The intronic branch point sequence is under strong evolutionary constraint in the bovine and human genome

Communications Biology, Journal Year: 2021, Volume and Issue: 4(1)

Published: Oct. 21, 2021

Abstract The branch point sequence is a cis-acting intronic motif required for mRNA splicing. Despite their functional importance, sequences are not routinely annotated. Here we predict in 179,476 bovine introns and investigate variability using catalogue of 29.4 million variants detected 266 cattle genomes. We localize the within degenerate heptamer “nnyTrAy”. An adenine residue at position 6, that acts as point, thymine 4 more strongly depleted mutations than coding suggesting extreme purifying selection. provide evidence affecting these evolutionarily constrained residues lead to alternative confirm evolutionary constraints on 115 SNPs established from 3,942 human genomes gnomAD database.

Language: Английский

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CRNKL1 Is a Highly Selective Regulator of Intron-Retaining HIV-1 and Cellular mRNAs

mBio, Journal Year: 2021, Volume and Issue: 12(1)

Published: Jan. 18, 2021

The HIV-1 Rev protein is a nuclear export factor for unspliced and incompletely spliced RNAs. Without Rev, these intron-retaining RNAs are trapped in the nucleus. A genome-wide screen identified nine proteins of spliceosome, which all enhanced expression from RNA after CRISPR/Cas knockdown. Depletion DHX38, WDR70, four Prp19-associated complex (ISY1, BUD31, XAB2, CRNKL1) resulted more than 20-fold enhancement levels cytoplasm. Targeting CRNKL1, BUD31 affected efficiencies to much larger extent splicing. Transcriptomic analyses further revealed that CRNKL1 also suppresses cytoplasmic subset cellular mRNAs, including some with selectively retained introns. Thus, CRNKL1-dependent retention novel mechanism regulation may have harnessed direct its splicing pattern.IMPORTANCE To regulate pattern, uses adaptor shuttle or partially mRNA nucleus In absence nucleus, but it unclear why. Here we identify whose depletion enhances RNA. one them, increases mRNA, suggesting be basic exploited by HIV-1.

Language: Английский

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TDP-43 maximizes nerve conduction velocity by repressing a cryptic exon for paranodal junction assembly in Schwann cells

eLife, Journal Year: 2021, Volume and Issue: 10

Published: March 10, 2021

TDP-43 is extensively studied in neurons physiological and pathological contexts. However, emerging evidence indicates that glial cells are also reliant on function. We demonstrate deletion of Schwann results a dramatic delay peripheral nerve conduction causing significant motor deficits mice, which directly attributed to the absence paranodal axoglial junctions. By contrast, paranodes central nervous system unaltered oligodendrocytes lacking TDP-43. Mechanistically, binds Neurofascin mRNA, encoding cell adhesion molecule essential for paranode assembly maintenance. Loss triggers retention previously unidentified cryptic exon, targets mRNA nonsense-mediated decay. Thus, required neurofascin expression, proper maintenance paranodes, rapid saltatory conduction. Our findings provide framework mechanism how cell-autonomous dysfunction caused by loss-of-function.

Language: Английский

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Manual annotation of Drosophila genes: a Genomics Education Partnership protocol

F1000Research, Journal Year: 2023, Volume and Issue: 11, P. 1579 - 1579

Published: Oct. 13, 2023

Annotating the genomes of multiple species allows us to analyze evolution their genes. While many eukaryotic genome assemblies already include computational gene predictions, these predictions can benefit from review and refinement through manual annotation. The Genomics Education Partnership (GEP; https://thegep.org/) developed a structural annotation protocol for protein-coding genes that enables undergraduate student faculty researchers create high-quality annotations be utilized in subsequent scientific investigations. For example, this has been by GEP engage students comparative involved insulin signaling pathway 27 Drosophila species, using D. melanogaster as reference genome. Students construct models lines empirical evidence including expression data (e.g., RNA-Seq), sequence similarity BLAST alignment), predictions. Quality control measures require each annotated at least two working independently, followed reconciliation submitted more experienced student. This article provides an overview describes how discrepancies are resolved produce final, set suitable analyses. adapted other questions expansion Muller F element) parasitoid wasps) provide additional opportunities participate genomics research. These efforts substantially improve quality publicly available genomic databases.

Language: Английский

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Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: Oct. 28, 2020

Abstract Microglial cells have emerged as potential key players in brain aging and pathology. To capture the heterogeneity of microglia across ages regions, to understand how genetic risk for neurological psychiatric disorders is related microglial function, large transcriptome studies are essential. Here, we describe analysis 255 primary human samples isolated at autopsy from multiple regions 100 subjects. We performed systematic analyses investigate various aspects heterogeneities, including region, age sex. mapped expression splicing quantitative trait loci showed that many disease susceptibility mediated through gene or microglia. Fine-mapping these nominated candidate causal variants within microglia-specific enhancers, novel associations with USP6NL Alzheimer’s disease, P2RY12 Parkinson’s disease. In summary, built most comprehensive catalog date effects on propose molecular mechanisms action functional several diseases.

Language: Английский

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