Pathogenic Mechanisms of Somatic Mutation and Genome Mosaicism in Aging

Abstract

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.

Keywords: age-related disease; aging; genome mosaicism; pathogenic effects; somatic DNA mutation; transcriptional noise.

Fig. 1.. Causes and consequences of somatic DNA mutations

Different types of DNA damage occur daily in every cell of an organism, including strand breaks, base modifications, and cross links. This damage is rapidly repaired through a large variety of pathways. However, errors that occur during DNA repair and replication result in de novo mutations, which range from single nucleotide variations to chromosomal aberrations. In contrast to DNA damage, mutations are irreversible and, therefore, inevitably accumulate over time. When mutations occur in germ cells, they become substrates for evolution, giving rise to diverse life forms and to genetic disease. When they occur in the soma, mutations can result in somatic genetic diseases, age-related diseases and possibly aging.

Fig. 2.. Pathogenic mechanisms of somatic genome mosaicism

De novo mutations occur and accumulate at all stages during the lifespan of an organism. (A) Mutations that occur early in development are likely to expand clonally, resulting in substantial proportions of cells in a tissue carrying the same mutation, even in the absence of selection. When such mutations disrupt genes associated with Mendelian diseases, their adverse effects may be similar to that of the germline mutations, depending on the proportion of cells affected by the mosaicism. (B) Cells in adult tissues that acquire de novo mutations may clonally expand in a process called somatic evolution. Such selfish mutations can form substantial clonal lineages, which may cause cancer and other age-related diseases that involve loss of proliferative homeostasis, such as atherosclerosis. (C) In each cell, mutations accumulate across its genome, including in those sequences that participate in functional networks. This may result in transcriptional noise, which in turn are likely to affect the signaling networks that are critical for maintaining organismal homeostasis.

Fig. 3.. How can mutation accumulation affect functional output of gene regulatory networks?

Cellular and organismal function is organized in complex gene regulatory networks (GRNs) involving interactions between large numbers of gene and their regulators, typically genes and their cis- and trans-acting elements. (A) Mutations inevitably accumulate in elements of each functional network in a stochastic manner. While initially insufficient in number to have an effect, eventually these mutations will collectively diminish the functional output of the GRN in an increasingly large number of cells, possibly through increased transcriptional noise (see text). (B) Increased noise in GRNs could explain defects in kinetics of cell signaling during aging, in which the response to external stimuli is blunted.