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Ton, J.

Publications and source records attributed to Ton, J..

3 recordsLinked to original sources

An evolutionary epigenetic clock in plants

Molecular clocks are the basis for dating the divergence between lineages over macro-evolutionary timescales (~105-108 years). However, classical DNA-based clocks tick too slowly to inform us about the recent past. Here, we demonstrate that stochastic DNA methylation changes at a subset of cytosines in plant genomes possess a clock-like behavior. This epimutation-clock is orders of magnitude faster than DNA-based clocks and enables phylogenetic explorations on a scale of years to centuries. We show experimentally that epimutation-clocks recapitulate known topologies and branching times of intra-species phylogenetic trees in the selfing plant A. thaliana and the clonal seagrass Z. marina, which represent two major modes of plant reproduction. This discovery will open new possibilities for high-resolution temporal studies of plant biodiversity.

evolutionary biology↗

Predicting antiviral resistance mutations in SARS-CoV-2 main protease with computational and experimental screening

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication and has been the focus of many drug discovery efforts since the start of the COVID-19 pandemic. Nirmatrelvir (NTV) is an inhibitor of SARS-CoV-2 Mpro that is used in the combination drug Paxlovid for the treatment of mild to moderate COVID-19. However, with increased use of NTV across the globe, there is a possibility that future SARS-CoV-2 lineages will evolve resistance to NTV. Early prediction and monitoring of resistance mutations could allow for measures to slow the spread of resistance and for the development of new compounds with activity against resistant strains. In this work, we have used in silico mutational scanning and inhibitor docking of Mpro to identify potential resistance mutations. Subsequent in vitro experiments revealed five mutations (N142L, E166M, Q189E, Q189I, and Q192T) that reduce the potency of NTV and of a previously identified non-covalent cyclic peptide inhibitor of Mpro. The E166M mutation reduced the half-maximal inhibitory concentration (IC50) of NTV 24-fold, and 118-fold for the non-covalent peptide inhibitor. Our findings inform the ongoing genomic surveillance of emerging SARS-CoV-2 lineages. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/505060v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@14f0713org.highwire.dtl.DTLVardef@15995feorg.highwire.dtl.DTLVardef@8689a7org.highwire.dtl.DTLVardef@b73a64_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

A single amino acid transporter controls the uptake of priming-inducing beta-amino acids and the associated trade-off between induced resistance and plant growth.

Selected beta-amino acids, such as beta-aminobutyric acid (BABA) and R-beta-homoserine (RBH), can prime plants for resistance against broad-spectrum diseases. Here, we describe a genome-wide screen of fully annotated Arabidopsis T-DNA insertion lines for impaired in RBH-induced immunity (iri) against the downy mildew pathogen Hyaloperonospora arabidopsidis, yielding 104 lines that were partially affected and 4 lines that were completely impaired in RBH-induced resistance. The iri1-1 mutant phenotype could be confirmed by an independent T-DNA insertion in the same gene, encoding the high-affinity amino acid transporter LHT1. Using uptake experiments with IRI1/LHT1-expressing yeast cells and mass spectrometry-based quantification of RBH and BABA in leaves of mutant and over-expression lines of IRI1/LHT1, we demonstrate that IRI1/LHT1 acts as the main transporter for cellular uptake and systemic distribution of RBH and BABA. Subsequent characterisation of mutant and over-expression lines of IRI1/LHT1 for induced resistance and growth responses revealed that the level of IRI1/LHT1 expression determines the trade-off between induced resistance and plant growth by RBH and BABA.

plant biology↗