Unraveling the Role of Tandem Repeats and Structural Variants in Addiction-Related Behaviors Using Heterogeneous Stock Rats

Project Abstract Drug abuse is a significant public health crisis, with over 106,000 drug-involved overdose deaths in the U.S. in 2021. Human genome-wide association studies (GWAS) have started to identify underlying causal genetic loci in addiction, but most of them sacrifice phenotypic granularity in order to obtain larger sample sizes. GWAS in model organisms such as N/NIH heterogeneous stock (HS) rats provide a valuable alternative that bridges this gap. However, determining the causal genes of addiction remains challenging because most GWAS studies focus on single nucleotide polymorphisms (SNPs) and overlook complex variants such as and tandem repeats (TRs) and structural variants (SVs). TRs and SVs are longer genome alterations compared to SNPs, which makes them hard to detect with short-read sequencing. This project proposes to address this serious limitation by using cutting-edge long reads sequence to discover and genotype TRs and SVs in support to investigate their roles in drug abuse using HS rats. The central hypothesis is that TRs and SVs contribute to the variability in gene expression, hence, affecting addiction-related behaviors in HS rats. In Aim 1, the TRs and SVs landscape in HS rats will be characterized using newly generated long reads in both inbred HS founders and outbred HS rats. Then, in Aim 2, a computational package will be developed to impute TRs and SVs to the whole population of over 20 thousand outbred HS rats. Finally, in Aim 3, quantitative trait loci mapping analysis will be performed to link TRs and SVs to gene expression and addiction-related behavioral traits. This innovative approach integrating long-read sequences focuses on underrepresented genetic variants, providing new insights into addiction genetics and potentially uncovering novel genetic mechanisms influencing addiction-related behaviors. Completion of this project will not only provide with the applicant with valuable training in behavioral genetics and bioinformatics and lead to potential therapeutic targets and strategies for preventing and treating drug abuse, but also create a community resource that will enhance ongoing rat genetic studies.