Stuart Macdonald

The majority of traits of medical, agricultural, and ecological significance exhibit quantitative variation among individuals. These complex traits are influenced by variation at hundreds or perhaps thousands of genes. Even though these complex traits are tremendously important for human health and organismal diversity, they have been difficult to characterize at the molecular level: For most complex traits we do not understand the genes that impact variation, and we lack insight into general questions about the architecture of trait variation (are causative alleles typically Single Nucleotide Polymorphisms or complex structural changes? are they at intermediate frequency or individually rare in populations? are there genes of large effect segregating for multiple causative alleles?)

By localizing and characterizing the precise set of DNA variants that contribute to variation in complex traits we can answer these questions. This is vital both for human health (can we assess whether a patient carries alleles at certain genes that may predispose them to develop disease? can we predict which individuals may have adverse reactions to therapeutic drug treatments?) and for evolutionary biology (how is genetic variation in complex traits maintained in the face of selection which should erode this variation?)

The Macdonald group uses the elite model genetic organism Drosophila melanogaster to answer these fundamental questions about the molecular genetics of complex traits. Drosophila is an excellent system due to the conservation of many genes and cellular/physiological pathways with humans, the massive amount of genetic and genomic data available, the simplicity with which large-scale experiments can be executed, and the ability to easily manipulate gene function via functional genetics tools (e.g., CRISPR genome editing.) We additionally leverage sophisticated genome sequencing technologies, and computationally-intensive analytical approaches, to examine the relationship between phenotype and genotype.

Current projects in the lab include developing a community resource for the dissection of complex trait variation (the Drosophila Synthetic Population Resource), and exploring the genetic basis of variation in toxin exposure, focusing particularly on heavy metal toxicity.