Project Summary/Abstract Myalgic encephalomyelitis (ME) is a disabling and complex disease with 1-2.5 million patients in the United States. ME patients have low quality of life and one in four are bed- or house-bound. ME is under-studied and under-funded, and there are no existing diagnostic tests, FDA-approved treatments or cure for ME. The causes of ME are unknown. ME patients exhibit elevated immune responses and enhanced inflammation. Endogenous retroviruses (ERVs) result from the fixation of ancient retroviral infections and integrations into the human genome. ERVs (n≈400,000) typically remain silenced; however, some ERVs can be transcriptionally reactivated. Activated ERVs resemble viral RNA and can therefore trigger immune responses and chronic inflammation, potentially leading to ME. Together with our collaborators, we have collected the largest deep sequencing data sets with deep phenotypes from ME patients. We recently developed a set of bioinformatics tools that allow us to genotype genome-wide individual ERVs and quantify individual ERV expression with high accuracy. With this R21 application, we propose to use these state-of-the-art tools to analyze existing and new deep sequencing data to address two Specific Aims. Aim 1: Identify distinct ERVs whose expression is associated with ME using RNA-Sequencing data. These analyses will, for the first time, quantify transcriptome- wide expressed ERVs individually; and allow for identification of activated distinct ERVs and ERV genes associated with ME. Aim 2: Identify ERV variants whose genotypes are associated with ME using whole- genome sequencing data. These analyses will produce genome-wide distinct ERV genotypes, and, for the first time, allow for identification of ME-associated individual ERVs and related genes. Upon completion of these two Aims, we will know whether ERVs and ME are linked at the transcriptomic and/or genomic level. Elucidating ERVs as risk factors in ME may lead to breakthroughs in ME treatment, such as repurposing existing FDA-approved anti-retroviral drugs which may reverse ERV effects.

Project Narrative Myalgic encephalomyelitis is a disabling disease with no diagnostic tests, FDA-approved treatments, or cure. This project aims to dissect the molecular determinants of myalgic encephalomyelitis through innovative approach to quantifying endogenous retrovirus expression and genotyping endogenous retrovirus variants. Elucidating roles of endogenous retroviruses in myalgic encephalomyelitis may lead to breakthroughs of anti- retroviral or anti-inflammatory treatments in this disease.