NSF Award
0746886
Mobile genetic elements have resided within eukaryotic genomes for hundreds of millions of years. These mobile elements include retroviruses that integrate into the genomes of their hosts as an essential step in their life cycle. While most such integration events are either deleterious or inconsequential to the host, on rare occasions they can be helpful, the retroviral genes responsible for the useful function can persist, and the function can become established as part of the host's repertoire. This phenomenon is referred to as "domestication" of the retroviral gene. Especially intriguing are those instances of domestication in which retroviral envelope genes remain in the host genome. These envelope genes are the same ones that enable retroviruses to infect the host cells. The genomes of primates and rodents contain domesticated retroviral envelope genes (called "syncytin" genes) that have important roles in placental function. Dr. Harmit Malik, the principal investigator of this project, has shown that a similar domestication event has taken place within the fruit fly Drosophila melanogaster. The domesticated gene, called Iris, was acquired from an insect retrovirus and has been maintained as a host gene for more than 25 million years. Unexpectedly, Iris continues to evolve rapidly whereas previous studies have shown that mammalian syncytin genes do not. The investigator will test two alternate hypotheses to account for Iris's preservation as a host gene. The first hypothesis, that Iris performs a beneficial role in D. melanogaster independent of any retrovirus, i.e., a "housekeeping role", will be tested using a combination of population genetics (fitness experiments), and cell biology (trafficking) experiments. Second, Dr. Malik will test whether Iris may have been domesticated because it protects the D. melanogaster genome against invasions by the insect retroviruses that it originated from, again using a combination of the two methods listed above, as well as fly infection (virology) methods. Finally, using reconstructed evolutionarily ancestral sequences, Dr. Malik will investigate what selective pressures drove the domestication of the Iris gene, starting from its evolutionary origins as an infectious agent. This research plan is the first to explicitly test the evolutionary significance of domesticated genes from retroviruses in a genetically tractable model organism, and is a striking example of "evolution in action." The strength of the proposal stems from an approach that iteratively combines functional and computational methods. In his research Dr. Malik has constantly striven to bridge these two fields to gain further insight into biological processes. <br/><br/>This multidisciplinary approach presents numerous training opportunities at various levels of experience, ranging from those appropriate for starting level researchers (population cage fitness experiments- appropriate for high school students or undergraduates), through those suitable for mid-level researchers (cell biology experiments- suitable for senior undergraduates and graduate students), to those requiring upper-level senior researchers (biochemistry experiments- suitable for graduate students and postdoctoral fellows). To facilitate further functional studies regarding the domestication of retroviral genes, Dr. Malik will establish a comprehensive, public database of recently domesticated eukaryotic genes with ancestries going back to retroelements. There is a pressing need for this kind of resource as well as for this kind of early formal introduction to "functional" evolutionary biology. As part of this project, Dr. Malik and his lab will use the existing infrastructure already in place at the Fred Hutchinson Cancer Research Center (FHCRC) to provide tutorial-based classes in bioinformatic searches primarily for high school science teachers. "Tests" for students, evaluation forms, and direct feedback from the high school teachers will be used to determine the efficacy of material. Tutorials that have been refined by two years of feedback will then be made publicly available to high school teachers across the country. For senior undergraduates and graduate students the investigator will also design and teach a course that explicitly addresses the role of evolutionary antagonism, or genetic conflict, in shaping genomes. Précis versions of this class will be also made available as seminars on the web. Dr. Malik will solicit opportunities to make presentations at primarily undergraduate institutions in the Puget Sound area (Seattle). Members of his lab will also either speak or present posters at conferences for under-represented minorities and women, where the MCB graduate program (jointly run by the FHCRC and Univ. of Washington) actively recruits incoming students. Members of the Malik Lab will also continue to make presentations in the Seattle community to impress upon a general public the role that evolutionary biology plays in the current understanding and practice of medicine.
