Long-read whole-genome analysis of human single cells

Joanna Hård (), Jeff E. Mold, Jesper Eisfeldt, Christian Tellgren-Roth, Susana Häggqvist, Ignas Bunikis, Orlando Contreras-Lopez, Chen-Shan Chin, Jessica Nordlund, Carl-Johan Rubin, Lars Feuk, Jakob Michaëlsson and Adam Ameur ()
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Joanna Hård: Karolinska Institutet
Jeff E. Mold: Karolinska Institutet
Jesper Eisfeldt: Karolinska Institutet
Christian Tellgren-Roth: Uppsala University
Susana Häggqvist: Uppsala University
Ignas Bunikis: Uppsala University
Orlando Contreras-Lopez: Royal Institute of Technology (KTH)
Chen-Shan Chin: GeneDX LLC
Jessica Nordlund: Uppsala University
Carl-Johan Rubin: Uppsala University
Lars Feuk: Uppsala University
Jakob Michaëlsson: Karolinska Institutet
Adam Ameur: Uppsala University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Long-read sequencing has dramatically increased our understanding of human genome variation. Here, we demonstrate that long-read technology can give new insights into the genomic architecture of individual cells. Clonally expanded CD8+ T-cells from a human donor were subjected to droplet-based multiple displacement amplification (dMDA) to generate long molecules with reduced bias. PacBio sequencing generated up to 40% genome coverage per single-cell, enabling detection of single nucleotide variants (SNVs), structural variants (SVs), and tandem repeats, also in regions inaccessible by short reads. 28 somatic SNVs were detected, including one case of mitochondrial heteroplasmy. 5473 high-confidence SVs/cell were discovered, a sixteen-fold increase compared to Illumina-based results from clonally related cells. Single-cell de novo assembly generated a genome size of up to 598 Mb and 1762 (12.8%) complete gene models. In summary, our work shows the promise of long-read sequencing toward characterization of the full spectrum of genetic variation in single cells.

Date: 2023
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DOI: 10.1038/s41467-023-40898-3

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