Genetics and evolution of lethal alleles in Drosophila

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Bad mutations arise in all species on Earth. Some mutations are so bad for the bearer that, when an individual inherits a copy from both parents, they cannot survive to adulthood. One would presume that such lethal mutations would rarely be observed, since natural selection should eliminate them rapidly from natural populations. However, for nearly a century studies in various species have found that such lethal variation is surprisingly common. At least two hypotheses can explain the persistence of such lethal variation: 1) lethal mutations arise at a high enough rate that they are replenished before natural selection can eliminate them all, and 2) a subset of lethal mutations may be actively maintained through natural selection, for example if they are slightly advantageous to bearers who carry only one copy. This project will use a mix of classical genetics and genome sequencing to identify the genes bearing these lethal mutations and to infer the evolutionary forces that cause the mutations to persist at such high abundance in natural populations. This research is vital to understanding the burden of such mutations on health as well as to understanding the persistence of variation in natural populations. This project will also contribute substantially to the education and training high school, college and graduate students. The project uses current science fiction as a backdrop for teaching fundamental principles in evolutionary biology.Hundreds of such mutations will be isolated using the model system Drosophila melanogaster from a natural population studied extensively 50 years ago. All of the lethal mutations isolated will be mapped using chromosomal deficiencies, and a subset will be mapped to single genes. This mapping will determine if the lethal effects result from single-locus, loss-of-function mutations, as often assumed. The continued research will focus especially on lethal mutations that are most prevalent in the natural population, since they are the best candidates for ones to have been actively been maintained by natural selection. The researchers will use modern population genetic approaches to infer the evolutionary forces that have acted on these abundant lethal alleles. The prevailing dogma has been that virtually all lethal mutations simply persist through a balance of mutation and selection, and this research will rigorously assess this long-standing question. This work is jointly funded by the Genetic Mechanisms Cluster in the Division of Molecular & Cellular Biology and the Evolutionary Processes Cluster in the Division of Environmental Biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.