Disrupting upstream translation in mRNAs is associated with human disease

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.

Somatic Functional Deletions of Upstream Open Reading Frame-Associated Initiation and Termination Codons in Human Cancer

“…Therefore, we assume that functional ablation of the uStop codon is the predominant cause for the observed decrease of CDS translation in this case. Upstream ORF-associated termination codons and the surrounding sequence context have been shown to mediate important regulatory functions, as discussed above for GCN4 [47] and recently described by Lee and colleagues [57]. In the context of carcinogenesis, a four bp frameshift mutation in a uORF of cyclin dependent kinase 1B (CDKN1B) was shown to induce a phenotype resembling multiple endocrine neoplasia syndrome type 4 by shifting the original uORF termination codon into another reading frame, leading to substantial lengthening of the uORF and the repression of CDKN1B CDS translation [29].…”

Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

“…This type of classification underpins the function through which different variants associate with disease etiology. For example, functional variants that occur in transcribed portions of the genome generally associate with altered transcript message or function (manifested as modified exonic sequences, alternative splicing, modified UTRs, altered ncRNA folding and/or gene fusions [96][97][98]). Interestingly, most GWAS/transcribed regulatory variants are not limited to protein coding genes but primarily localize in transcribed non-coding sequences that may generate regulatory transcripts with low or no protein coding potential [99][100][101][102].…”

Triazolyl Dibenzo[a,c]phenazines Stabilize Telomeric G‐quadruplex and Inhibit Telomerase

“…These structures consist of G‐quartets, formed by the association of four guanine bases through the hydrogen bonding interactions of Hoogsteen type base‐pairing [1b] . They are prevalent at crucial positions of the genome, including telomeric ends, promoter regions (e. g., cMYC , [3] BCL 2 , [4] c‐KIT , [5] VEGF , [6] KRAS [7] ), introns, [8] untranslated regions (UTRs), [9,10] etc [8,9,11,12] . G4s present in the telomeric region in particular, were among the first G4 structures found to be biologically relevant [13] .…”