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Genome Res. 2017 Apr;27(4):512-523. doi: 10.1101/gr.215517.116. Epub 2017 Feb 24.

One thousand somatic SNVs per skin fibroblast cell set baseline of mosaic mutational load with patterns that suggest proliferative origin.

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Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Program in Neurodevelopment and Regeneration, Yale University, New Haven, Connecticut 06520, USA.
Child Study Center, Yale University, New Haven, Connecticut 06520, USA.
Department of Psychiatry and Behavioral Sciences and Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.
Program in Computation Biology and Bioinformatics, Yale University, New Haven, Connecticut 06520, USA.
Department of Computer Science, Yale University, New Haven, Connecticut 06520, USA.
Department of Genetics, Yale University, New Haven, Connecticut 06520, USA.
Department of Neuroscience, Yale University, New Haven, Connecticut 06520, USA.


Few studies have been conducted to understand post-zygotic accumulation of mutations in cells of the healthy human body. We reprogrammed 32 skin fibroblast cells from families of donors into human induced pluripotent stem cell (hiPSC) lines. The clonal nature of hiPSC lines allows a high-resolution analysis of the genomes of the founder fibroblast cells without being confounded by the artifacts of single-cell whole-genome amplification. We estimate that on average a fibroblast cell in children has 1035 mostly benign mosaic SNVs. On average, 235 SNVs could be directly confirmed in the original fibroblast population by ultradeep sequencing, down to an allele frequency (AF) of 0.1%. More sensitive droplet digital PCR experiments confirmed more SNVs as mosaic with AF as low as 0.01%, suggesting that 1035 mosaic SNVs per fibroblast cell is the true average. Similar analyses in adults revealed no significant increase in the number of SNVs per cell, suggesting that a major fraction of mosaic SNVs in fibroblasts arises during development. Mosaic SNVs were distributed uniformly across the genome and were enriched in a mutational signature previously observed in cancers and in de novo variants and which, we hypothesize, is a hallmark of normal cell proliferation. Finally, AF distribution of mosaic SNVs had distinct narrow peaks, which could be a characteristic of clonal cell selection, clonal expansion, or both. These findings reveal a large degree of somatic mosaicism in healthy human tissues, link de novo and cancer mutations to somatic mosaicism, and couple somatic mosaicism with cell proliferation.

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