MRC Institute of Genetics & Molecular Medicine
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European Research Council Consolidator Grant awarded to Joe Marsh

€655 million has been awarded between 327 of Europe’s top scientists, including support for the Beyond the Loss-of-function Paradigm project: December 2020

Joe Marsh

This week the European Research Council announced the winners of its latest Consolidator Grant competition, awarding funding to researchers across Europe as part of the Horizon 2020 research and innovation programme. With this support, the new grantees will have a chance to build upon their teams and gain far-reaching impact.

Congratulations to Dr Joe Marsh of the MRC Human Genetics Unit who has been awarded a Consolidator Grant for Protein Structure, Molecular Mechanisms and Human Genetic Disease: Beyond the Loss-of-function Paradigm.

The ability to identify damaging genetic variants is central to the diagnosis, treatment and prevention of human disease. When trying to understand the effects of protein-coding variants, the ‘loss-of-function paradigm’ has been omnipresent, which is the idea that genetic disease is usually caused by mutations that are disruptive to protein structure or interactions.

Often overlooked, however, is the fact that many disease-causing mutations act via alternate molecular mechanisms, such as the dominant-negative effect or gain of function, and Joe’s research group’s preliminary work has shown that these tend to be poorly predicted by essentially all currently available computational approaches.

The goal of the project is to investigate how consideration of molecular mechanism and protein structure can help us to better understand and predict disease-causing mutations by using extensive computational modelling and analysis, and a novel high-throughput experimental strategy that will allow researchers to measure the effects of tens of thousands of mutations across several human disease genes.

The knowledge gained, experimental data measured and the tools developed will improve researchers’ ability to identify novel pathogenic variants, and thus diagnosis of human genetic disorders.

The ERC Consolidator Grants are awarded to outstanding researchers of any nationality and age, with at least seven and up to twelve years of experience after PhD, and a scientific track record showing great promise. Research must be conducted in a public or private research organisation located in one of the EU Member States or Associated Countries. The funding, of up to €2 million per grant, is provided for up to five years and mostly covers the employment of researchers and other staff to consolidate the grantees' teams.

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