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Harvey, C. J.

Publications and source records attributed to Harvey, C. J..

3 recordsLinked to original sources

geneML: Gene annotation across diverse fungal species using deep learning

Accurate gene prediction remains a major bottleneck in fungal genomics, where lineage diversity and alternative splicing challenge existing ab initio methods. Here, we present geneML, a deep learning-based gene prediction tool tailored to fungal genomes. Across nine reference genomes spanning diverse fungal taxa, geneML improved gene-level F1 score from 64.9 to 67.1 compared to BRAKER3 with protein-based hints, driven by substantially higher recall (69.0 vs. 64.1) at equivalent precision. geneML also remains fast, averaging around 6 minutes per genome on a standard 8-core CPU. A key feature of geneML is its ability to predict alternative transcripts. Compared to Fusarium graminearum Iso-Seq control data, it achieves 41.1% transcript recall and 71.1% precision, outperforming AUGUSTUS (33.8% recall, 48.9% precision), one of the few tools that support isoform prediction. The predicted transcript diversity is consistent with experimentally observed fungal alternative splicing patterns. Reannotation of the curated training dataset further suggests improved biological completeness, with geneML recovering 15.3% more genes containing complete PFAM domains than the reference annotation. These results demonstrate that geneML enables faster, more sensitive, and more biologically informative fungal genome annotation. geneML is available as an open-source command-line tool at https://github.com/hexagonbio/geneML. Key Points- geneML improves gene prediction accuracy over both classical and recent deep learning-based methods, while substantially improving recall. - geneML predicts alternative transcripts with higher precision and recall than AUGUSTUS, expanding functional annotation. - Runtime was 32-fold decreased over BRAKER3, enabling efficient high-throughput genome annotation. - geneML identifies novel genes and recovers missing annotations, especially in under-annotated non-Ascomycete genomes.

bioinformatics↗

An antifungal with a novel mechanism of action discovered via resistance gene-guided genome mining

Invasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised individuals. Despite this, antifungal drug development has stagnated, with few novel agents and fewer novel targets explored in recent decades. Here, we validate acetolactate synthase (ALS), an enzyme critical for branched-chain amino acid biosynthesis and absent in humans, as a promising target for new therapeutics. Using resistance gene-guided genome mining, we discovered a biosynthetic gene cluster in Aspergillus terreus encoding HB-35018 (1), a novel spiro-cis-decalin tetramic acid that potently inhibits ALS. Biochemical and antifungal assays demonstrate that 1 surpasses existing ALS inhibitors in efficacy against Aspergillus fumigatus and other pathogenic fungi. Structural studies via cryo-electron microscopy reveal a unique covalent binding interaction between compound 1 and ALS, distinct from known inhibitors and finally, we demonstrate that ALS is essential for the virulence in a mouse model of invasive aspergillosis. These findings position ALS as a promising target for antifungal development and demonstrate the potential of resistance gene-guided genome mining for antifungal discovery.

bioengineering↗

HEx: a heterologous expression platform for the discovery of fungal natural products

For decades, fungi have been a source of FDA-approved natural products such as penicillin, cyclosporine, and the statins. Recent breakthroughs in DNA sequencing suggest that millions of fungal species exist on Earth with each genome encoding pathways capable of generating as many as dozens of natural products. However, the majority of encoded molecules are difficult or impossible to access because the organisms are uncultivable or the genes are transcriptionally silent. To overcome this bottleneck in natural product discovery, we developed the HEx (Heterologous EXpression) synthetic biology platform for rapid, scalable expression of fungal biosynthetic genes and their encoded metabolites in Saccharomyces cerevisiae. We applied this platform to 41 fungal biosynthetic gene clusters from diverse fungal species from around the world, 22 of which produced detectable compounds. These included novel compounds with unexpected biosynthetic origins, particularly from poorly studied species. This result establishes the HEx platform for rapid discovery of natural products from any fungal species, even those that are uncultivable, and opens the door to discovery of the next generation of natural products.\n\nSummaryHere we present the largest scale effort reported to date toward the complete refactoring and heterologous expression of fungal biosynthetic gene clusters utilizing HEx, a novel synthetic biology platform.

synthetic biology↗