcriptomics reveals changes to myogenic gene expression programs and altered fat metabolism. This multi-scale convergence establishes that the two human rDNA arrays function as independent genetic factors with divergent consequences for cellular physiology and human health.