ORCID Profile
0000-0002-5771-9177
Current Organisation
INSERM
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Publisher: Springer Science and Business Media LLC
Date: 26-11-2018
Publisher: Cold Spring Harbor Laboratory
Date: 28-08-2020
DOI: 10.1101/2020.08.27.270819
Abstract: The adenosine analogue remdesivir has emerged as a frontline antiviral treatment for SARS-CoV-2, with preliminary evidence that it reduces the duration and severity of illness 1 . Prior clinical studies have identified adverse events 1,2 , and remdesivir has been shown to inhibit mitochondrial RNA polymerase in biochemical experiments 7 , yet little is known about the specific genetic pathways involved in cellular remdesivir metabolism and cytotoxicity. Through genome-wide CRISPR-Cas9 screening and RNA sequencing, we show that remdesivir treatment leads to a repression of mitochondrial respiratory activity, and we identify five genes whose loss significantly reduces remdesivir cytotoxicity. In particular, we show that loss of the mitochondrial nucleoside transporter SLC29A3 mitigates remdesivir toxicity without a commensurate decrease in SARS-CoV-2 antiviral potency and that the mitochondrial adenylate kinase AK2 is a remdesivir kinase required for remdesivir efficacy and toxicity. This work elucidates the cellular mechanisms of remdesivir metabolism and provides a candidate gene target to reduce remdesivir cytotoxicity.
Publisher: IEEE
Date: 13-04-2021
Publisher: Cold Spring Harbor Laboratory
Date: 11-06-2021
DOI: 10.1101/2021.06.08.21258515
Abstract: The genetic basis of most traits is highly polygenic and dominated by non-coding alleles. It is widely assumed that such alleles exert small regulatory effects on the expression of cis -linked genes. However, despite the availability of gene expression and epigenomic data sets, few variant-to-gene links have emerged. It is unclear whether these sparse results are due to limitations in available data and methods, or to deficiencies in the underlying assumed model. To better distinguish between these possibilities, we identified 220 gene-trait pairs in which protein-coding variants influence a complex trait or its Mendelian cognate. Despite the presence of expression quantitative trait loci near most GWAS associations, by applying a gene-based approach we found limited evidence that the baseline expression of trait-related genes explains GWAS associations, whether using colocalization methods (8% of genes implicated), transcription-wide association (2% of genes implicated), or a combination of regulatory annotations and distance (4% of genes implicated). These results contradict the hypothesis that most complex trait-associated variants coincide with homeostatic eQTLs, suggesting that better models are needed. The field must confront this deficit, and pursue this “missing regulation.”
Publisher: Springer Science and Business Media LLC
Date: 12-08-2019
Publisher: Springer Science and Business Media LLC
Date: 03-04-2017
DOI: 10.1038/NG.3831
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
Location: France
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Christopher Cassa.