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

Author

Listed:
  • Cheng-Yong Tham

    (National University of Singapore)

  • LaiFong Poon

    (Duke-NUS Medical School)

  • TingDong Yan

    (Duke-NUS Medical School
    Shanghai University)

  • 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
    Guangzhou Medical University)

  • 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
    The Chinese University of Hong Kong-Shenzhen)

  • Hai Wei Song

    (Agency for Science, Technology and Research, (A*STAR))

  • William Ying Khee Hwang

    (Duke-NUS Medical School
    Singapore General Hospital
    National Cancer Centre Singapore)

  • Bin Tean Teh

    (Duke-NUS Medical School
    Agency for Science, Technology and Research, (A*STAR)
    Division of Medical Science, National Cancer Centre)

  • Patrick Tan

    (National University of Singapore
    Duke-NUS Medical School
    National Heart Centre Singapore
    Genome Institute of Singapore, Agency for Science, Technology and Research, (A*STAR))

  • Lifeng Xu

    (University of California)

  • Angela S. Koh

    (National Heart Centre Singapore, Duke-NUS Medical School)

  • Motomi Osato

    (National University of Singapore
    Kumamoto University)

  • Shang Li

    (Duke-NUS Medical School
    National University of Singapore)

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.

Suggested Citation

  • 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, 2023. "High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35823-7
    DOI: 10.1038/s41467-023-35823-7
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    References listed on IDEAS

    as
    1. Charles R. Harris & K. Jarrod Millman & Stéfan J. Walt & Ralf Gommers & Pauli Virtanen & David Cournapeau & Eric Wieser & Julian Taylor & Sebastian Berg & Nathaniel J. Smith & Robert Kern & Matti Picu, 2020. "Array programming with NumPy," Nature, Nature, vol. 585(7825), pages 357-362, September.
    2. Elizabeth H. Blackburn, 2000. "Telomere states and cell fates," Nature, Nature, vol. 408(6808), pages 53-56, November.
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