Decoding the human brain at scale: long-read sequencing resources for neurodegeneration | LC26

Abstract
We have generated thousands of long-read whole-genome sequences from human brain tissue, providing a foundation for allele-specific methylation analysis and the development of ancestry-aware epigenetic aging clocks trained across over 28 million CpG sites. Building on this resource, we developed SA-LRR, a scalable platform for high-throughput Oxford Nanopore Technologies (ONT) cDNA sequencing of postmortem brain tissue. SA-LRR couples an automated wet lab protocol with a Snakemake end-to-end pipeline, achieving median read lengths of around two kilobases from biobank-grade samples and enabling accurate recovery of full-length isoforms. Validated across an initial cohort of postmortem brain samples, SA-LRR is now being deployed at scale across hundreds of aging and Alzheimer's disease brains, generating matched long-read DNA, methylation, and RNA data from the same individuals. This integrated multi-modal resource will enable allele-specific transcript analysis and isoform-resolved investigation of neurodegeneration across ancestrally diverse cohorts, with all protocols and pipelines openly available.

Biography
Kimberley Billingsley is leading the Applied Neurogenomics team at the National Institutes of Health (NIH) Center for Alzheimer’s and Related Dementias. Her work focuses on generating large-scale high-value datasets to study the impact of structural variants and tandem repeats in neurodegenerative diseases. Kimberley obtained her PhD from the University of Liverpool studying the role of transposable elements in Parkinson's disease.