DNA methylation analysis using long-read sequencing

Beyond the primary genetic code, DNA carries a second layer of information in the form of epigenetic modifications, predominantly DNA methylation. DNA methylation is a dynamic process involved in gene regulation, aging, and disease, yet its genome-wide and allele-specific regulation has been difficult to resolve with traditional technologies. Using long-read sequencing, we investigate how genetic variation and aging shape the human methylome with parent-of-origin resolution. We show that much of the observed correlation between DNA methylation and gene expression is driven by underlying DNA sequence variants. We further identify widespread age-associated methylation changes across the genome and develop a highly accurate methylation aging clock. Finally, by resolving methylation to parental haplotypes, we uncover parent-of-origin–specific aging effects concentrated at imprinted loci, indicating erosion of imprinting fidelity with age.