High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform

Cheng-Yong Tham, LaiFong Poon, TingDong Yan, Javier Yu Peng Koh, Muhammad Khairul Ramlee, Vania Swee Imm Teoh, Suihan Zhang, Yi Cai, Zebin Hong, Gina S. Lee, Jin Liu, Hai Wei Song, William Ying Khee Hwang, Bin Tean Teh, Patrick Tan, Lifeng Xu, Angela S. Koh, Motomi Osato () and Shang Li ()
Additional contact information
Cheng-Yong Tham: National University of Singapore
LaiFong Poon: Duke-NUS Medical School
TingDong Yan: Duke-NUS Medical School
Javier Yu Peng Koh: Duke-NUS Medical School
Muhammad Khairul Ramlee: Duke-NUS Medical School
Vania Swee Imm Teoh: National University of Singapore
Suihan Zhang: University of California
Yi Cai: Duke-NUS Medical School
Zebin Hong: Agency for Science, Technology and Research, (A*STAR)
Gina S. Lee: National Heart Centre Singapore, Duke-NUS Medical School
Jin Liu: Centre for Quantitative Medicine, Duke-NUS Medical School
Hai Wei Song: Agency for Science, Technology and Research, (A*STAR)
William Ying Khee Hwang: Duke-NUS Medical School
Bin Tean Teh: Duke-NUS Medical School
Patrick Tan: National University of Singapore
Lifeng Xu: University of California
Angela S. Koh: National Heart Centre Singapore, Duke-NUS Medical School
Motomi Osato: National University of Singapore
Shang Li: Duke-NUS Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length due to the lack of high-throughput method with nucleotide resolution for individual telomere. Here, we describe a workflow to capture telomeres using newly designed telobaits in human culture cell lines as well as clinical patient samples and measure their length accurately at nucleotide resolution using single-molecule real-time (SMRT) sequencing. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that are dispersed throughout the telomere repeat region. The presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which affects the binding of shelterin complexes at the chromosomal ends and telomere protection. These findings may have profound implications in human aging and diseases.

Date: 2023
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DOI: 10.1038/s41467-023-35823-7

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