Rothschild Daphna, Pritchard Jonathan K, Barna Maria
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Senior author.
medRxiv. 2025 Sep 4:2025.09.02.25334953. doi: 10.1101/2025.09.02.25334953.
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.
真核生物核糖体RNA（rRNA）基因在被称为扩展片段（ES）的非保守区域表现出高度变异性。由于基因组中存在大量rRNA拷贝，编辑ES具有挑战性，其重要性仍不明确。在本研究中，我们分析了英国生物银行人群中的rRNA变异频率，发现高度丰富的ES变异与人类健康和生理存在因果联系。我们开发了一种核糖体变异分析（RiboVAn）方法，既识别可遗传的种系变异，也识别更大比例的低遗传度、可能是体细胞的变异。最具遗传性的变异聚集在28S rRNA的四个ES内，es15l中的特定变异与肥胖相关，es39l与身体尺寸相关，es27l与血液相关性状和疾病相关。在功能变异与某些rDNA染色体相关联的情况下，观察到变异染色体特异性。这些发现将rRNA序列变异与人类性状建立了因果联系，并确定ES在人类生理学中具有独特且重要的功能。
