Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type

Abstract

BackgroundThe lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer.ResultsTo analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions.ConclusionsOur analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions.

Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure

“…We used deconstructSigs 46 to delineate the contribution of mutational signatures with the default Cosmic 30 signature option. Somatic mutation data from normal human tissue were obtained from a recent publication 47 . MSI status of the samples was determined by the PCAWG mutational signatures working group and obtained from the synapse repository: https://www.…”

Reduced Expression of VEGF-A in Human Retinal Pigment Epithelial Cells and Human Muller Cells Following CRISPR-Cas9 Ribonucleoprotein-Mediated Gene Disruption

“…These mutations, as well as a single nucleotide substitution seen at the predicted cute site in the control RPE cells, likely represent the well-established phenomenon of single nucleotide variants that result from clonal expansion of human cells. 26 VEGF is constitutively expressed in the eye and there is a concern that gene therapy may eliminate intraocular VEGF and result in unforeseen consequences. Systemic neutralization of VEGF using gene augmentation of sFlt-1, a soluble VEGF receptor, via adenovirus in mice showed no effects on the normal vasculature but a significant cell loss in the inner and outer nuclear layers.…”

“…These mutations, as well as a single nucleotide substitution seen at the predicted cute site in the control RPE cells, likely represent the well-established phenomenon of single nucleotide variants that result from clonal expansion of human cells. 26 …”

Mutations in normal tissues—some diagnostic and clinical implications

“…Comparable mutations were also discovered in healthy eyelid skin, removed during blepharectomy [ 12 ]. Another study examined kidney, fat, and muscle cells from donors of different ages [ 30 ]. The investigations identified a mutation-prone cell type in the kidney while also delineating an age-related decline in DNA repair capacity.…”