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

Periodic Reporting for period 3 - ZMOD (Blood Vessel Development and Homeostasis: Identification and Functional Analysis of Genetic Modifiers)

Reporting period: 2019-10-01 to 2021-03-31

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, that is 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.
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 have just recently published a follow up paper entitled ‘Genetic compensation triggered by mutant mRNA degradation’ (El-Brolosy et al., 2019).
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.