Targeting endogenous retrovirus Gag genes for biomarker development in type 1 diabetes

Project Summary: Approximately 5-8% of the genome consists of remnants of ancient retroviruses that were integrated into the host genome through germ line infection. These retroviruses are known as endogenous retroviruses (ERVs). Some ERV proviruses have a complete or partial genome structure and can produce viral antigens and pseudo-viruses that interact with the immune system. Human endogenous retroviruses (HERVs) have been linked to autoimmune diseases such as type 1 diabetes (T1D). In our study, which focuses on the relationship between ERVs and autoimmunity using deep sequencing, we unexpectedly discovered a connection between the number of sequence variants encoding an open reading frame (ORF) of the ERV gene Gag and disease progression in both a non-obese diabetic (NOD) mouse model and human T1D patients. Abnormal sequence variants of ERV Gag genes could potentially be associated with increased autoimmune activation. In this study, we will use deep sequencing to measure the Gag gene variants with ORFs as biomarkers. The experiments aim to further investigate NOD mice and various T1D-susceptible and -resistant mouse strains in order to understand the mechanism that regulates the expression of these gene variants. Furthermore, we will expand the study on T1D patients by including autoantibody-negative and prediabetic controls to validate whether this sequencing-based biomarker could be used to screen high-risk children, stage pre-diabetic patients, and predict the onset of diabetes.