Active Human Transposable Elements: Long-Read Sequencing Technologies, Computational Analysis, and Implications for Human Disease

Transposable elements (TEs) constitute nearly half of the human genome and shape chromatin organization, gene regulation and genome evolution. We have large gaps in understanding their influence to physiology and pathology for now. In humans, the most active elements—LINE-1 (L1), Alu, and SVA retain some copies with the ability to evade epigenetic repression and mobilize via target-primed reverse transcription (TPRT), whereas copies become inactive through fragmentation, mutation, or nesting, a process where a TE segments integrates into another TE segment. TE activity contributes to genomic instability and has been implicated in aging, cancer, neurological disorders, chromatin organization, and epigenetic regulation. Studying TEs is challenging due to their repetitive and polymorphic nature. Recent advances in sequencing technologies, including short- and long-read platforms, combined with specialized bioinformatic pipelines, now allow more comprehensive characterization of TE insertions, deletions, expression, and epigenetic status. Computational approaches vary in sensitivity, specificity, and resource requirements, and their performance is influenced by sequencing modality, coverage, and the reference genome used. Assembly-based and read-based methods, as well as tools integrating methylation or single-cell data, provide complementary insights into TE biology. Here we review the biology of active human TE. Survey state of the art short and long-read pipelines for TE analysis. And highlight their applications in studies of aging cancer and other complex diseases. We also provide practical guidance for selecting appropriate sequencing strategies and tools for TE-focused projects, and discuss emerging approaches and open questions in the field.