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Strand-seq and the future of personalized genomics

Nature Genetics (2026)Cite this article

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Abstract

Sequencing the human genome came with the promise of refined risk assessment for heritable diseases, drug responses and other applications of personalized genomics. Genome-wide association studies that linked thousands of genetic alterations to heritable disorders have partially delivered on this promise. However, many patients with rare diseases remain undiagnosed after genome sequencing, in part because conventional sequencing studies struggle to characterize and phase all genomic variation. Chromosome-length phasing, enabled by the single-cell Strand-seq technique in combination with long-read data, has done much to improve the situation. For example, new diploid assembly analyses for personal genomes allow nearly complete descriptions of genomic variation. Moreover, a new Strand-seq-based phasing method can leverage DNA methylation to assign genetic variants not just to haplotypes but to maternally or paternally inherited homologous chromosomes, representing a new frontier in personalized genomics. Here we review the principles and application of Strand-seq, a key enabler of these developments.

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Fig. 1: Principle of the Strand-seq method.
Fig. 2: Strand-seq library preparation.
Fig. 3: Examples of Strand-seq libraries for genome analysis.
Fig. 4: Generation of haplotypes for homologous chromosomes using Strand-seq.
Fig. 5: Inversion signals in Strand-seq data.

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Acknowledgements

We thank M. Hills for providing critical comments on the manuscript, and various funding agencies for supporting the Strand-seq work in the laboratory of P.M.L. These include grants from Genome Canada, Genome BC (323ECC), the Government of British Columbia and the BC Cancer Foundation, as well as grants from the Canadian Institutes of Health Research (PJT-159787 and PWUZ GR028457), Canada Foundation for Innovation (grants 40044 and 43153) and US National Institutes of Health (grant U24 HG007497 RPPR). V.C.T.H. is supported by a UK Horizons Ember Fellowship, a School of Biological Sciences–Isaac Newton Trust Joint Seed Funding Award and the Gatsby Charitable Foundation. Supplementary Video 1 was produced by A. Villalbi, I. Schrader, S. Jones and P.M.L. with financial support from AstraZeneca and Merck. We owe a depth of gratitude to the many people who helped to develop and improve the Strand-seq method over the years. These people include E. Falconer, L. Chavez, U. Naumann, A. Sanders, M. Hills, H. Zahn, M. Hirst, D. Porubsky, V. Guryev, D. Spierings, N. van Wietmarschen, E.-J. Uringa, R. Coope, D. Chan and Y. Wang. Together, we explored hundreds of avenues, most of them dead ends, but nevertheless instructive. We also thank all of the people who have helped to explore applications of the Strand-seq method in studies funded by the National Institutes of Health, European Research Council and Canadian Institutes of Health Research. Key to ongoing work exploring the applications of Strand-seq are I. Schrader, S. Jones and many other collaborators in Vancouver, as well as E. Eichler, J. Korbel, D. Porubsky, C. Lee and other members of the Human Genome Structural Variation Consortium. We thank current and past members of the Terry Fox Flow Cytometry core facility for excellent technical support with the sorting of cells and nuclei. We thank D. Chan, Y. Wang, T. Nguyen, M. Lee and T. Leung, the current members of the Strand-seq core facility (https://www.bccrc.ca/dept/tfl/services/strand-seq-core), for great team work, efficient data production and expert technical assistance.

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  1. Crop Science Centre, Department of Plant Sciences, University of Cambridge, Cambridge, UK

    Vincent C. T. Hanlon

  2. Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada

    Peter M. Lansdorp

  3. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

    Peter M. Lansdorp

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  1. Vincent C. T. Hanlon
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V.C.T.H. and P.M.L. both contributed to conceptualization and writing of the manuscript.

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Correspondence to Vincent C. T. Hanlon or Peter M. Lansdorp.

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Competing interests

P.M.L. is a founder and shareholder of Repeat Diagnostics, a company that offers clinical leukocyte telomere length measurements, and Evident Genomics, a company providing parent-of-origin-aware genome analysis. V.C.T.H. and P.M.L. are listed as inventors on US patent 2025/0146052 Al, issued 8 May 2025.

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Hanlon, V.C.T., Lansdorp, P.M. Strand-seq and the future of personalized genomics. Nat Genet (2026). https://doi.org/10.1038/s41588-026-02548-4

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