Seminar: Dr. Didier Stainier, Max Planck Institutes for Heart and Lung Research
Title: Transcriptional Adaptation, a Newly Discovered Mode of Genetic Compensation
Speaker: Dr. Didier Stainier, Max Planck Institutes for Heart and Lung Research
Host: Dr. Yantao Li
Abstract: Each human genome has been reported to contain approximately 100 loss-of-function (LoF) variants, with roughly 20 genes completely inactivated. Some of these completely inactivated genes are essential genes, and yet they are present in a homozygous state in apparently healthy individuals. This totally unexpected lack of phenotype has also been observed in commonly studied model organisms including yeast, flies, worms, plants, fish, and mice. Various hypotheses have been proposed to explain these findings including Genetic Compensation (GC). GC manifests itself as altered gene/protein expression, or function, which leads to a wild-type-like phenotype in homozygous mutant or heterozygous individuals who would be predicted to exhibit clear defects (reviewed by El-Brolosy and Stainier, PLoS Genetics, 2017). Traditionally, GC has been thought to involve protein feedback loops such that if one component of a regulatory pathway is deficient, a compensatory rewiring within a network or the activation of a functionally redundant gene occurs. However, not every major regulatory network has evolved to incorporate such complex features. Another mechanism of GC is the newly identified process of Transcriptional Adaptation (TA): some deleterious mutations, but not all, trigger the transcriptional modulation of so-called adapting genes. In some cases, e.g., when one (or more) of the upregulated adapting genes is functionally redundant with the mutated gene, this process compensates for the loss of the mutated gene’s product. Notably, unlike other mechanisms underlying genetic robustness, TA is not triggered by the loss of protein function. This unexpected observation has prompted studies into the machinery of TA and the contexts in which it functions.
We discovered TA while trying to understand the phenotypic differences between knockout (mutant) and knockdown (antisense treated) zebrafish embryos (Rossi et al., Nature, 2015). Further studies identified additional examples of TA in zebrafish as well as examples in mouse and human cell lines. By generating and analyzing several mutant alleles for these genes, including non-transcribing alleles, we found that mutant mRNA degradation is required to trigger TA (El-Brolosy et al., Nature, 2019). Based on these and other data, we hypothesize that all mutations that cause mutant mRNA degradation can trigger TA. We have also observed TA in C. elegans, and through a targeted RNAi screen followed by genetic analysis, found a role for small RNA biogenesis in this process (Serobyan et al., eLife, 2020). This presentation will also go over our unpublished data on TA including the transgenerational inheritance of this process.
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