ABSTRACT Huntington’s disease (HD) is a devastating and fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat in the HTT gene that triggers cell death with specificity towards neurons in the striatum and cortex. Although the underlying genetic mutation was discovered over 25 years ago, there is still no cure or effective treatment despite extensive efforts. The HTT CAG repeat mutation is highly unstable both in transmissions to subsequent generations and somatically. Notably the repeat undergoes dramatic tissue- specific somatic expansion, particularly in the brain regions affected in the disorder, strongly suggesting that somatic HTT CAG length increases in target tissues contribute to HD pathogenesis. Recent human genetic data provide compelling support for somatic CAG expansion as a driver of the rate of HD pathogenesis, identifying DNA repair genes as modifiers of disease onset in HD patients, many of which modify somatic CAG expansion in accurate genetic HD knock-in mouse models. In this study, we will perform experiments to deeply interrogate these modifier genes at a number of fundamental levels. In Aim 1 we will use genetic experiments in the mouse to test the impact of altering somatic expansion on disease expression. In Aim 2, we will perform biochemical studies in patient cells and in mouse models to understand the mechanism of action and functional consequences a human modifier variant. In Aim 3 we will examine the impacts of human modifier variation on CAG instability and gene expression in specific cell types in the brain. Together, these experiments that are driven by human genetic data, will provide critical insight into mechanisms of disease modification in HD and will guide development of therapeutics targeting CAG expansion.