Tandem repeats (TRs)—short DNA motifs repeated consecutively—are a highly variable variant class that make up 3-8% of the human genome. Once thought of as “junk DNA,” these repetitive elements have now been implicated in over 50 neurodegenerative disorders including Huntington’s disease and ALS. Collectively, these disorders present major diagnostic and therapeutic challenges. My dissertation leverages advances in long-read sequencing and computational genomics to overcome longstanding barriers to TR analysis, focusing on improved detection, characterization, and mechanistic understanding of repeat expansion disorders. In Chapter II, I introduce HMMSTR, a bioinformatics tool that accounts for errors from Oxford Nanopore long-read technology paired with a targeted sequencing panel. This approach delivers high coverage and accurate genotyping across 60 disease-associated loci simultaneously, not only identifying both normal and pathogenic expansions but also revealing unexpected and previously unrecognized co-occurring repeat expansions of unknown significance in individuals with neurodegenerative disease. This strategy demonstrates strong potential for more cost-effective, comprehensive diagnostics and opens avenues for studying the diversity at TR loci. In Chapter III, I apply these methods to an in-depth analysis of Spinocerebellar Ataxia 27B (SCA27B), a highly prevalent repeat expansion disorder found in FGF14. Here, I conduct sequence analysis of members in affected families and confirm established inheritance patterns. Interestingly, we find variable disease presentation among both those with full and intermediate expansions suggesting that FGF14 expansion alone may not solely determine disease severity and possible genetic or environmental modifiers. These findings underscore the complexity of genotype-phenotype relationships and the need for future work examining how additional genetic factors may influence disease penetrance and clinical outcomes. Expanding the focus genome wide, in Chapter IV, I investigate TRs in the context of their association with mobile element insertions (MEIs). Recent repeat expansion disorder loci found in non-coding regions of the genome have strikingly co-located with MEIs. Here, I leverage 100 PacBio HiFi genomes from individuals of diverse ancestry to assess STR stability at STRs associated and not associated with MEIs. My analyses show that MEI-associated STRs represent a diverse but distinctive class of STRs that show an evolutionary balance between transposable element activity and genome stability. Young, mobile MEIs such as Alus and SVAs are enriched for long and highly variable STRs, while older elements tend to stabilize over time, illustrating a connection between MEI lineage and TR evolution. This work highlights MEIs as crucial contributors to STR diversity and underlines their intertwined role in shaping genome evolution and the emergence of disease-associated expansions. Together, these studies advance computational and experimental frameworks for TR detection and interpretation, offering new insights into the architecture of TR instability and improving avenues for patient diagnostics, counseling, and the discovery of novel disease mechanisms.