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. 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. 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. 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%. We estimate that on average a fibroblast cell in children has 1035 mostly benign mosaic SNVs. 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 reprogrammed 32 skin fibroblast cells from families of donors into human induced pluripotent stem cell (hiPSC) lines. Vaccarino2,3,9 1ĭepartment 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 3Child Study Center, Yale University, New Haven, Connecticut 06520, USA 4Department of Psychiatry and Behavioral Sciences and Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA 5Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA 6Program in Computation Biology and Bioinformatics, Yale University, New Haven, Connecticut 06520, USA 7Department of Computer Science, Yale University, New Haven, Connecticut 06520, USA 8 Department of Genetics, Yale University, New Haven, Connecticut 06520, USA 9Department of Neuroscience, Yale University, New Haven, Connecticut 06520, USA 2įew studies have been conducted to understand post-zygotic accumulation of mutations in cells of the healthy human body. One thousand somatic SNVs per skin fibroblast cell set baseline of mosaic mutational load with patterns that suggest proliferative origin Alexej Abyzov,1,2 Livia Tomasini,2,3 Bo Zhou,4 Nikolaos Vasmatzis,1 Gianfilippo Coppola,2,3 Mariangela Amenduni,2,3 Reenal Pattni,4 Michael Wilson,2,3 Mark Gerstein,2,5,6,7 Sherman Weissman,2,8 Alexander E.
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