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- Title
Disrupting upstream translation in mRNAs is associated with human disease.
- Authors
Lee, David S. M.; Park, Joseph; Kromer, Andrew; Baras, Aris; Rader, Daniel J.; Ritchie, Marylyn D.; Ghanem, Louis R.; Barash, Yoseph
- Abstract
Ribosome-profiling has uncovered pervasive translation in non-canonical open reading frames, however the biological significance of this phenomenon remains unclear. Using genetic variation from 71,702 human genomes, we assess patterns of selection in translated upstream open reading frames (uORFs) in 5'UTRs. We show that uORF variants introducing new stop codons, or strengthening existing stop codons, are under strong negative selection comparable to protein-coding missense variants. Using these variants, we map and validate gene-disease associations in two independent biobanks containing exome sequencing from 10,900 and 32,268 individuals, respectively, and elucidate their impact on protein expression in human cells. Our results suggest translation disrupting mechanisms relating uORF variation to reduced protein expression, and demonstrate that translation at uORFs is genetically constrained in 50% of human genes. The significance of translated upstream open reading frames is not well known. Here, the authors investigate genetic variants in these regions, finding that they are under high evolutionary constraint and may contribute to disease.
- Subjects
STOP codons; GENETIC translation; EXOMES; PHENOMENOLOGICAL biology; PROTEIN expression; HUMAN genes; TRANSLATIONS
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-21812-1