Selection and surveillance of 5S ribosomal RNA genes in human populations

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SUMMARY The 5S ribosomal RNA gene is present in the human genome not once but in ∼80 copies, arranged head to tail in a single array of ribosomal DNA on chromosome 1 - one of the most repetitive and least explored regions of the genome. Its product is one of the four RNAs in every ribosome and, when ribosome assembly fails, it activates the tumour suppressor p53. Whether these copies vary in sequence between people, and whether such variation has physiological or pathological consequences, is unknown. Using telomere-to-telomere genome assemblies, whole-genome sequences from ∼490 000 UK Biobank participants, and ∼940 GTEx transcriptomes, we find that every person carries copies bearing substitutions or indels, and that ∼10% of people express such variant 5S rRNA. Mutating every position of the gene in vitro , we find that variants blocking incorporation into the ribosome map to the uL5/uL18 interface and activate p53. Remarkably, these same variants are depleted from human populations: selection has acted on the step that p53 monitors. Ribosomal DNA is thus a functional source of human genetic variation, long invisible to genome-wide analysis and shaped by the p53 pathway it controls. HIGHLIGHTS A single chromosome-1 array makes every person a carrier of variant 5S rRNA genes Saturation mutagenesis maps 5S variants that block assembly and activate p53 Assembly-blocking variants are purged from human populations via p53 surveillance eTOC Sengl et al. resolve sequence variation across the human 5S rDNA array, one of the genome’s least-explored regions. Variant 5S rRNAs are expressed; and variants that block ribosome assembly activate p53 and are removed from human populations by selection. Abstract Figure

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