Phenotypic variability due to genetic buffering: The role of environmental factors

• Applicants: Privatdozent Dr. Thomas Haarmann-Stemmann; Andrea Rossi, Ph.D.
• Subject Area: Toxicology, Laboratory Medicine ; General Genetics and Functional Genome Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506104882

Genetic factors can induce and contribute to the development of diseases and aging phenotypes. The dominant and recessive genetic patterns of inheritance described by Mendel represent the extremes of a spectrum of states. It has been demonstrated that the effects of deleterious genetic variations, which would be expected to cause severe phenotypes, can be buffered by cells, thereby mitigating the resulting phenotype. This process known as genetic buffering is based on different mechanisms, such as genetic compensation, transcriptional adaptation and phenotypic plasticity. The factors which are known to contribute to genetic buffering are, in part, thought to be non-genetic in nature, but knowledge in this regard is scarce.In the present application, we postulate that genetic buffering is affected by changing environmental conditions. Genetic buffering is often achieved through the expression of modifier genes. One example is the upregulation of Utrophin in patients with Duchenne muscular dystrophy (DMD), a rare genetic disorder caused by mutations of the dystrophin gene. We want to elucidate whether and how genetic buffering and the regulation of modifier genes are influenced by environmental factors. To this end, we already generated and characterized human induced pluripotent stem cells (iPSCs) and respective mutants which recapitulate, at a molecular level, DMD and Actin-B (ACTB)-associated syndromes, i.e. human monogenic diseases with a wide phenotypic variance. The corresponding modifier genes were identified and validated by RNA sequencing and qPCR analyses, respectively. In the applied research project, we will expose the generated iPSCs to sub-toxic and low toxic concentrations of exposure-relevant environmental factors (air pollutants, food contaminants) and assess their impact on the expression of modifier genes. Given that all of the applied environmental factors may stimulate the generation of reactive oxygen species, and oxidative stress is capable of modulating the expression of genes, incl. including modifier genes, in rodent disease models, we expect to find profound alterations in the expression pattern of the modifier genes. We will next assess the underlying mode of action by focusing on direct effects either on modifier gene regulation or on the genetic compensation machinery. Particularly, we will investigate the effect of the exposure to environmental pollutants at nucleic acid resolution, i.e. by analyzing epigenetic DNA- and epitranscriptomic RNA modifications as well as the global transcriptome. Given that the modulation of genetic buffering and modifier genes is clinically relevant, libraries of small molecules which may modulate the environmentally-susceptible modifiers, will be screened. These studies will provide fundamental insights into the relevance of environmental factors for genetic buffering.

• DFG Programme: Research Grants