Telomere variant sequences encode the genetic blueprint for allele-specific telomere length

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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Publication Details

Journal
Nature Communications
Published
2026-09-07
DOI
https://doi.org/10.1038/s41467-026-77310-9
Primary Topic
Telomeres, Telomerase, and Senescence
Type
article
Field-Weighted Citation Impact
0.00

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article

Telomere variant sequences encode the genetic blueprint for allele-specific telomere length

Patrick Tan, William Ying Khee Hwang, Lifeng Xu, Takashi Minami et al.
Nature Communications
Telomeres, Telomerase, and Senescence
article

Telomere variant sequences encode the genetic blueprint for allele-specific telomere length

Patrick Tan, William Ying Khee Hwang, Lifeng Xu, Takashi Minami, Manvendra K. Singh, Lai-Fong Poon, Masafumi Fukuda, Jin Liu, Bin Tean Teh, Goro Sashida, Motomi Osato, Angela S. Koh, Shang Li, Tatsuro Kondoh, Xiaoran Chai, Jue Lin, Hengrui Liu
article en

Abstract

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.

Nature Communications
Agency for Science, Technology and Research (SG), SingHealth (SG), National University of Singapore (SG), Kumamoto Health Science University (JP), University of California, San Francisco (US), Singapore General Hospital (SG), Social Welfare Department (HK), Chinese University of Hong Kong, Shenzhen (CN), Kumamoto University Hospital (JP), Duke-NUS Medical School (SG), National Cancer Centre Singapore (SG), National Heart Centre Singapore (SG), Singapore Clinical Research Institute (SG), Genome Institute of Singapore (SG), Institute of Molecular and Cell Biology (SG), University of California, Davis (US), Kumamoto University (JP)
Oxford Nanopore Technologies, National Cancer Centre of Singapore, Duke-NUS Medical School, Agency for Science, Technology and Research, National University of Singapore, Singapore General Hospital, National Natural Science Foundation of China, Chinese University of Hong Kong, Genome Institute of Singapore, Shenzhen Fundamental Research Program, University of California, Davis, University of California, San Francisco, Medical Research Council, National Medical Research Council, Japan Society for the Promotion of Science, Institute of Molecular and Cell Biology
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