A comprehensive view of somatic mosaicism by single-cell DNA analysis

Luquette, L. J., Coorens, T. H. H., Natu, A., Suvakov, M., Caplin, A., Jun, M. S., Mo, A., Pelt, J., Anderson, L., Berselli, M., Bhamidipati, S., Blanchard, T., Brew, J., Chun, H.-J. E., Chun, H., Dehankar, M. K., Feng, W. C., Furatero, R., Grochowski, C. M., Ho, E., Jang, Y., Kottapalli, K., Leonard, M. K., Lim, N. S., Lindsay, T., Nicholson, S., Raimondi, I., Runnels, A., Scharlee, C., Shin, J., Veit, A. D., VonDran, M., Wang, Y., Yuan, D. J., Zhao, Y., Bell, T. J., Ardlie, K., Doddapaneni, H., Fulton, R., Germer, S., Landau, D., Oh, J. W., Park, P. J., Vaccarino, F. M., Walsh, C. A., Abyzov

Harvard University · biorxiv

Paper

Abstract

Single-cell DNA sequencing offers a powerful means of studying somatic mosaicism but requires careful analysis to mitigate DNA amplification-related artifacts. We performed primary template-directed amplification (PTA) and sequencing of 102 nuclei from postmortem lung and colon tissues of a 74-year-old male. Single-cell mutation burdens and spectra were validated by duplex sequencing and revealed heterogeneity across organs and cells, including signatures of APOBEC activity and tobacco exposure. Cells from both tissues exhibited chromosomal aneuploidies, loss of chromosome Y, and chromosomal rearrangements including rearrangements of the T-cell receptor loci indicative of T-cells. Shared embryonic mutations between cells enabled reconstruction of cellular ancestries from the zygote, which were validated by bulk sequencing. Collectively, we demonstrate a comprehensive approach for single-cell genomics that yields an expansive view of diverse somatic mutation types from development through aging across diverse tissues--insights that are obscured in bulk sequencing and only partially captured by other single-cell methods.

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Research summary

The paper demonstrates a comprehensive approach to single-cell genomics that reveals diverse somatic mutation types across tissues, contributing to our understanding of aging processes. The insights into somatic mosaicism and its implications for aging mechanisms provide a foundation for exploring the root causes of age-related changes.

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