A5105181168- RNA Research and Splicing
- RNA modifications and cancer
- Forensic and Genetic Research
- Genomics and Rare Diseases
- RNA and protein synthesis mechanisms
- Chemistry and Stereochemistry Studies
- RNA regulation and disease
- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- Genetic Neurodegenerative Diseases
- Ubiquitin and proteasome pathways
Brown University
2019-2024
John Brown University
2022-2023
To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), most common neurodevelopmental disorder, a high throughput Massively Parallel Splicing Assay (MaPSY) was employed and identified 42 exonic mutants out 725 coding de novo variants discovered sequencing ASD families. A redesign minigene constructs MaPSY revealed that upstream exons with strong 5' splice sites increase magnitude skipping phenotypes observed downstream exons. Select hits were validated by...
Humans coexisted and interbred with other hominins which later became extinct. These archaic are known to us only through fossil records for two cases, genome sequences. Here, we engineer Neanderthal Denisovan sequences into thousands of artificial genes reconstruct the pre-mRNA processing patterns these extinct populations. Of 5,169 alleles tested in this massively parallel splicing reporter assay (MaPSy), report 962 exonic mutations that correspond differences exon recognition between...
The molecular mechanism by which inborn errors of the human RNA lariat-debranching enzyme 1 (DBR1) underlie brainstem viral encephalitis is unknown. We show here that accumulation lariats in DBR1-deficient cells interferes with stress granule (SG) assembly, promoting proteasome degradation at least G3BP1 and G3BP2, two key components SGs. In turn, impaired assembly SGs, normally recruit PKR, impairs PKR activation activity against viruses, including HSV-1. Remarkably, genetic ablation...
Abstract Background The removal of introns occurs through the splicing a 5′ splice site (5′ss) with 3′ (3′ss). These two elements are recognized by distinct components spliceosome. However, in higher eukaryotes contain many matches to and splice-site motifs that presumed not be used. Results Here, we find these sites can We also occurrences AGGT motif function as either 5′ss or 3′ss—previously referred dual-specific (DSSs)—within introns. Analysis Sequence Read Archive reveals 3.1-fold...
Precision medicine and sequence-based clinical diagnostics seek to predict disease risk or identify causative variants from sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting genotype-phenotype prediction challenges; participants build models, undergo assessment, share key findings. In the past, few CAGI challenges have addressed impact sequence on splicing. CAGI5, two (Vex-seq MaPSY) involved effect variants, primarily...
Abstract High-throughput splicing assays have demonstrated that many exonic variants can disrupt splicing; however, splice-disrupting distribute non-uniformly across genes. We propose the existence of exons are particularly susceptible to variants, which we refer as hotspot exons. Hotspot also more perturbation through drug treatment and knock-down RNA-binding proteins. develop a classifier for use it infer estimate 1400 in human genome hotspots. Using panels reporters, demonstrate how...
Abstract Background DNA sequencing is increasingly incorporated into the routine care of cancer patients, many whom also carry inherited, moderate/high-penetrance variants associated with other diseases. Yet, prevalence and consequence such remain unclear. Methods We analyzed germline genomes 10,389 adult cases in TCGA cohort, identifying pathogenic/likely pathogenic autosomal-dominant genes, autosomal-recessive 59 medically actionable genes curated by American College Molecular Genetics...
Abstract Humans co-existed and interbred with other hominins which later became extinct. These archaic are known to us only through fossil records for two cases, genome sequences. Here we engineer Neanderthal Denisovan sequences into thousands of artificial genes reconstruct the pre-mRNA processing patterns these extinct populations. Of 5,224 alleles tested in this massively parallel splicing reporter assay (MaPSy), report 969 exonic mutations (ESMs) that correspond differences exon...