Single cell whole genome and transcriptome sequencing links somatic mutations to cell identity and ancestry

Natu, A.; Dehankar, M. K.; Pattni, R.; Suvakov, M.; Olisov, D.; Tomasini, L.; Jang, Y.; Huang, Y.; Benito-Garragori, E.; Hasenfeld, P.; Korbel, J.; Urban, A. E.; Abyzov, A.; Vaccarino, F. M.

doi:10.1101/2025.10.28.685157

bioRxiv · 10.1101/2025.10.28.685157

Single cell whole genome and transcriptome sequencing links somatic mutations to cell identity and ancestry

Natu, A.·Dehankar, M. K.·Pattni, R.·Suvakov, M.·Olisov, D.·Tomasini, L.·Jang, Y.·Huang, Y.·Benito-Garragori, E.·Hasenfeld, P.·Korbel, J.·Urban, A. E.·Abyzov, A.·Vaccarino, F. M.

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Abstract

The role of somatic mutations in human development and disease is obscured by difficulties in characterizing mutations at the single cell level and identifying cell types carrying them. Here we analysed somatic genomes of clonal iPSC lines and of single-cells after whole-genome amplification (scWGA) by PTA and ResolveOme from skin fibroblasts, blood and urine of a live donor. Mutation burden and spectra converged across approaches, revealing heterogeneous mutational footprints across cells driven by environmental exposures (UV damage and chemotherapy) and lymphocyte differentiation. Aneuploidies in single cells were detected by all the approaches and were orthogonally validated by Strand-seq. Uniquely, ResolveOme enabled cell-type identification using single-cell transcriptomes. Using a newly developed method accounting for noise and allele drop-out in scWGA, we de novo reconstructed the cell phylogenetic tree for this donor. Together, scWGA establishes a powerful foundation for comprehensive, cell type-aware, lineage-aware profiling of somatic mutations at single cell level.

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Natu, A., Dehankar, M. K., Pattni, R., Suvakov, M., Olisov, D., Tomasini, L., Jang, Y., Huang, Y., Benito-Garragori, E., Hasenfeld, P., Korbel, J., Urban, A. E., Abyzov, A., Vaccarino, F. M.. 2025-10-29. Single cell whole genome and transcriptome sequencing links somatic mutations to cell identity and ancestry. https://doi.org/10.1101/2025.10.28.685157

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