Pathogenic Mechanisms of Somatic Mutation and Genome Mosaicism in Aging

Age-related accumulation of postzygotic DNA mutations results in tissue genetic heterogeneity known as somatic mosaicism. Although implicated in aging as early as the 1950s, somatic mutations in normal tissue have been difficult to study because of their low allele fractions. With the recent emergen...

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Bibliographic Details
Published in:Cell 2020-07, Vol.182 (1), p.12-23
Main Authors: Vijg, Jan, Dong, Xiao
Format: Article
Language:English
Subjects:
age-related disease
aging
Aging - genetics
Clone Cells
Disease - genetics
Gene Regulatory Networks
Genome
genome mosaicism
Humans
Mosaicism
Mutation - genetics
pathogenic effects
somatic DNA mutation
transcriptional noise
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Summary:Age-related accumulation of postzygotic DNA mutations results in tissue genetic heterogeneity known as somatic mosaicism. Although implicated in aging as early as the 1950s, somatic mutations in normal tissue have been difficult to study because of their low allele fractions. With the recent emergence of cost-effective high-throughput sequencing down to the single-cell level, enormous progress has been made in our capability to quantitatively analyze somatic mutations in human tissue in relation to aging and disease. Here we first review how recent technological progress has opened up this field, providing the first broad sets of quantitative information on somatic mutations in vivo necessary to gain insight into their possible causal role in human aging and disease. We then propose three major mechanisms that can lead from accumulated de novo mutations across tissues to cell functional loss and human disease. Vijg and Dong review recent insights that reveal how common genetic mosaicism is and propose three mechanisms through which somatic mutations could contribute to aging and age-related pathology.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2020.06.024