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Gilchrist, C. L. M.

Publications and source records attributed to Gilchrist, C. L. M..

7 recordsLinked to original sources

An nf-core framework for the systematic comparison of alternative modeling tools: the multiple sequence alignment case study

The computational complexity of many key bioinformatics problems has resulted in numerous alternative heuristic solutions, where no single approach consistently outperforms all others. This creates difficulties for users trying to identify the most suitable tool for their dataset and for developers managing and evaluating alternative methods. As data volumes grow, deploying these methods becomes increasingly difficult, highlighting the need for standardized frameworks for seamless tool deployment and comparison in HPC environments. Multiple sequence aligners (MSAs) rank among the most commonly employed modeling techniques in bioinformatics, playing a crucial role in applications such as protein structure prediction, phylogenetic reconstruction, and variant effect prediction. The NP-hardness of MSAs makes them a major example of problems where heuristics stand central, as no optimal solution can be currently obtained, within the limits of operational computational requirements. Here, we present a pilot design of an nf-core framework for streamlined tool deployment and rigorous performance evaluation focusing on the MSAs software ecosystem. By integrating the most popular MSA tools and focusing on a modular, and extensible architecture, we aspire to provide a key platform supporting MSA deployment, evaluation, and algorithmics development to the MSA community, and a proof-of-principle to the wider bioinformatics community.

bioinformatics↗

Multiple Protein Structure Alignment at Scale with FoldMason

Protein structure is conserved beyond sequence, making multiple structural alignment (MSTA) essential for analyzing distantly related proteins. Computational prediction methods have vastly extended our repository of available proteins structures, requiring fast and accurate MSTA methods. Here, we introduce FoldMason, a progressive MSTA method that leverages the structural alphabet from Foldseek, a pairwise structural aligner, for multiple alignment of hundreds of thousands of protein structures, exceeding alignment quality of state-of-the-art methods, while two orders of magnitudes faster than other MSTA methods. FoldMason computes confidence scores, offers interactive visualizations, and provides essential speed and accuracy for large-scale protein structure analysis in the era of accurate structure prediction. Using Flaviviridae glycoproteins, we demonstrate how FoldMasons MSTAs support phylogenetic analysis below the twilight zone. FoldMason is free open-source software: foldmason.foldseek.com and webserver: search.foldseek.com/foldmason.

bioinformatics↗

Rapid and Sensitive Protein Complex Alignment with Foldseek-Multimer

Advances in computational structure prediction will vastly augment the hundreds of thousands of currently-available protein complex structures. Translating these into discoveries requires aligning them, which is computationally prohibitive. Foldseek-Multimer computes complex alignments from compatible chain-to-chain alignments, identified by efficiently clustering their superposition vectors. Foldseek-Multimer is 3-4 orders of magnitudes faster than the gold standard, while producing comparable alignments; allowing it to compare billions of complex-pairs in 11 hours. Foldseek-Multimer is open-source software: github.com/steineggerlab/foldseek, webserver: search.foldseek.com and the BFMD database.

bioinformatics↗

UFCG: database of universal fungal core genes and pipeline for genome-wide phylogenetic analysis of fungi

In phylogenomics the evolutionary relationship of organisms is studied by their genomic information. A common approach to phylogenomics is to extract related genes from each organism, build a multiple sequence alignment and then reconstruct evolution relations through a phylogenetic tree. Often a set of highly conserved genes occurring in single-copy, called core genes, are used for this analysis, as they allow efficient automation within a taxonomic clade. Here we introduce the Universal Fungal Core Genes (UFCG) database and pipeline for genome-wide phylogenetic analysis of fungi. The UFCG database consists of 61 curated fungal marker genes, including a novel set of 41 computationally derived core genes and 20 canonical genes derived from literature, as well as marker gene sequences extracted from publicly available fungal genomes. Furthermore, we provide an easy-to-use, fully automated and open-source pipeline for marker gene extraction, training and phylogenetic tree reconstruction. The UFCG pipeline can identify marker genes from genomic, proteomic and transcriptomic data, while producing phylogenies consistent with those previously reported, and is publicly available together with the UFCG database at https://ufcg.steineggerlab.com.

bioinformatics↗

cblaster: a remote search tool for rapid identification and visualisation of homologous gene clusters

Genes involved in coordinated biological pathways, including metabolism, drug resistance and virulence, are often collocalised as gene clusters. Identifying homologous gene clusters aids in the study of their function and evolution, however existing tools are limited to searching local sequence databases. Tools for remotely searching public databases are necessary to keep pace with the rapid growth of online genomic data. Here, we present cblaster, a Python based tool to rapidly detect collocated genes in local and remote databases. cblaster is easy to use, offering both a command line and a user-friendly graphical user interface (GUI). It generates outputs that enable intuitive visualisations of large datasets, and can be readily incorporated into larger bioinformatic pipelines. cblaster is a significant update to the comparative genomics toolbox. cblaster source code and documentation is freely available from GitHub under the MIT license (github.com/gamcil/cblaster).

bioinformatics↗

clinker & clustermap.js: Automatic generation of gene cluster comparison figures

SummaryGenes involved in biological pathways are often collocalised in gene clusters, the comparison of which can give valuable insights into their function and evolutionary history. However, comparison and visualisation of gene cluster homology is a tedious process, particularly when many clusters are being compared. Here, we present clinker, a Python based tool, and clustermap.js, a companion JavaScript visualisation library, which used together can automatically generate accurate, interactive, publication-quality gene cluster comparison figures directly from sequence files. Availability and ImplementationSource code and documentation for clinker and clustermap.js is available on GitHub (github.com/gamcil/clinker and github.com/gamcil/clustermap.js, respectively) under the MIT license. clinker can be installed directly from the Python Package Index via pip. ContactE-mail: cameron.gilchrist@research.uwa.edu.au, yitheng.chooi@uwa.edu.au

bioinformatics↗

CRISPR-mediated activation of biosynthetic gene clusters for bioactive molecule discovery in filamentous fungi

Accessing the full biosynthetic potential encoded in the genomes of fungi is limited by the low expression of most biosynthetic gene clusters (BGCs) under common laboratory culture conditions. CRISPR-mediated transcriptional activation (CRISPRa) of fungal BGC could accelerate genomics-driven bioactive secondary metabolite discovery. In this work, we established the first CRISPRa system for filamentous fungi. First, we constructed a CRISPR/dLbCas12a-VPR-based system and demonstrated the activation of a fluorescent reporter in Aspergillus nidulans. Then, we targeted the native nonribosomal peptide synthetase-like (NRPS-like) gene micA in both chromosomal and episomal contexts, achieving increased production of the compound microperfuranone. Finally, multi-gene CRISPRa led to the discovery of the mic cluster product as dehydromicroperfuranone. Additionally, we demonstrated the utility of the variant dLbCas12aD156R-VPR for CRISPRa at room temperature culture conditions. Different aspects that influence the efficiency of CRISPRa in fungi were investigated, providing a framework for the further development of fungal artificial transcription factors based on CRISPR/Cas.Competing Interest StatementThe authors have declared no competing interest.View Full Text

synthetic biology↗