Transcriptional Adaptation and Genetic Compensation

Organisms utilize several mechanisms to compensate for the damaging consequences of genetic perturbations.

One such mechanism is the newly identified process of transcriptional adaptation (TA): in this process, certain deleterious mutations trigger the transcriptional modulation of so-called adapting genes.

In some cases, e.g., when one of the upregulated genes is functionally redundant with the mutated gene, TA leads to functional compensation. Notably, unlike other modes of compensation, 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.

Following our discovery of TA (Rossi et al., 2015), we have shown that in zebrafish embryos and mouse cell lines, mutant mRNA degradation triggers this process (El-Brolosy et al., 2019).

We also observed TA in C. elegans and found that small RNA biogenesis, in addition to mutant mRNA degradation, is required for this process (Serobyan et al., 2020).

While these and other studies have documented the importance of TA and its occurrence across phylogenetically distant organisms, several key questions remain in terms of how TA arises and how prevalent it is.

In this proposal, we aim to investigate the mechanisms that underlie TA, including 1) what determines which genes are targeted as adapting genes during TA, and 2) how the expression of these genes is modulated during TA.

These studies will be carried out in zebrafish, C. elegans, mice, and multiple mouse and human cell lines, capitalizing on the genetic and biochemical approaches available in each model system, while simultaneously allowing us to analyze the conservation of the mechanisms underlying TA. In addition, we will investigate the relevance of TA in human health and disease.

Ultimately, this work will further our understanding of the mechanisms that modulate genetic and phenotypic robustness in humans.