Somatic mutations, genome mosaicism, cancer and aging

Abstract

Genomes are inherently unstable due to the need for DNA sequence variation in the germ line to fuel evolution through natural selection. In somatic tissues mutations accumulate during development and aging, generating genome mosaics. There is little information about the possible causal role of increased somatic mutation loads in late-life disease and aging, with the exception of cancer. Characterizing somatic mutations and their functional consequences in normal tissues remains a formidable challenge due to their low, individual abundance. Here, I will briefly review our current knowledge of somatic mutations in animals and humans in relation to aging, how they arise and lead to genome mosaicism, the technology to study somatic mutations and how they possibly could cause non-clonal disease.

Figure 1

The genome harbors all the instructions for providing function to the somatic cells of an organism. Random alterations in its information content in the germ line drive evolutionary change, while similar changes in the somatic cells could be the cause of aging.

Figure 2

Schematic depiction of mutation accumulation during development and aging. Cancer-causing mutations (red check mark) are actively selected for, resulting in the clonal development of a tumor (beige). Occasionally, a mutation is subject to genomic drift (green check mark) and also leads to clonal amplification (green).

Figure 3

Single-cell analysis is required for detecting low-abundant, random mutations. The A > G mutation (red check mark) can only be distinguished from sequencing errors after single-cell, whole genome amplification when it shows up in ~50% of the reads (red; one mutated allele). Polymorphic variants (SNPs; blue) are also observed in the unamplified control DNA extracted from the bulk cell population. SNPs are variants between the genome of our cells and the reference genome. They are electronically discarded.

Figure 4

Paired-end sequencing allows the identification of a large variety of structural variation as discrepancies after aligning the sequencing reads to the reference genome.

Figure 5

Age-related, cell functional divergence as a consequence of stochastic effects. Functional decline is indicated by increasing darkness. Even in a young tissue, the function of highly differentiated cells in an organ or tissue is never maximized. The old tissue is different in the sense that there are many more cells that have suffered functional decline, with some of them dying (cross) or eliminated (open space). Others have grown into a hyperplastic or neoplastic lesion (not shown) or have been replaced by fibrosis (not shown).