Eukaryotic ribosomal RNA (rRNA) genes exhibit hyper-variability at non-conserved regions known as Expansion Segments (ESs). Due to the numerous rRNA copies in the genome, editing ESs is challenging, and their significance remains unclear. In this study, we analyze rRNA variant frequencies in the UK Biobank population, revealing that highly abundant ES variations are causally linked to human health and physiology. We developed a Ribosome Variation Analysis (RiboVAn) method, identifying both heritable germline variants and a larger proportion of low-heritability, likely somatic variants. The most heritable variants cluster within four ESs of the 28S rRNA, with specific variants in es15l associated with adiposity, es39l linked to body dimensions, and es27l associated with blood-related traits and diseases. Variant-chromosome specificity is observed where functional variants are linked to certain rDNA chromosomes. These findings causally link rRNA sequence variation to human traits and establish that ESs have distinct and important functions in human physiology.

The authors have declared no competing interest.

M.B. is supported by the National Institutes of Health grant R01HD086634. J.K.P. and D.R are supported by RO1 HG014005 and HG008140.

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The study used the whole genome sequencing and phenotypes of the UKBB cohort and the whole genome sequencing of the H7-hESC cell line. Both UKBB and H7-hESC are published datasets. The H7-hESC rDNA is available under BioProject ID PRJNA926787 under accession numbers SRR23196516 (H7-hESC whole genome sequencing).

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↵3 Senior author

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In this study we analyzed the whole genome sequencing and phenotypes of the UKBB cohort and the whole genome sequencing of the H7-hESC cell line. Both UKBB and H7-hESC are published datasets. The H7-hESC rDNA is available under BioProject ID PRJNA926787 under accession numbers SRR23196516 (H7-hESC whole genome sequencing). We generated an extended ES atlas with extended 150bp reference sequences as Extended Data to this publication (Data S1). This is the same ES atlas as we previously published 8 with 150bp flanking reference sequences to allow longer 150bp reads found in the UKBB dataset to map to the atlas. The RiboVAn pipeline is available at https://github.com/daphnar/rRNA/RiboVan

https://github.com/daphnar/rRNA/RiboVan