Diverse mutational landscapes in human lymphocytes.
Diverse mutational landscapes in human lymphocytes.
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DOI：
10.1038/s41586-022-05072-7
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发表时间：
2022-08
期刊：
影响因子：
64.8
通讯作者：
Campbell, Peter J.
中科院分区：
文献类型：
--
作者：
Machado, Heather E.;Mitchell, Emily;Obro, Nina F.;Kubler, Kirsten;Davies, Megan;Leongamornlert, Daniel;Cull, Alyssa;Maura, Francesco;Sanders, Mathijs A.;Cagan, Alex T. J.;McDonald, Craig;Belmonte, Miriam;Shepherd, Mairi S.;Braga, Felipe A. Vieira;Osborne, Robert J.;Mahbubani, Krishnaa;Martincorena, Inigo;Laurenti, Elisa;Green, Anthony R.;Getz, Gad;Polak, Paz;Saeb-Parsy, Kourosh;Hodson, Daniel J.;Kent, David G.;Campbell, Peter J.
The lymphocyte genome is prone to many threats, including programmed mutation during differentiation, 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. Sequencing of individual human lymphocyte clones shows that they are highly prone to mutations, with higher burdens in memory cells than in naive cells arising from mutational processes associated with differentiation and tissue residency.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
端粒：一种倍性 - 敏锐的方法，用于从整个基因组测序数据中估算端粒长度。
影响因子：
4.6
作者：
Farmery JHR;Smith ML;NIHR BioResource - Rare Diseases;Lynch AG
通讯作者：
Lynch AG
影响因子：
30.8
作者：
Campbell, Peter J.;Stephens, Philip J.;Pleasance, Erin D.;O'Meara, Sarah;Li, Heng;Santarius, Thomas;Stebbings, Lucy A.;Leroy, Catherine;Edkins, Sarah;Hardy, Claire;Teague, Jon W.;Menzies, Andrew;Goodhead, Ian;Turner, Daniel J.;Clee, Christopher M.;Quail, Michael A.;Cox, Antony;Brown, Clive;Durbin, Richard;Hurles, Matthew E.;Edwards, Paul A. W.;Bignell, Graham R.;Stratton, Michael R.;Futreal, P. Andrew
通讯作者：
Futreal, P. Andrew
影响因子：
14.8
作者：
Ellis, Peter;Moore, Luiza;Campbell, Peter J.
通讯作者：
Campbell, Peter J.
影响因子：
--
作者：
Jones, David;Raine, Keiran M;Campbell, Peter J
通讯作者：
Campbell, Peter J