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AThi oHSC ATlo oHSC WES - Identifying clonal differences or differences in mutation burden between autophagy engaging and non-engaging hematopoietic stem cells during mouse aging.

ABSTRACT: We performed paired WES from DNA isolated from AThi and ATlo hematopoietic stem cells (FACS sorted on the basis of GFP marker intensity, 33% GFPlo as ATHi, 33% GFPhi as ATlo) using tail DNA as an internal control to identify somatic mutations. Few mutations were called at a variant allele frequency of ≥ 5% in this bulk sequencing approach, in line with recent results obtained with more sensitive methods. We also observed a high degree of shared mutations between AThi and ATlo oHSCs within each biological replicate, and no conserved mutations across biological replicates. The majority of called mutations were intronic or synonymous single nucleotide variants with limited expected consequences for their encoded proteins. Taken together, these results indicate that differing autophagy levels in oHSCs are not explained by clonal divergence or differential mutagenic burden, nor do they point to mutagenic burden as a driver of oHSC dysfunction in 24-month-old mice. They also do not provide evidence for clonal evolution between AThi and ATlo oHSC subsets.

ORGANISM(S): Mus musculus

PROVIDER: GSE230270 | GEO | 2024/05/15

REPOSITORIES: GEO

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Project description:International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not been identified by conventional epidemiology yet potentially make a substantial contribution to cancer burden1. This pertains to clear cell renal cell carcinoma (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence2. Some carcinogens generate somatic mutations and a complementary strategy for detecting past exposures is to sequence the genomes of cancers from populations with different incidence rates and infer underlying causes from differences in patterns of somatic mutations. Here, we sequenced 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in >70% cases and <2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher kidney cancer incidence rates (p-value <6 × 10−18). Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, geographically variable, mutagenic exposures potentially affecting 10s of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics. Linked cross omic data sets:Geographic variation of mutagenic exposures in kidney cancer genomes – patient metadata files (Mutographs) associated with this study are available in the European Genome-Phenome Archive: https://ega-archive.org/datasets/EGAD00001012223.

Dataset Information

AThi oHSC ATlo oHSC WES - Identifying clonal differences or differences in mutation burden between autophagy engaging and non-engaging hematopoietic stem cells during mouse aging.

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