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dc.contributor.authorMachado, Heather E
dc.contributor.authorMitchell, Emily
dc.contributor.authorØbro, Nina F
dc.contributor.authorKübler, Kirsten
dc.contributor.authorDavies, Megan
dc.contributor.authorLeongamornlert, Daniel
dc.contributor.authorCull, Alyssa
dc.contributor.authorMaura, Francesco
dc.contributor.authorSanders, Mathijs A
dc.contributor.authorCagan, Alex TJ
dc.contributor.authorMcDonald, Craig
dc.contributor.authorBelmonte, Miriam
dc.contributor.authorShepherd, Mairi S
dc.contributor.authorVieira Braga, Felipe A
dc.contributor.authorOsborne, Robert J
dc.contributor.authorMahbubani, Krishnaa
dc.contributor.authorMartincorena, Iñigo
dc.contributor.authorLaurenti, Elisa
dc.contributor.authorGreen, Tony
dc.contributor.authorGetz, Gad
dc.contributor.authorPolak, Paz
dc.contributor.authorSaeb-Parsy, Kourosh
dc.contributor.authorHodson, Daniel
dc.contributor.authorKent, David G
dc.contributor.authorCampbell, Peter J
dc.date.accessioned2022-07-08T23:30:38Z
dc.date.available2022-07-08T23:30:38Z
dc.date.issued2022-08-10
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338957
dc.description.abstractThe 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.
dc.publisherSpringer Science and Business Media LLC
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCambridge Stem Cell Institute
dc.titleDiverse mutational landscapes in human lymphocytes.
dc.typeArticle
dc.publisher.departmentDepartment of Haematology
dc.date.updated2022-07-07T13:22:25Z
prism.publicationNameNature
dc.identifier.doi10.17863/CAM.86364
dcterms.dateAccepted2022-07-05
rioxxterms.versionofrecord10.1038/s41586-022-05072-7
rioxxterms.versionAM
dc.contributor.orcidLeongamornlert, Daniel [0000-0002-3486-3168]
dc.contributor.orcidCagan, Alex TJ [0000-0002-7857-4771]
dc.contributor.orcidMahbubani, Krishnaa [0000-0002-1327-2334]
dc.contributor.orcidMartincorena, Iñigo [0000-0003-1122-4416]
dc.contributor.orcidLaurenti, Elisa [0000-0002-9917-9092]
dc.contributor.orcidGreen, Tony [0000-0002-9795-0218]
dc.contributor.orcidGetz, Gad [0000-0002-0936-0753]
dc.contributor.orcidSaeb-Parsy, Kourosh [0000-0002-0633-3696]
dc.contributor.orcidHodson, Daniel [0000-0001-6225-2033]
dc.contributor.orcidKent, David G [0000-0001-7871-8811]
dc.contributor.orcidCampbell, Peter J [0000-0002-3921-0510]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (203151/Z/16/Z)
pubs.funder-project-idWellcome Trust (203151/A/16/Z)
pubs.funder-project-idBloodwise (15008)
pubs.funder-project-idWellcome Trust (107630/Z/15/Z)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/P002293/1)
pubs.funder-project-idEuropean Research Council (715371)
pubs.funder-project-idMRC (via University of York) (MR/V005502/1)
cam.issuedOnline2022-08-10
cam.orpheus.successMon Aug 15 07:57:16 BST 2022 - Embargo updated
cam.orpheus.counter3
cam.depositDate2022-07-07
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2023-02-10


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