Telomere variant sequences encode a genetic blueprint for allele-specific telomere length (dataset 2)

Recent advances in long-read sequencing have enabled allele-specific telomere length measurements at nucleotide resolution, uncovering extreme heterogeneity in telomere length between alleles that is determined at birth and gradually shortens with age. The shortening over time makes steady-state telomere length in human somatic cells a promising biomarker for age-associated diseases.

However, the mechanisms underlying allele-specific telomere maintenance and its stability remain poorly understood. Here, we developed a high-resolution workflow combining PacBio and Nanopore long-read sequencing platforms to map allele-specific telomere length in human blood samples as well as cultured cell lines. By tracing allele-specific telomeric sequence in family members across multiple generations, we show that the allele-specific telomeric variant sequences (TVSs) are heritable (with mean similarity score > 0.95) and underlie the extreme heterogeneity of telomere length between alleles.