A comprehensive rRNA variation atlas in health and disease

The hundreds of copies of ribosomal-DNA genes are the dark-matter of the human genome as it is unknown whether they possess sequence variation that forms different types of ribosomes. Here, we have overcome the technical hurdle of long-read sequencing of full-length ribosomal-RNA (rRNA) and developed an efficient algorithm for rRNA-variant detection. We discovered hundreds of variants that are not silent but are incorporated into translating ribosomes. These include tens of abundant variants within functionally important domains of the ribosome. Strikingly, variants assemble into distinct ribosome subtypes encoded on different chromosomes. With this first atlas of expressed rRNA-variants, we discover the impact of rRNA variation on health and disease. Across human tissues, we observe tissue-specific variant expression in endoderm/ectoderm derived tissues. In cancer, low abundant rRNA-variants become highly expressed. Together, this study provides a curated atlas for exploring rRNA variation and functionally links ribosome variation to tissue-specific biology and cancer.