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I.R.F. / Aging news / General / 11052001

Somatic Mosaicism and Aging
Posted on: May 20, 2011

From the fertilization of an egg until the death of an individual, somatic cells can accumulate genetic changes, such that cells from different tissues or even within the same tissue differ genetically. The presence of multiple cell clones with distinct genotypes in the same individual is referred to as "somatic mosaicism". Many endogenous factors such as mobile elements, DNA polymerase slippage, DNA double-strand break, inefficient DNA repair, unbalanced chromosomal segregation and some exogenous factors such as nicotine and UV expo- sure can contribute to the generation of somatic mutations, thereby leading to somatic mosaicism. Such changes can potentially affect the epigenetic patterns and levels of gene expression, and ultimately the phenotypes of cells. Although recent studies suggest that somatic mosaicism is widespread during normal development and aging, its implications for heightened disease risks are incompletely understood.

In the wild, most animals die before becoming old, whereas human life expectancy has increased by more than 30 years during the 20th century alone. Therefore, the cellular machinery responsible for maintaining genomic integrity in aging tissue has not experienced strong selection pressure until recently. Somatic mutations and the incidences of cancer are frequent in aging tissue. Recurrent DNA damage and inefficient repair over multiple rounds of cell division are common and lead to an increased extent of heterogeneity in aging tissues. Integrated experimental strategies combining shuttle vector technology, transgenic mice and electrophoretic separation principles have facilitated early research on somatic mutations in aging genomes. Using this technology it has been found that the deletions, inversions and translocations of genetic material are more common in aging mice compared with young ones. These studies showed that aging genomes tend to contain visible chromosomal changes, mitotic recombination, whole gene deletions, intragenic deletions and point mutations.

A key mutagenic factor in aging tissues is represented by reactive oxygen species, which in turn is related to diet and lifestyle. DNA damage by reactive oxygen and other factors commonly trigger the activation of p53, which is a key tumor suppressor gene, leading to apoptosis. The expression of dominant-negative p53 in adult neurons has been shown to increase both the life span and genotoxic stress resistance in Drosophila, implying that there exists a compromise between an increase in genotoxic stress resistance and an increase in the burden of somatic mutations in the genome. In addition, the loss of methylation and gene expression heterogeneity also act as mutagenic factors. In aging tissues, gene expression becomes increasingly heterogeneous, which correlates with genomic abnormalities. It remains to be explored whether transcription-coupled DNA repair plays a role in generating (or maintaining) somatic mutations in aging tissues.

The telomeres of chromosomes comprise repetitive sequences that offer protection against DNA degradation. The length of telomere repeats, which functions as a clock for the number of cell divisions, is reduced over time during aging, thereby limiting the replicative capacity of cells. Telomere shortening occurs stochastically, such that the telomere length varies between individuals and among cells within an individual. Cell-to-cell variation in telomere length represents a special case of somatic mosaicism associated with aging.

Aging-associated somatic mutations give rise to several disorders including cancer and neurodegenerative diseases such as Parkinson's disease. Under normal conditions, DNA damage triggers apoptosis, but in tumor cells the selective inactivation of p53 leads to escape from apoptosis and neoplastic growth. A detailed characterization of the somatically acquired genetic alterations occurring during normal development and aging is important for our understanding of the mutational landscape leading to aberrant developmental processes such as neurodegeneration, cancer or acquired resistance against drugs. The frequency of somatic mutations can vary across the genome. It will be interesting to see whether there exist genomic regions that are highly resistant to somatic mutations and whether various factors such as genomic context and chromatin structures play a role in such intrinsic resistance. Knowledge of the rate of somatic mutations and of the functional constraints on those alterations will provide valuable insights for estimating tissue heterogeneity, the development of resistance against drugs and cancer progression, which can be used for diagnostic and prognostic purposes.

Source: Subhajyoti De; Somatic mosaicism in healthy human tissues; Trends in Genetics 879; (2011) 1-7; doi:10.1016/j.tig.2011.03.002
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