Viral Evolution

Through resources at Harvard University and the Broad Institute, we are applying next generation, high-throughput sequencing technologies to the creation of tailored sequencing pipelines for Lassa and other deadly viruses. Using state-of-the-art sequencing technologies, we have developed novel approaches for sequencing the full-length genome of both Lassa and Ebola viruses. Lassa virusWith the capacity to generate millions of base pairs of data from small sample volumes, we are able to assemble complete viral genomes for identification and genetic analysis of known and unknown viruses.

Our hope is to carry out in-depth genomic analysis and diversity studies, elucidating regions of selection and identifying novel strains. The ability to generate full-length sequences will help in creating accurate phylogenies for both Lassa and Ebola viruses, as well as refine our ability to predict and identify regions of selection and high mutation within the genomes of these viruses.

With an established pipeline for full-length genomic sequencing we can easily track how the virus is changing and spreading over multiple outbreaks through time. This allows us to enhance essential epidemiological data that is used to understand virus behavior during an outbreak. By increasing viral genomic databases, our hope is to improve diagnostic capabilities that will ultimately lead to more timely diagnosis and early treatment regimens.

We are also interested in tracking mutations and identifying hotspots in the viral genome that may be under high selection pressure or mutation rate. By studying infection over the entire course of disease, we can pinpoint regions in the genome that may be changing due to spontaneous mutations or pressure from the host environment, as well as look at how each gene is changing over time. This information is imperative in understanding the etiology of viral hemorrhagic fever infection, including how the virus evades host immune response, evolutionary strategies of the virus, and possible therapeutic and diagnostic targets.

Previous studies have obtained partial nucleoprotein (NP) gene sequences from 54 Lassa virus strains and have determined that Lasa virus in West Africa consists of four lineages, one from Guinea, Liberia and Sierra Leone and three from Nigeria. The overall strain variation in the partial NP gene sequence alone was found to be as high as 27% at the nucleotide level and 15% at the amino acid level. However, only a handful of fully sequenced Lassa virus genomes exist in the database and very little work has been carried out examining the variation in Lassa virus genome sequence and influence on disease pathogenesis and immune response. Viral differences could have a major role in determining the ability of the virus to infect the host, adapt to and/or evade the immune response, cause pathogenic effects and ultimately determine survival. A better understanding of the degree of genetic variation in Lassa virus strains, mutation rates and current selection pressure is critical for a complete model of interaction between the virus and the human immune response.

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