Biology subjects

Angevin, L.

Publications and source records attributed to Angevin, L..

4 recordsLinked to original sources

bioRxiv2026

Sourmash accurately profiles strains from long-read metagenomes preserving gene content

Background. Metagenomic strain-level profiling remains challenging because closely related bacterial strains often share more than 99% average nucleotide identity (ANI). However, they can differ substantially in gene content and functional potential. Sourmash uses k-mer sketches with FracMinHash to compare sequencing reads against reference databases, which makes it an interesting approach for strain-level profiling. Because it compares sketches rather than full alignments, it enables fast searches against large reference databases. However, its ability to recover biologically relevant strains and preserve community gene content has not been specifically assessed. Here, we evaluated the performance of sourmash for strain-level identification abundance, functional gene content recovery, and abundance estimations using five mock communities of increasing complexity with known composition. Results. We first assessed whether nucleotide similarity reflects functional similarity between strains. Gene content similarity was generally consistent with ANI but revealed important divergences between closely related strains. For example, Escherichia coli strains sharing more than 98% ANI showed gene content similarities ranging from 20% to 57%, highlighting that nucleotide similarity alone is insufficient to assess functional proximity and consequently the accuracy of strain identification. Above sufficient genome coverage, sourmash identified strains either exactly or with closely related strains sharing highly conserved gene content. These closely related strains provided a biologically relevant representation of the expected functional potential of the mock communities. Gene content recovery was highly accurate, with F1 scores ranging from 0.942 to 0.998 across the five mock communities. Genome abundances estimated against sourmash-identified genomes closely matched the expected community composition: Pearson correlation coefficients ranged from 0.823 to 1 at strain level and from 0.978 to 1 at species level. Conclusions. Our results show that sourmash provides a biologically relevant approach for strain-level characterisation in microbial ecosystems. Even when the exact strain could not be identified, closely related strains retained most of the expected gene content and abundance estimations were accurate, supporting the use of sourmash for downstream functional profiling or metabolic network reconstruction.

bioinformatics↗

bioRxiv2026

Using Mapping-Profiles to Refine Strain-Level Metagenomic Classification

Metagenomic classification at the strain level remains challenging due to high sequence similarity among closely related genomes, which leads to ambiguous read mappings and frequent false-positive strain detections. Reducing such errors improves the reliability of strain-level analyses, which is critical for applications such as pathogen detection. We introduce StrainRefine, a post-mapping refinement method that analyzes read-reference mapping profiles to resolve ambiguous assignments among highly similar genomes. The method represents candidate reference genomes using binary profiles that capture read-support patterns and measures similarity between references based on profile overlap. The method clusters references based on similar mapping profiles, filters weakly supported genomes, and reassigns reads to representative references, reducing redundant reporting of near-identical strains. StrainRefine substantially reduces false-positive strain detections while preserving recall and improving agreement between predicted and true abundance profiles. On large-scale metagenomic datasets, it achieves a substantially improved precision-recall balance compared to existing mapping-based approaches, with the standalone method obtaining the highest read-level classification accuracy on the most complex evaluated dataset. Unlike many strain-level tools designed for individual species, StrainRefine operates without prior assumptions about sample composition or curated species-specific reference collections, while still achieving comparable performance in single-species settings on species-specific reference databases. These results highlight mapping-profile similarity as an effective signal for improving strain-level metagenomic classification.

bioinformatics↗

bioRxiv2025

Discovery and chemical biology of CDK8 inhibitors reveals insights for kinase inhibitor development.

Protein kinase inhibitors are a key class of targeted cancer therapies, but finding compounds that show on-target efficacy with minimal toxicity remains challenging. CDK8 and CDK19 are paralogous kinases that regulate Mediator complex to promote transcriptional responses to extracellular signals and have also been reported to facilitate genome replication. Preclinical studies show that CDK8/19 inhibitors may have therapeutic benefit in several cancers, but whether effective inhibition of Mediator kinases is cytotoxic is debated. Here, we present a multi-modal approach for discovery of specific kinase inhibitors, and find that most CDK8/19 inhibitors show off-target toxicity and/or insufficient on-target engagement in cells. We describe several novel high affinity CDK8/19 inhibitors, report that loss of CDK8/19 activity is not cytotoxic but reduces cell proliferation without affecting DNA replication, and provide evidence that most inhibitors can bind in type I or type II modes. Our approach is applicable to any kinase inhibitor development program.

biochemistry↗

bioRxiv2022

CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium

CDK8 and CDK19 form a conserved cyclin-dependent kinase subfamily that interacts with the essential transcription complex, Mediator, and also promotes transcription by phosphorylating the C-terminal domain (CTD) of RNA polymerase II. Cells lacking either CDK8 or CDK19 are viable and have limited transcriptional alterations, but whether the two kinases redundantly control cell differentiation is unknown. Here, we find that CDK8 is dispensable for RNA polII CTD phosphorylation, regulation of gene expression, normal intestinal homeostasis and efficient tumourigenesis in mice. Furthermore, CDK8 is largely redundant with CDK19 in the control of gene expression. Yet, while their combined deletion in intestinal organoids reduces long-term proliferative capacity, it is not lethal and allows differentiation. Nevertheless, in double mutant organoids, the cystic fibrosis transmembrane conductance regulator (CFTR) pathway is transcriptionally and functionally downregulated, leading to mucus accumulation and increased secretion by goblet cells. This phenotype can be recapitulated by pharmacological inhibition of CDK8/19 kinase activity. Thus, the Mediator kinases are not essential for cell proliferation and differentiation, but they cooperate to regulate tissue-specific transcriptional programmes.

cell biology↗