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Dataset ID
Description
Technology
Samples
EGAD00001006591
Stem cells within prostate epithelium frequently undergo malignant transformation, but there is limited information on their clonal dynamics and mutation burden in healthy human prostates. We sequenced whole genomes from 409 microdissections of prostate epithelium across 8 donors, using phylogenetic reconstruction with spatial mapping in a 59-year-old man’s prostate to provide high-resolution reconstruction of tissue dynamics across the lifespan. Somatic mutation burden increases linearly with age, at ~16 mutations/year/clone, and is higher in peripheral than peri-urethral regions. The 24-30 independent glandular subunits are established as rudimentary ductal structures during fetal development by 5-10 embryonic cells each. Puberty induces formation of further side branches and terminal acini by local stem cells disseminated through the rudimentary ducts during development. During adult tissue maintenance, clonal expansions are small, with limited geographic scope and minimal migration. Driver mutations are rare in normal ageing prostate epithelium, but the one canonical driver we did observe generated a sizable intraepithelial clonal expansion. By resolving unbiased, continuously occurring lineage-marking mutations, we define stem cell dynamics through embryogenesis, puberty and ageing, with relevance for prostate cancer.
HiSeq X Ten
49
EGAD00001006641
During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.
HiSeq X Ten
Illumina NovaSeq 6000
1
EGAD00001016809
Mutations accumulate in normal human cells over the course of an individual’s lifetime. Early studies have shown differences in mutation rates and mutational signatures between cell types, but the range of tissues investigated has been constrained by limitations of DNA sequencing technologies. Here, we employ genome-wide NanoSeq single molecule duplex sequencing to survey the mutation landscapes of 53 normal cell types and tissue structures purified by laser-capture microdissection and flow sorting. Single base substitution mutation rates ranged from ~3/year in spermatogonia and sperm contributing to the male germline, to ~20/year in postmitotic neurons, ~50/year in mitotically active colorectal epithelial cells, ~60/year in kidney proximal tubule cells and hepatocytes, 100s/year in ultraviolet light exposed skin epidermis and from 10-50/year across the other cell types. At least 18 single base substitution and 9 small insertion and deletion mutational signatures contribute to mutation burdens, some to all cell types, some to subsets of cell types and others to a single cell type. Known exogenous mutagen exposures and endogenous mutational processes account for some mutational signatures but the origins and mechanisms underlying many are uncertain. This comprehensive survey of mutagenesis provides a foundation for understanding somatic evolution in human cell populations in health and disease.
HiSeq X Ten
Illumina NovaSeq 6000
6
