Genome-wide mutational signatures of immunological diversification in normal lymphocytes

Machado, H.; Mitchell, E.; Obro, N.; Kubler, K.; Davies, M.; Maura, F.; Leongamornlert, D.; Sanders, M.; Cagan, A.; McDonald, C.; Belmonte, M.; Shepherd, M.; Osborne, R.; Mahbubani, K.; Martincorena, I.; Laurenti, E.; Green, A.; Getz, G.; Polak, P.; Saeb-Parsy, K.; Hodson, D.; Kent, D.; Campbell, P.

doi:10.1101/2021.04.29.441939

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bioRxiv · 10.1101/2021.04.29.441939

Genome-wide mutational signatures of immunological diversification in normal lymphocytes

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Abstract

A lymphocyte suffers many threats to its genome, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse microenvironments. After developing protocols for single-cell lymphocyte expansions, we sequenced whole genomes from 717 normal naive and memory B and T lymphocytes and hematopoietic stem cells. Lymphocytes carried more point mutations and structural variation than stem cells, accruing at higher rates in T than B cells, attributable to both exogenous and endogenous mutational processes. Ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every one on-target IGV mutation during the germinal center reaction. Structural variation was 16-fold higher in lymphocytes than stem cells, with ~15% of deletions being attributable to off-target RAG activity. One Sentence SummaryThe mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.

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Machado, H., Mitchell, E., Obro, N., Kubler, K., Davies, M., Maura, F., Leongamornlert, D., Sanders, M., Cagan, A., McDonald, C., Belmonte, M., Shepherd, M., Osborne, R., Mahbubani, K., Martincorena, I., Laurenti, E., Green, A., Getz, G., Polak, P., Saeb-Parsy, K., Hodson, D., Kent, D., Campbell, P.. 2021-04-30. Genome-wide mutational signatures of immunological diversification in normal lymphocytes. https://doi.org/10.1101/2021.04.29.441939

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