The mutational landscape of human somatic and germline cells

Abstract

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 .

Dissecting single-cell genomes through the clonal organoid technique

“…The territory of a stem cell can spread even further through rounds of dynamic fission and fusion of its crypts 53 . Although the frequency in various tissue types is uncertain, clonal patches are known to form in many tissue types, such as the liver 54 , uterus 52 , placenta 55 , and other pan-body tissues 56 . As in cancer tissues, the cells in a clonal patch share all somatic mutations acquired in the genome of the MRCA cell.…”

“…In practice, microdissected tissues are not always single clones but usually include multiple clones 56 , either because the size of the clonal structure is smaller than the dissected structure or because the excised tissue overlaps the boundaries between multiple clonal patches. Clonality in excised tissue can be inferred from genome sequences using the number of discovered somatic mutations and their variant allele fractions (VAFs) 56 . Monoclonal patches show a substantial number of somatic mutations, with a VAF peak of ~50%.…”

“…The mutation rate of adult stem cells in crypts was 43.6 somatic base substitutions per year, and ~1% of the adult stem cells in the apparently normal colorectal crypts harbored known cancer driver mutations, such as AXIN2 and PIK3CA . Morphologically normal bladder 58 , 59 , liver 54 , endometrium 52 , and pan-body tissues of human individuals 56 have been explored by similar techniques.…”

“…The microdissection technique is accurate and easy to scale up but requires preclonalized anatomical structures, which are not always present in human tissues. As briefly mentioned above, the clonality of patches can be investigated according to the distribution of VAFs in somatic mutations 56 . Genomes in polyclonal patches cannot be further investigated due to the loss of sensitivity in the mutation detection, as mentioned above.…”

Nature of spontaneously arising single base substitutions in normal cells

“…Cause of mutations Reference SBS1 ACG>ATG, GCG>GTG, CCG>CTG Spontaneously arising deamination of 5-methylcytosine causes CpG>TpG mutations, representing an aging signature. Second most frequent mutation after SBS5 (Abascal et al, 2021;Fryxell & Zuckerkandl, 2000;Li et al, 2021;Lindahl, 1993) SBS2 TCA>TTA, TCT>TTT Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytosine deaminases (Lee-Six et al, 2019;Nik-Zainal et al, 2012) SBS4 CCA>CAA, CCC>CAC, CCT>CAT Tobacco smoke, frequently seen in hepatocytes (Alexandrov et al, 2016;Li et al, 2021) SBS5 ATA>ACT, ATG>ACG, ATT>ACT Mutations linearly accumulate with age, result from multiple mutational processes, and account for 50-90% of somatic mutations and 85% in male germ cells (Alexandrov et al, 2015(Alexandrov et al, , 2020Li et al, 2021;Moore et al, 2021) SBS7 TCC>TTC, TCA>TTA, TCC>TTC, CCC>CTC UV-light exposure (Forbes et al, 2017) SBS13 TCA>TGA, TCT>TGT APOBEC cytosine deaminases (Lee-Six et al, 2019;Nik-Zainal et al chromosome segregation in the M phase (Fig. 2).…”