Abstract
Telomere length is a biomarker of aging and disease risk. Most human studies have assessed average telomere length, limiting our understanding of variability across chromosome arms. Using long-read sequencing data from >2500 All of Us participants, we estimate chromosome-specific telomere lengths and characterize sources of biological and technical variation. Telomere length varies by chromosome arm, accounting for 9.1% of total variance. Substantial variance (8.9%) in chromosome-specific telomere lengths is attributable to individual, independent of age, suggesting that inter-individual differences in length are established at birth and maintained through life. Age is inversely associated with length for all arms, but longer arms show stronger association. We demonstrate that chromosome-specific telomere estimates enable analysis of disease associations for individual telomeres and for individuals’ shortest telomere. Overall, this work highlights the utility of long-read sequencing for population-scale analysis of chromosome-specific telomere lengths and provides a framework to guide future studies.
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Data availability
The data generated in this study, including the chromosome-specific TLs from Telogator2 and TelSeq TLs, have been deposited in the community workspace titled Jain_et_al_csTL_Nature_Comm, accessed within the featured workspace collection of the All of Us Researcher Workbench (https://support.researchallofus.org/hc/en-us/articles/360059633052-Featured-Workspaces). Access to this data is available to researchers affiliated with institutions that have signed a Data Use agreement with the All of Us Research program and who have obtained controlled tier access (https://www.researchallofus.org/register/). Supplementary Data 10 includes the list of Human Pangenome Reference Consortium samples analyzed, along with links for accessing the data.
Code availability
The code used to generate chromosome-specific telomere length estimates with Telogator2 is available on GitHub: https://github.com/niyati1211/All-of-Us-chromosome-specific-telomere-lengths84. The code used to produce the main Figures and Supplementary Figs. have been deposited in the community workspace titled Jain_et_al_csTL_Nature_Comm, accessed within the featured workspace collection of the All of Us Researcher Workbench.
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Acknowledgements
We gratefully acknowledge All of Us participants, who provided data and biological samples that supported this research. We also thank the National Institutes of Health’s All of Us Research Program for enabling access to the data examined in this study. This work was supported by grants U01HG007601 (to B.L.P.), R35ES028379 (to B.L.P.), 1R01GM154421 (to L.S.C.), 1U01MH139345 (to L.S.C.), P30ES027792 (to H.A.), R03HL172114 (to B.A.), and 1OT2OD036445 (to B.A. and H.A.).
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N.J. contributed to study conception, performed analyses, interpreted the data, and wrote the main manuscript text.
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Jain, N., Luo, J., Yang, Y. et al. Determinants of chromosome-specific telomere lengths among 2573 All of Us participants. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71172-x
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DOI: https://doi.org/10.1038/s41467-026-71172-x
