Ribosome heterogeneity arising from common and rare rRNA sequence variants affects diverse human phenotypes

Abstract

rRNA genes exhibit intra-individual hyper-variability and an outstanding question is their role in human health and disease. These include variants positioned at enigmatic regions of rRNA named Expansion-Segments (ESs) that protrude from the core of the ribosome, with poorly understood functions. In this study, we analyze rRNA variants in the UK Biobank population, revealing that common rRNA variations that give rise to ribosome subtypes, affect human physiology and rare rRNA-mutations affect diseases. We developed a Ribosome-Variation-Analysis (RiboVAn) method, identifying ribosome subtypes as heritable and a larger proportion of low-heritability rRNA-mutations. The heritable variants included ones in es15l associated with adiposity, es39l with body dimensions, and es27l with blood-related traits and diseases. Variant-chromosome specificity is observed where ribosome subtypes are linked to distinct acrocentric chromosomes. Burden analysis linked rRNA-mutations to diverse diseases including cancer and acute myocardial infarction. These findings causally link rRNA variation to human traits, disease, and establish that ESs have distinct and important functions in human physiology.