McGrath lab has been awarded a prestigious R01 grant from the National Institute of General Medical Sciences (NIGMS) to work on understanding the mechanisms behind the extensive effects of genetic epistasis and organismal age on complex mixture of common and rare variants that shape most biological traits. Improved understanding of these processes could identify principals useful for predicting how causal factors act in novel genetic backgrounds and therapeutic techniques to take advantage of their non-linear effects to ameliorate disease. The broad objective of the proposed research is the identification of causative genetic variants affecting reproduction in C. elegans with age- dependent effect sizes and epistatic interactions. Once in hand, we will mechanistically dissect their causes in the context of organ and multicellular circuit function. We will study how life history changes in sperm number, a limited resource necessary for reproduction, creates age-dependent genetic architecture. Finally we will study how epistasis and aging are shaped by the function of the underlying neural circuit responsible for regulation of reproduction. These experiments will leverage C. elegans tractability to identify principles relevant to the study of human diseases.
Successfully building on their IBB seed grant, the Lu and McGrath lab have received an R21 from the National Institute of Aging to develop SWADE (for selection of weak alleles using directed evolution) as a novel approach to select multigenic changes to any trait of choice. Development of this approach could revolutionize how forward genetics is done in the lab to identify new genes that regulate biological traits and also identify non-additive interactions. SWADE harnesses the power of evolution to select for phenotypes with small effect. Selection is provided for by using microfluidic-based sorting of thousands of worms based upon a fluorescent marker.
Hang Lu (professor in Chemical and Molecular Engineering) and Patrick McGrath have received an IBB seed grant to develop directed evolution approaches to evolve new traits of interest. As proof of principal, they will evolve extensions to lifespan using microfluidics/automated fluorescent microscopy pioneered by the Lu lab. Causative mutations will be identified using next-generation sequencing and quantitative genetics approaches. This seed grand provides $100,000 of support over two years.
Weipeng Zhuo, graduate student in the McGrath lab, was a co-first author on a paper describing a size-sorting device to separate C. elegans animals by state. This paper was published in Lab on a Chip. Congrats Weipeng!
Patrick was awarded this grant from the EMF to study how complex genetics can influence the aging process in the small nematode C. elegans. In humans, lifespan is a heritable trait, meaning that differences in our genes influence how fast we age. The McGrath lab plans to identify new signaling pathways controlling aging by harnessing directed evolution to evolve multigenic changes to C. elegans lifespan. This grant provides $400,000 of support over 4 years.
Patrick McGrath published a review paper in Current Opinion in Neurobiology. This paper describes how genetics can affect the function and properties of the nervous system.