Nanopore whole-genome sequencing reveals conserved chromosome-specific telomere architecture across tissues and populations

Abstract

Telomeres are repetitive nucleoprotein structures that cap the ends of linear chromosomes and are essential for maintaining genomic stability. While individual chromosome ends maintain distinct telomere lengths, the extent of this conservation across tissues and populations remains unclear due to the difficulty of analyzing repetitive telomeric sequences. Here, we show that high-coverage whole-genome Nanopore sequencing enables robust measurement of telomere length at the level of individual chromosomes. Nanopore reads yield reproducible telomere length estimates across replicates, in contrast to PacBio HiFi reads. Across > 250 individuals from 1000 Genomes and the SMaHT projects, chromosome-specific telomere length patterns are conserved across individuals and tissues, with tissues from the same individual showing highly similar patterns. This conserved landscape suggests coordinated regulation, whose disruption may contribute to genomic instability. Nanopore sequencing also allows simultaneous detection of structural variants, including disruption of TERT and NHP2 that drive global telomere shortening. Furthermore, our quantification of telomere variant repeats in positional context indicates active telomerase-mediated elongation. Our integrated profiling of telomere length and structural variation enables inference of variant effects on chromosome-specific telomere dynamics and may uncover risk factors for short telomere syndromes and cancer. Importantly, positionally fully resolved telomeric variant repeat patterns may predict activated telomere maintenance mechanisms with high accuracy. SignificanceResolving chromosome-specific telomere length and variant-repeat architecture across tissues and individuals provides a framework to dissect coordinated telomere maintenance, its disruption by genetic variants, and how this shapes telomere mosaicism and disease risk.