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Characterization and Quantification of the Human Endogenous Retrovirus Transcriptome Open Access

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The human genome is host to thousands of Human Endogenous Retroviruses (HERVs) – remnants of ancient exogenous retroviral infections – that altogether comprise almost 8 percent of the human genome. Several lines of evidence suggest that HERVs may in fact play an important role in human biology. There is conflicting evidence regarding the existence of pathogenic HERVs, although associations between disease and HERV expression have been found in cancer, autoimmune disease, and amyotrophic lateral sclerosis. Another possibility is that the only HERV elements remaining the genome, through millennia of purifying selection, are those that have a neutral or beneficial, rather than pathogenic, impact on the human host. In the developing human embryo, HERVs are believed to make key contributions to the transcriptome and regulatory networks. Studies profiling the transcriptome of single cells during development have revealed dynamic gene and HERV expression patterns that are both stage- and lineage-specific. However, these studies did not determine the transcription of single HERV proviruses at specific genomic locations.Currently, single-locus quantification of repetitive element transcription using next-generation sequencing (NGS) is a major technological challenge. Two important limitations have prevented this technique from being widely adopted. First, the precise location and structure of HERV elements in the genome is largely unknown, and a consistent classification and nomenclature has not been established. Second, computational algorithms for mapping sequence reads to repetitive elements have not been developed. In this dissertation, I aim to resolve these two challenges by creating a reference set of HERV elements in the human genome and developing a computational approach to accurately quantify HERV expression. I will use these tools to investigate HERV expression in neurodevelopment, psychiatry, and embryonic development.

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