SCIENCE@home

Monogenic and polygenic inheritance become instruments for clonal selection

Po-Ru Loh,G. Genovese,S. Mccarroll

Published 2019 in bioRxiv

ABSTRACT

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.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-89 of 89 references · Page 1 of 1

CITED BY

Showing 1-100 of 188 citing papers · Page 1 of 2

12
Next