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Journal Article
Monogenic and polygenic inheritance become instruments for clonal selection
2020
Overview
Clonally expanded blood cells that contain somatic mutations (clonal haematopoiesis) are commonly acquired with age and increase the risk of blood cancer
1
–
9
. The blood clones identified so far contain diverse large-scale mosaic chromosomal alterations (deletions, duplications and copy-neutral loss of heterozygosity (CN-LOH)) on all chromosomes
1
,
2
,
5
,
6
,
9
, but the sources of selective advantage that drive the expansion of most clones remain unknown. Here, to identify genes, mutations and biological processes that give selective advantage to mutant clones, we analysed genotyping data from the blood-derived DNA of 482,789 participants from the UK Biobank
10
. We identified 19,632 autosomal mosaic chromosomal alterations and analysed these for relationships to inherited genetic variation. We found 52 inherited, rare, large-effect coding or splice variants in 7 genes that were associated with greatly increased vulnerability to clonal haematopoiesis with specific acquired CN-LOH mutations. Acquired mutations systematically replaced the inherited risk alleles (at
MPL
) or duplicated them to the homologous chromosome (at
FH
,
NBN
,
MRE11
,
ATM
,
SH2B3
and
TM2D3
). Three of the genes (
MRE11
,
NBN
and
ATM
) encode components of the MRN–ATM pathway, which limits cell division after DNA damage and telomere attrition
11
–
13
; another two (
MPL
and
SH2B3
) encode proteins that regulate the self-renewal of stem cells
14
–
16
. In addition, we found that CN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote the expansion of haematopoietic cells to replace their homologous (allelic) counterparts, increasing polygenic drive for blood-cell proliferation traits. Readily acquired mutations that replace chromosomal segments with their homologous counterparts seem to interact with pervasive inherited variation to create a challenge for lifelong cytopoiesis.
Analysis of blood-derived DNA from participants in the UK Biobank demonstrates that clonal expansions of acquired copy-neutral loss of heterozygosity mutations act on inherited alleles along a chromosome arm by modifying their allelic dosages.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Adult
/ Aged
/ Alleles
/ Biobanks
/ Cardiovascular Diseases - genetics
/ Cardiovascular Diseases - pathology
/ DNA
/ Female
/ Genes
/ Genetic Predisposition to Disease
/ Genomes
/ Hematologic Neoplasms - genetics
/ Hematologic Neoplasms - pathology
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Loss of Heterozygosity - genetics
/ Male
/ Multifactorial Inheritance - genetics
/ Mutation
/ Proteins
/ Science
/ Segments
