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Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232573 | GEO | 2024/02/06

REPOSITORIES: GEO

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Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [rare_3utr_gnomad.motif_activity]

Project description:Understanding the function of rare non-coding genetic variants represents a significant challenge. Here, we developed MapUTR, a screen to identify rare 3’ UTR variants affecting mRNA abundance post-transcriptionally. Among 17,301 rare variants, an average of 24.5% were functional, with 70% in cancer-related genes, many in critical cancer pathways. This observation motivated a further interrogation of 11,929 cancer somatic mutations, uncovering 3,928 (33%) functional mutations in well-established cancer driver genes, such as CDKN2A. Functional MapUTR variants were enriched in miRNA targets and protein-RNA interaction sites. Based on MapUTR, we define a new metric, untranslated tumor mutation burden (uTMB), reflecting the amount of somatic functional MapUTR variants of a tumor. We showed the potential of uTMB in predicting patient survival. Through prime editing, we characterized three variants in cancer-relevant genes (MFN2, FOSL2, and IRAK1), illustrating their cancer-driving potential. Our study elucidates the function of thousands of non-coding variants, nominates non-coding cancer driver mutations, and demonstrates their potential contributions to cancer.

2024-02-06 | GSE232571 | GEO

Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [prime_editing_3utr]

2024-02-06 | GSE232570 | GEO

Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [rare_cosmic]

2024-02-06 | GSE232572 | GEO

Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes

Project description:Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes

| PRJNA972738 | ENA

Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [prime_editing_3utr]

Project description:Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [prime_editing_3utr]

| PRJNA972739 | ENA

Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [rare_3utr_gnomad.motif_activity]

Project description:Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [rare_3utr_gnomad.motif_activity]

| PRJNA972741 | ENA

Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [rare_cosmic]

Project description:Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [rare_cosmic]

| PRJNA972740 | ENA

A Massively Parallel Screen of 5'UTR Mutations Identifies Variants Impacting Translation and Protein Production in Neurodevelopmental Disorder Genes.

Project description:De novo mutations cause a variety of neurodevelopmental disorders including autism. Recent whole genome sequencing from individuals with autism has shown that many de novo mutations also occur in untranslated regions (UTRs) of genes, but it is difficult to predict from sequence alone which mutations are functional, let alone causal. Therefore, we developed a high throughput assay to screen the transcriptional and translational effects of 997 variants from 5'UTR patient mutations. This assay successfully enriched for elements that alter reporter translation, identifying over 100 potentially functional mutations from probands. Studies in patient-derived cell lines further confirmed that these mutations can alter protein production in individuals with autism, and some variants fall in genes known to cause syndromic forms of autism, suggesting a diagnosis for these individual patients. Since UTR function varies by cell type, we further optimized this high throughput assay to enable assessment of mutations in neurons in vivo. First, comparing in cellulo to in vivo results, we demonstrate neurons have different principles of regulation by 5'UTRs, consistent with a more robust mechanism for reducing the impact of RNA secondary structure. Finally, we discovered patient mutations specifically altering the translational activity of additional known syndromic genes LRRC4 and ZNF644 in neurons of the brain. Overall our results highlight a new approach for assessing the impact of 5'UTR mutations across cell types and suggest that some cases of neurodevelopmental disorder may be caused by such variants.

| S-EPMC10635273 | biostudies-literature

Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution.

Project description:3' untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3'UTR function, suggesting that simple sequences predominately explain 3'UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3'UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.

| S-EPMC8487971 | biostudies-literature

A Massively Parallel Screen of 5′UTR Mutations Identifies Variants Impacting Translation and Protein Production in Neurodevelopmental Disorder Genes

Project description:De novo mutations cause a variety of neurodevelopmental disorders including autism. Recent whole genome sequencing has identified hundreds of mutations in untranslated regions (UTRs) of genes from individuals with autism, but it is impossible to predict from sequence alone which are functional, and thus might be causal. Therefore, we developed a high throughput assay to screen the consequence over 1,000 variants from 5'UTRs mutations on transcript abundance and translation efficiency. This assay successfully enriched for elements that alter reporter translation, identifying over 100 potentially functional mutations. Studies in patient-derived cell lines further confirmed these mutations alter protein production in individuals in autism, including for multiple genes known to cause of syndromic forms autism, suggesting a diagnosis for these individual patients. Since UTR function varies by cell type, we further optimized this high throughput assay to enable assessment of mutations in neurons of the living brain. Neurons demonstrate profoundly different principles of regulation by 5'UTRs, consistent with more robust mechanism for reducing impact of 5'UTR RNA structure. Overall our results highlight a new approach for assessing the impact of 5’UTR across cell types and suggest some cases of neurodevelopmental disorder may be caused by such variants.

2023-11-08 | GSE246381 | GEO

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