Diverse mutational landscapes in human lymphocytes

Heather E. Machado, Emily Mitchell, Nina F. Øbro, Kirsten Kübler, Megan Davies, Daniel Leongamornlert, Alyssa Cull, Francesco Maura, Mathijs A. Sanders, Alex T. J. Cagan, Craig McDonald, Miriam Belmonte, Mairi S. Shepherd, Felipe A. Vieira Braga, Robert J. Osborne, Krishnaa Mahbubani, Iñigo Martincorena, Elisa Laurenti, Anthony R. Green, Gad Getz, Paz Polak, Kourosh Saeb-Parsy, Daniel J. Hodson, David G. Kent () and Peter J. Campbell ()
Additional contact information
Heather E. Machado: Wellcome Sanger Institute
Emily Mitchell: Wellcome Sanger Institute
Nina F. Øbro: University of Cambridge
Kirsten Kübler: Broad Institute of MIT and Harvard
Megan Davies: University of Cambridge
Daniel Leongamornlert: Wellcome Sanger Institute
Alyssa Cull: University of York, Wentworth Way
Francesco Maura: Sylvester Comprehensive Cancer Center
Mathijs A. Sanders: Wellcome Sanger Institute
Alex T. J. Cagan: Wellcome Sanger Institute
Craig McDonald: University of Cambridge
Miriam Belmonte: University of Cambridge
Mairi S. Shepherd: University of Cambridge
Felipe A. Vieira Braga: Wellcome Sanger Institute
Robert J. Osborne: Wellcome Sanger Institute
Krishnaa Mahbubani: University of Cambridge
Iñigo Martincorena: Wellcome Sanger Institute
Elisa Laurenti: University of Cambridge
Anthony R. Green: University of Cambridge
Gad Getz: Broad Institute of MIT and Harvard
Paz Polak: Oncological Sciences, Icahn School of Medicine at Mount Sinai
Kourosh Saeb-Parsy: University of Cambridge
Daniel J. Hodson: University of Cambridge
David G. Kent: University of Cambridge
Peter J. Campbell: Wellcome Sanger Institute

Nature, 2022, vol. 608, issue 7924, 724-732

Abstract: Abstract The lymphocyte genome is prone to many threats, including programmed mutation during differentiation1, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life. Off-target effects of immunological diversification accounted for approximately half of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity. DNA damage from ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory cells. The mutation burden and signatures of normal B cells were broadly similar to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes that are active across normal ontogeny. The 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.

Date: 2022
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DOI: 10.1038/s41586-022-05072-7

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