Grant: Project Grant

One of Mendelian genetics' most fundamental features is the genetic interaction between alleles of the same gene in diploid organisms. Alleles can be dominant or recessive, relative to each other. Since discovering this fundamental principle, we have learned much about why many human diseases are associated with recessive alleles, which often have reduced activity compared to the WT allele. A normal allele of a gene is sufficient to produce a healthy cell or organism, as its gene product is produced in sufficient amounts and is sufficiently active to mask the presence of the weakened gene copy. However, we surprisingly know relatively little about other types of relationships, for instance, in cases where a weakened gene copy can mask the WT allele (negative dominance). This poses an essential challenge in interpreting and predicting complex phenotypes based on genome sequences. Indeed, most methods used to predict the impact of mutations on phenotypic traits such as disease do so in the paradigm of loss of activity and stability. Dominant negative mutations are thus in a blind spot. Here, we will leverage the power of model organisms and recent developments in gene editing and high-throughput screening to identify the molecular principles by which these complex relationships can manifest themselves from the physical association of the product of two alleles in living cells. Our results will uncover how the biophysical assembly of proteins impacts the mode of inheritance of the traits they contribute to. Our work will shed light on one of the most fundamental aspects of genetic inheritance that has manifold impacts on human health.