One thousand somatic SNVs per skin fibroblast cell set baseline of mosaic mutational load with patterns that suggest proliferative origin.
Level 5 - mechanism / opinion, no new human data
Bench research and in vitro genomic analysis of reprogrammed cell lines (graded by design analogy).
PubMed 28235832 · doi:10.1101/gr.215517.116
What was done
Investigators reprogrammed 32 skin fibroblast cells from donor families into human induced pluripotent stem cell (hiPSC) lines to examine clonal genomes without single-cell amplification artifacts. They measured single-nucleotide variants (SNVs), confirmed variant allele frequencies in parental fibroblast populations using ultradeep sequencing (down to 0.1%) and droplet digital PCR (down to 0.01%), and compared mutational loads between pediatric and adult donors.
What was found
Fibroblast cells from children contained an average of 1,035 mostly benign mosaic SNVs per cell. An average of 235 SNVs per line were directly confirmed in parental fibroblast populations at allele frequencies down to 0.1%, with additional variants confirmed down to 0.01% by droplet digital PCR. Adult cells showed no significant increase in SNV count compared to pediatric cells. Mosaic variants were distributed uniformly across the genome, showed mutational signatures associated with cell proliferation and cancer, and had allele frequency distributions with distinct narrow peaks.
Why it matters
This study provides a quantitative baseline for somatic mosaicism in healthy human cells, showing that hundreds of benign mutations accumulate routinely during development rather than solely via aging.
Limits
The study evaluated only 32 hiPSC lines derived from an unspecified number of individual donors. It assessed only cultured skin fibroblasts, so the mutational baseline may not reflect other tissue types or non-proliferative lineages.
Cited by
- supports When somatic cells are reprogrammed into induced pluripotent stem cells, somatic DNA mutations are retained and persist.