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Nxf1 natural variant E610G is a semi-dominant suppressor of IAP-induced RNA processing defects.

ABSTRACT: Endogenous retroviruses and retrotransposons contribute functional genetic variation in animal genomes. In mice, Intracisternal A Particles (IAPs) are a frequent source of both new mutations and polymorphism across laboratory strains. Intronic IAPs can induce alternative RNA processing choices, including alternative splicing. We previously showed IAP I∆1 subfamily insertional mutations are suppressed by a wild-derived allele of the major mRNA export factor, Nxf1. Here we show that a wider diversity of IAP insertions present in the mouse reference sequence induce insertion-dependent alternative processing that is suppressed by Nxf1CAST alleles. These insertions typically show more modest gene expression changes than de novo mutations, suggesting selection or attenuation. Genome-wide splicing-sensitive microarrays and gene-focused assays confirm specificity of Nxf1 genetic modifier activity for IAP insertion alleles. Strikingly, CRISPR/Cas9-mediated genome editing demonstrates that a single amino acid substitution in Nxf1, E610G, is sufficient to recreate a quantitative genetic modifier in a co-isogenic background.

SUBMITTER: Concepcion D

PROVIDER: S-EPMC4383553 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Funding institutions often solicit text-based research proposals to evaluate potential recipients. Leveraging the information contained in these documents could help institutions understand the supply of research within their domain. In this work, an end-to-end methodology for semi-supervised document clustering is introduced to partially automate classification of research proposals based on thematic areas of interest. The methodology consists of three stages: (1) manual annotation of a document sample; (2) semi-supervised clustering of documents; (3) evaluation of cluster results using quantitative metrics and qualitative ratings (coherence, relevance, distinctiveness) by experts. The methodology is described in detail to encourage replication and is demonstrated on a real-world data set. This demonstration sought to categorize proposals submitted to the US Army Telemedicine and Advanced Technology Research Center (TATRC) related to technological innovations in military medicine. A comparative analysis of method features was performed, including unsupervised vs. semi-supervised clustering, several document vectorization techniques, and several cluster result selection strategies. Outcomes suggest that pretrained Bidirectional Encoder Representations from Transformers (BERT) embeddings were better suited for the task than older text embedding techniques. When comparing expert ratings between algorithms, semi-supervised clustering produced coherence ratings ~ 25% better on average compared to standard unsupervised clustering with negligible differences in cluster distinctiveness. Last, it was shown that a cluster result selection strategy that balances internal and external validity produced ideal results. With further refinement, this methodological framework shows promise as a useful analytical tool for institutions to unlock hidden insights from untapped archives and similar administrative document repositories.Supplementary informationThe online version contains supplementary material available at 10.1007/s11192-023-04689-3.

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Nxf1 natural variant E610G is a semi-dominant suppressor of IAP-induced RNA processing defects.

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