Inferring the genetic basis of quantitative traits is foundational to understanding the biological mechanisms that underlie complex phenotypes such as behavior, homeostasis, and disease. Mapping genotype to phenotype has been transformational for understanding and treating diseases controlled by a single gene, or monogenic. However, understanding complex, highly polygenic phenotypes with currently available approaches can take decades of research from fields of researchers to make progress, if the problem is even solvable with current methodologies.

Dr. Caroline Holmes will transform the process of unraveling polygenic phenotypes in Dr. Michael Desai’s lab at Harvard University. Dr. Holmes will develop new computational approaches and use high-throughput experiments to learn the structure of interactions between genes involved in a particular phenotype. Holmes then will test her predictions of interactions with mutational perturbations. Ultimately, Holmes will develop methods to improve the generalizability of genotype to phenotype maps and test their accuracy on a distinct microbe that was not used to train the system. If successful, Holmes’ methods would rapidly catalyze the process of understanding and rationally perturbing polygenic phenotypes.

Holmes’ longstanding interest in both biology and physics dates back to her studies and research as an undergraduate student at Emory University. Her graduate studies emphasized the physics side as Holmes mainly used theoretical approaches in the labs of Dr. Bialek and Dr. Palmer at Princeton University. However, many of Holmes’ research applications were still biological in nature. For example, Holmes demonstrated that non-24 hour circadian periods can compensate for systematic error that arises as a result of seasonality. Holmes will now develop quantitative experimental systems during her postdoctoral research and combine this with her expertise in theoretical approaches to make inroads into complex polygenic phenotypes.