@article{d320a93422754125b5c6126fd2be9f62,
title = "Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects",
abstract = " Clonal haematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Since mutations in HSPCs often drive leukaemia, we hypothesised that HSPC fitness substantially contributes to transformation from CHIP to leukaemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals.We find that gene-specific fitness differences can outweigh inter-individual variation and therefore could form the basis for personalised clinical management.",
author = "Robertson, {Neil A.} and {Latorre Crespo}, Eric and {Terradas Terradas}, Maria and {Lemos Portela}, Jorge and Purcell, {Alison C.} and Ben Livesey and Robert Hillary and Lee Murphy and Angie Fawkes and Louise Macgillivray and Mhairi Copland and Marioni, {Riccardo E} and Marsh, {Joseph A} and Harris, {Sarah A.} and Cox, {Simon R.} and Deary, {Ian J} and Schumacher, {Linus J} and Kristina Kirschner and Tamir Chandra",
note = "Funding Information: K.K. received a reagent grant from ArcherDX/Invitae. L.M. consults for Illumina. M.C. has received research funding from Cyclacel and Incyte, is/has been an advisory board member for Novartis, Incyte, Pfizer and Jazz Pharmaceuticals and has received honoraria from Astellas, Novartis, Incyte, Pfizer and Jazz Pharmaceuticals. The remaining authors declare no competing interests. Funding Information: We gratefully acknowledge the contributions of the LBC participants and members of the LBC research team who collect and manage the LBC data. We thank C. P. Ponting for critical reading of the manuscript. We would also like to thank B. Tait for his help, advice and patience throughout. LBC1921 was supported by the UK{\textquoteright}s Biotechnology and Biological Sciences Research Council (BBSRC) (SR176) to I.J.D; by a Royal Society–Wolfson Research Merit Award to I.J.D.; and by the Chief Scientist Office of the Scottish Government{\textquoteright}s Health Directorates (CZB/4/505; ETM/55) to I.J.D. LBC1936 is supported by the BBSRC and the Economic and Social Research Council (BB/W008793/1) to S.R.C; Age UK (Disconnected Mind project, which supports S.E.H) to I.J.D and S.R.C.; the Medical Research Council (MR/M01311/1 to I.J.D. and MR/K026992/1 to S.R.C.); and the University of Edinburgh. K.K. is funded by a John Goldman Fellowship, sponsored by Leukaemia U.K. (2019/JGF/003 to K.K.) and received CRUK Glasgow Centre funding (C7932/A25142 to K.K.) and CRUK Scotland Centre funding (CTRQQR-2021\100006 to K.K.). M.T.T. and N.A.R. are supported by Medical Research Council-funded Ph.D. studentships (MR/N013166/1 to M.T.T. and N.A.R.). T.C. and L.S. are supported by Chancellor{\textquoteright}s Fellowships held at the University of Edinburgh. J.A.M. is a Lister Institute Research Prize Fellow. E.L.C. is a cross-disciplinary postdoctoral fellow supported by funding from the University of Edinburgh and the Medical Research Council (MC_UU_00009/2). S.R.C. is supported by a Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society (221890/Z/20/Z). We are also grateful for funding from the Howat Foundation (grant holder, M.C.). Funding Information: We gratefully acknowledge the contributions of the LBC participants and members of the LBC research team who collect and manage the LBC data. We thank C. P. Ponting for critical reading of the manuscript. We would also like to thank B. Tait for his help, advice and patience throughout. LBC1921 was supported by the UK{\textquoteright}s Biotechnology and Biological Sciences Research Council (BBSRC) (SR176) to I.J.D; by a Royal Society–Wolfson Research Merit Award to I.J.D.; and by the Chief Scientist Office of the Scottish Government{\textquoteright}s Health Directorates (CZB/4/505; ETM/55) to I.J.D. LBC1936 is supported by the BBSRC and the Economic and Social Research Council (BB/W008793/1) to S.R.C; Age UK (Disconnected Mind project, which supports S.E.H) to I.J.D and S.R.C.; the Medical Research Council (MR/M01311/1 to I.J.D. and MR/K026992/1 to S.R.C.); and the University of Edinburgh. K.K. is funded by a John Goldman Fellowship, sponsored by Leukaemia U.K. (2019/JGF/003 to K.K.) and received CRUK Glasgow Centre funding (C7932/A25142 to K.K.) and CRUK Scotland Centre funding (CTRQQR-2021\100006 to K.K.). M.T.T. and N.A.R. are supported by Medical Research Council-funded Ph.D. studentships (MR/N013166/1 to M.T.T. and N.A.R.). T.C. and L.S. are supported by Chancellor{\textquoteright}s Fellowships held at the University of Edinburgh. J.A.M. is a Lister Institute Research Prize Fellow. E.L.C. is a cross-disciplinary postdoctoral fellow supported by funding from the University of Edinburgh and the Medical Research Council (MC_UU_00009/2). S.R.C. is supported by a Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society (221890/Z/20/Z). We are also grateful for funding from the Howat Foundation (grant holder, M.C.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = jul,
day = "4",
doi = "/10.1038/s41591-022-01",
language = "English",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
}