bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.09.09.287912

Disrupting upstream translation in mRNAs leads to loss-of function associated with human disease

Lee, D. S. M.·Park, J.·Kromer, A.·Regeneron Genetics Center,·Rader, D. J.·Ritchie, M. D.·Ghanem, L. R.·Barash, Y.
View original source ↗Export metadata ↓

Abstract

Ribosome-profiling has uncovered pervasive translation in 5UTRs, 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 5UTRs. 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 new gene-disease associations in two independent biobanks containing exome sequencing from 10,900 and 32,268 individuals respectively, and demonstrate their impact on gene expression in human cells. Our results establish new mechanisms relating uORF variation to loss-of-function of downstream genes, and demonstrate that translated uORFs are genetically constrained regulatory elements in 40% of human genes.

Source connections

Explore related subjects

genomicsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Lee, D. S. M., Park, J., Kromer, A., Regeneron Genetics Center,, Rader, D. J., Ritchie, M. D., Ghanem, L. R., Barash, Y.. 2020-09-12. Disrupting upstream translation in mRNAs leads to loss-of function associated with human disease. https://doi.org/10.1101/2020.09.09.287912

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Braarudosphaera bigelowii genome reveals cellular remodeling around a nitrogen-fixing organelle

Braarudosphaera bigelowii hosts the nitrogen-fixing cyanobacterial organelle UCYN-A, or the nitroplast, but the absence of a reference genome has limited investigation of the genomic features accompanying this association. Here, we present nuclear and organellar genome resources for the cultured B. bigelowii strain FR-21. The assembly comprises a 472.1-Mb nuclear genome together with representative nitroplast, chloroplast, and mitochondrial genomes of 1.49 Mb, 107 kb, and 44 kb, respectively. The four genomic compartments have strongly differentiated GC compositions, consistent with their distinct evolutionary origins. The large nuclear genome does not appear to reflect a corresponding expansion of protein-coding capacity. Repeat annotation indicates that approximately 77% of the nuclear assembly is repetitive, leaving approximately 108 Mb of nonrepetitive sequence containing roughly 16,000 predicted protein-coding genes. Phylogenomic analysis places B. bigelowii within the expected diversity of haptophytes, indicating that its unusual diazotrophic lifestyle is not associated with an anomalous phylogenetic position. Comparative analysis of nitrogen metabolism genes reveals extensive remodeling of host nitrogen acquisition and assimilation. B. bigelowii lacks major components required for nitrate and nitrite assimilation and has reduced capacity to use urea, cyanate, and several internally recycled nitrogen sources. In contrast, ammonium transport and the glutamine synthetase-glutamate synthase pathway are retained. This combination suggests reduced flexibility in nitrogen use and a host metabolism increasingly centered on ammonium supplied by the nitroplast. B. bigelowii also encodes an expanded set of flavodoxin and cryptochrome genes. Eleven of 14 flavodoxin candidates and 21 of 39 cryptochrome candidates contained motifs linked to nitroplast targeting. Together with previous evidence that some of these proteins are abundantly imported into the nitroplast, these expansions point to host-encoded roles in nitroplast redox metabolism and diel regulation. These genome resources establish a foundation for investigating nitroplast protein import, host-organelle metabolic integration, and the genomic consequences of acquiring an intracellular nitrogen-fixing compartment. They further show that the evolution of the B. bigelowii-UCYN-A relationship involved substantial remodeling of genome architecture and nitrogen metabolism in both partners.

genomics↗
bioRxiv2026

Dissecting functional elements in giant genomes using the first generation of high quality salamander assemblies

Salamanders are an enduring and historically significant group that helped originate multiple scientific fields of study, including regeneration, cytogenetics, experimental embryology, cloning, evolutionary developmental biology and evolution of extreme genome size. We generated a high-quality, single haplotype assembly for the 32 Gb axolotl (Ambystoma mexicanum) genome using an F1 hybrid between axolotl and a divergent relative the tiger salamander (A. tigrinum). Using multi-genome alignments to other salamanders that meet VGP metrics, we leveraged strong conservation of karyotypic structure to identify >523,000 highly conserved non-coding elements within massively expanded intronic and intergenic regions, the vast majority of which are unique to the salamander lineage. Orthogonal measures of chromatin state and enhancer activity confirmed that many conserved elements correspond to cis-regulatory sequences and identified several thousand that are utilized during regeneration. The conserved elements identified here will enable robust functional genomic analyses of tissue regeneration and other traits that uniquely empower salamander models in biological research.

genomics↗
bioRxiv2026

Genomic Correlates of APOBEC-Associated Mutagenesis in Esophageal Squamous Cell Carcinoma

Background and Aims: APOBEC-associated mutagenesis is prominent in esophageal squamous cell carcinoma (ESCC), but genomic features associated with its intertumoral variability remain incompletely characterized. We investigated genomic correlates of APOBEC-associated mutagenesis while accounting for the compositional structure of mutational signature data. Methods: Mutational signatures were analyzed in 552 ESCC tumors from eight countries. APOBEC-associated mutagenesis was quantified as SBS2 plus SBS13 using absolute mutation counts and proportional contributions. Associations with co-occurring mutational signatures, total SBS burden, recurrent driver-gene alterations, and country were evaluated using correlation, sensitivity, and multivariable analyses. Principal component and regression-model robustness were additionally assessed. Results: APOBEC burden varied markedly across tumors (median, 2,002 mutations; IQR, 987-4,346). Several associations observed using signature proportions were not maintained in absolute-count analyses: SBS1, SBS3, and SBS5 changed direction, indicating sensitivity to compositional representation. In contrast, SBS18 remained inversely associated with APOBEC-associated mutagenesis in all variable pairings examined: proportion versus proportion (Spearman rho = -0.527), APOBEC proportion versus SBS18 absolute count (r = -0.435), and absolute count versus absolute count (Pearson r = -0.319, P = 1.59 x 10^-14; Spearman rho = -0.317). These are distinct comparisons rather than discrepant estimates. Notably, this cohort-wide relationship was primarily characterized by higher APOBEC burden in SBS18-negative than SBS18-positive tumors rather than a continuous inverse relationship among SBS18-positive tumors. The multivariable model had an in-sample R^2 of 0.400 but lower and variable 10-fold cross-validated performance (mean R^2 = 0.273). Country added little explanatory information to this model (delta R^2 = 0.008; global P = 0.402). ZNF750-mutant tumors had higher APOBEC burden than wild-type tumors (BH-FDR q = 0.0032), although only 12 tumors carried ZNF750 alterations. Conclusion: Genomic correlates of APOBEC-associated mutagenesis in ESCC are sensitive to the representation of mutational signature activity. SBS18 showed the most consistent inverse association, whereas the ZNF750 association warrants independent validation.

genomics↗