Machado, Heather E, Øbro, Nina F, Williams, Nicholas et al. (18 more authors) (2023) Convergent somatic evolution commences in utero in a germline ribosomopathy. Nature Communications. 5092. ISSN 2041-1723
Abstract
Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © The Author(s) 2023 |
Keywords: | Humans,Young Adult,Adult,Germ Cells,Chromosomes, Human, Pair 7,Gene Dosage,Hematopoietic Stem Cells,Mutation |
Dates: |
|
Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 30 Aug 2023 09:22 |
Last Modified: | 16 Oct 2024 19:23 |
Published Version: | https://doi.org/10.1038/s41467-023-40896-5 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s41467-023-40896-5 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:202851 |
Download
Filename: s41467_023_40896_5.pdf
Description: Convergent somatic evolution commences in utero in a germline ribosomopathy
Licence: CC-BY 2.5