The ends of human chromosomes are capped by specialized nucleoprotein structures, termed telomeres, which are essential for genome stability. Recent advances in long-read sequencing have enabled allele-specific telomere length measurements at nucleotide resolution, uncovering extreme heterogeneity in telomere length between alleles. The progressive telomere 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 and underlie the extreme heterogeneity of telomere length between alleles. Continuous cell proliferation likely drives the slow but stochastic evolution of allele-specific TVSs, resulting in asymmetry in telomere inheritance from father and mother (p-value = 2.354e-7). Targeted deletion of allele-specific TVSs using CRISPR-Cas9 resets telomere length, further confirming their causal role in the control of allele-specific telomere maintenance. These results indicated that TVSs are heritable genetic elements underlying the allele-specific telomere length. The authors use long-read sequencing to map allele-specific telomere lengths and telomere variant sequences (TVS). They find that TVSs dispersed along the telomere repeat region are heritable genetic elements that account for the extreme heterogeneity of telomere length between alleles.
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