RT Journal Article SR Electronic T1 Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.05.27.446006 DO 10.1101/2021.05.27.446006 A1 Neil A. Robertson A1 Eric Latorre-Crespo A1 Maria Terradas-Terradas A1 Alison C. Purcell A1 Benjamin J Livesey A1 Joseph A. Marsh A1 Lee Murphy A1 Angie Fawkes A1 Louise MacGillivray A1 Mhairi Copland A1 Riccardo E. Marioni A1 Sarah E. Harris A1 Simon R. Cox A1 Ian J. Deary A1 Linus J. Schumacher A1 Kristina Kirschner A1 Tamir Chandra YR 2021 UL http://biorxiv.org/content/early/2021/06/04/2021.05.27.446006.abstract AB The prevalence of clonal haematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. Since mutations in stem cells often drive leukaemia, we hypothesised that stem cell fitness substantially contributes to transformation from CHIP to leukaemia. Stem cell fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. It is currently unknown whether mutations in different CHIP genes lead to distinct fitness advantages that could form the basis for patient stratification. We set out to quantify the fitness effects of CHIP drivers over a 12 year timespan in older age, using longitudinal error-corrected sequencing data. We developed a new method based on drift-induced fluctuation (DIF) filtering to extract fitness effects from longitudinal data, and thus quantify the growth potential of variants within each individual. Our approach discriminates naturally drifting populations of cells and faster growing clones, while taking into account individual mutational context. We show that gene-specific fitness differences can outweigh inter-individual variation and therefore could form the basis for personalised clinical management.Competing Interest StatementKK received a reagent grant from ArcherDX/ Invitae. LM consults for Illumina.