Blood Vessel Development and Homeostasis: Identification and Functional Analysis of Genetic Modifiers

Project Information

ZMOD

Grant agreement ID: 694455

DOI

10.3030/694455

Project closed

EC signature date 21 June 2016

Start date 1 October 2016

End date 30 September 2021

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 4 - ZMOD (Blood Vessel Development and Homeostasis: Identification and Functional Analysis of Genetic Modifiers)

Reporting period: 2021-04-01 to 2021-09-30

Summary of the context and overall objectives of the project

Genetic robustness refers to the ability of organisms to withstand mutations, showing little or no phenotype, or compromised viability. Our studies on genetic robustness are specifically trying to understand mechanisms of genetic compensation, which is defined as ‘changes in RNA or protein levels that can functionally compensate for the loss of function of another gene’. This work is important for society because it will allow one to better understand phenotypic variability within the human population, in other words, why people with the same mutation often exhibit very different phenotypes. In addition, our work aims to identify genes that can functionally compensate for the loss of function of another gene in the context of certain vascular diseases. In terms of the conclusions of the actions, work done during the funding period has clearly shown the importance of the new mode of genetic compensation we uncovered, as well as its complexity.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

This project started with our efforts to understand the phenotypic differences between knockout (mutant) and knockdown (antisense treated) phenotypes in zebrafish embryos, leading to the publication of a paper entitled ‘Genetic compensation induced by deleterious mutations but not gene knockdowns’ (Rossi, Kontarakis et al., 2015). Since these initial observations, which have attracted a lot of attention, we have been working to understand underlying mechanisms and published follow up papers entitled ‘Genetic compensation triggered by mutant mRNA degradation’ (El-Brolosy et al., 2019), and ‘Transcriptional adaptation in C. elegans’ (Serobyan et al., 2020), as well as several reviews (El-Brolosy and Stainier, 2017; Sztal and Stainier, 2020; Kontarakis and Stainier, 2020; Jakutis and Stainier, 2021).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Many mechanistic questions remain to be answered of course, and so we are continuing these studies using a variety of state-of-the-art approaches in different model organisms as well as in mammalian cells in culture.

mRNA degradation