Long-read sequencing maps transposable element variation and its regulatory and epigenetic effects in the human brain
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Transposable elements (TEs) are mobile DNA sequences that shape genome architecture and gene regulation, yet their roles in the human brain remain largely unresolved. Short-read sequencing lacks the resolution to accurately map TE insertions, detect associated structural variants, and resolve highly repetitive regions. Here, we leverage long-read whole-genome sequencing to profile germline TE insertions in postmortem brain tissue from two ancestrally diverse cohorts: the North American Brain Expression Consortium (NABEC; European ancestry, n = 205) and the Human Brain Collection Core (HBCC; African and African-admixed ancestry, n = 146). We identified 2,842 and 1,660 high-confidence non-reference insertions in HBCC and NABEC, respectively, spanning Alu , LINE-1, and SVA elements. We then also further characterized complex short tandem repeat and variable number tandem repeat variation within reference SVA and Alu loci. Reference TEs were also found to mediate complex structural variants at loci implicated in brain development and neurodegenerative disease, with several showing ancestry-specific patterns. Integration of bulk RNA-sequencing data identified TE expression quantitative trait loci, including insertions that modulate neuronal gene expression. Single-nucleus RNA sequencing revealed cell-type-specific effects of TE regulation across cortical populations. Long-read methylation profiling further demonstrated age-associated epigenetic regulation of both reference and non-reference Alu elements. As a community resource, we release a catalog of TE insertions, allele frequencies, and ancestry-specific distributions to enable future functional and disease-focused investigations. Together, these findings highlight the widespread regulatory and epigenetic influence of TEs in the human brain and establish long-read sequencing as a powerful approach for uncovering cell-type- and population-specific TE dynamics.
Authors: Alexis Ayuketah, Melissa Meredith, Cristian Groza, Jon Moller, Kensuke Daida, Adam Catching, Cory Weller, Cedric Kouam, Luis Paulin, Laksh Malik, Breeana Baker, Fangle Hu, Sarah Bromberek, Pilar Alvarez Jerez, Kimberly Paquette, Michal Izydorczyk, Bida Gu, Mark J. P. Chaisson, Ben Middlehurst, Vivien J. Bubb, John P. Quinn, Emma Price, Andrew B. Singleton, Miten Jain, Cornelis Blauwendraat, Mike Nalls, Mark R Cookson, Xylena Reed, Fritz J. Sedlazeck, Clément Goubert, Kimberley J. Billingsley
Institutions: National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, Montreal Heart Institute, Université de Montréal, Baylor College of Medicine, Johns Hopkins University, UCL Queen Square Institute of Neurology, University College London, University of Southern California, University of Liverpool, National Institute of Allergy and Infectious Diseases, Northeastern University, National Cancer Institute, Center for Cancer Research, University of Arizona
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: STRIDES , NIH STRIDES - Azure and Associated Services and Training., STRIDES, UCSC Graduate Program in Genome Sciences, Procurement and Characterization of Postmortem Brain Tissue, Center for Alzheimer's and Related Dementias (CARD): Long-read DNA sequencing of Alzheimers Disease and Related Dementias cases, Single-molecule sequence assembly and analysis, Center for Alzheimer's and Related Dementias (CARD): Harmonized Data-Derived Resources for the Alzheimer's Disease and Related Dementias Community
OpenAlex ID: W7167375454