EAGER: Assembling the Immunoglobulin Loci Across Mammalian Species and Across the Human Population

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The ongoing COVID-19 pandemic raised the challenge of developing new computational techniques for understanding the immune response to emerging pathogens. This project will develop a new computer program for analyzing the parts of the genome that are responsible for immune responses to pathogens. This will enable analyses of the development of immunity to the virus in human populations by characterizing the mutations that are essential to the immune response. This research will also enhance understanding of the immune responses in bats, which are hosts to large numbers of coronaviruses, and in llamas, which are potentially an important source for a robust vaccine against the virus. The project will also develop a Massive Online Open Course “Bioinformatics of SARS-COV-2” that will cover various aspects of computational analysis of emerging pathogens, and the challenges of analyzing these complex and dynamic parts of the human genome. Information about the immunoglobulin-encoding regions in the genome is critically important for analyzing the immune response to the novel SARS-CoV-2 coronavirus, developing antibody drugs against SARS-COV-2, and testing future vaccines against SARS-CoV-2. However, there are still no algorithms for inferring the sequences of the highly complex and rapidly evolving immunoglobulin (IG) loci. Moreover, although the immunoglobulin genes within the IG loci form the building blocks of antibodies, there are still no software tools for accurate identification of these genes. This project will develop a new algorithm for assembling and annotating the IG loci. These methods will be applied to multiple mammalian genomes with a focus on assembling the unusually complex IG loci in bats to characterize their immune response to coronaviruses. A second focus will be assembly of camelid IG loci to aid in developing vaccines against SARS-COV-2, taking advantage of the simpler and more stable antibodies present in this group. The project will also focus on assembling the highly variable immunoglobulin loci in multiple COVID-19 patients with the goal of revealing functionally important mutations in these loci. The project entails substantial risk, because the IG loci have been recalcitrant to all previous assembly attempts, but enhanced understanding of mammalian immunoglobin genes would greatly enhance the ability of society to predict and respond to current and future pandemics.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.