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Monogenic and polygenic inheritance become instruments for clonal selection

View ORCID ProfilePo-Ru Loh, View ORCID ProfileGiulio Genovese, View ORCID ProfileSteven A McCarroll
doi: https://doi.org/10.1101/653691
Po-Ru Loh
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
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  • For correspondence: poruloh@broadinstitute.org giulio.genovese@gmail.com mccarroll@hms.harvard.edu
Giulio Genovese
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
3Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
4Department of Genetics, Harvard Medical School
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  • For correspondence: poruloh@broadinstitute.org giulio.genovese@gmail.com mccarroll@hms.harvard.edu
Steven A McCarroll
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
3Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
4Department of Genetics, Harvard Medical School
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  • For correspondence: poruloh@broadinstitute.org giulio.genovese@gmail.com mccarroll@hms.harvard.edu
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Abstract

Clonally expanded blood cells with somatic mutations (clonal hematopoiesis, CH) are commonly acquired with age and increase risk of later blood cancer. To identify genes and mutations that give selective advantage to mutant clones, we identified among 482,789 UK Biobank participants some 19,632 autosomal mosaic chromosomal alterations (mCAs), including deletions, duplications, and copy number-neutral loss of heterozygosity (CNN-LOH). Analysis of these acquired mutations, along with inherited genetic variation, revealed 52 inherited, rare, large-effect coding or splice variants (in seven genes) that greatly (odds ratios of 11 to 758) increased vulnerability to CH with specific acquired CNN-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 seven genes (MRE11, NBN, and ATM) encode components of the MRN-ATM pathway, which limits cell division after DNA damage and telomere attrition; another two (MPL, SH2B3) encode proteins that regulate stem cell self-renewal. In addition to these monogenic inherited forms of CH, we found a common and surprisingly polygenic form: CNN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote hematopoietic cell proliferation to replace their homologous (allelic) counter-parts, increasing polygenic drive for blood-cell proliferation traits. This dynamic reveals a challenge for lifelong cytopoiesis in any genetically diverse species: individuals inherit unequal proliferative genetic potentials on paternally and maternally derived chromosomepairs, and readily-acquired mutations that replace chromosomal segments with their homologous counterparts give selective advantage to mutant cells.

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Posted May 29, 2019.
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Monogenic and polygenic inheritance become instruments for clonal selection
Po-Ru Loh, Giulio Genovese, Steven A McCarroll
bioRxiv 653691; doi: https://doi.org/10.1101/653691
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Monogenic and polygenic inheritance become instruments for clonal selection
Po-Ru Loh, Giulio Genovese, Steven A McCarroll
bioRxiv 653691; doi: https://doi.org/10.1101/653691

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