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.
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.
DNA mutations as a consequence of errors during DNA damage repair, replication, or mitosis are the substrate for evolution. In multicellular organisms, mutations can occur in the germline and also in ...somatic tissues, where they are associated with cancer and other chronic diseases and possibly with aging. Recent advances in high-throughput sequencing have made it relatively easy to study germline de novo mutations, but in somatic cells, the vast majority of mutations are low-abundant and can be detected only in clonal lineages, such as tumors, or single cells. Here we review recent results on somatic mutations in normal human and animal tissues with a focus on their possible functional consequences.
Genome instability and aging Vijg, Jan; Suh, Yousin
Annual review of physiology,
01/2013, Letnik:
75
Journal Article
Recenzirano
Genome instability has long been implicated as the main causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation ...to environmental mutagens. To cope with the tens of thousands of chemical lesions introduced into the genome of a typical cell each day, a complex network of genome maintenance systems acts to remove damage and restore the correct base pair sequence. Occasionally, however, repair is erroneous, and such errors, as well as the occasional failure to correctly replicate the genome during cell division, are the basis for mutations and epimutations. There is now ample evidence that mutations accumulate in various organs and tissues of higher animals, including humans, mice, and flies. What is not known, however, is whether the frequency of these random changes is sufficient to cause the phenotypic effects generally associated with aging. The exception is cancer, an age-related disease caused by the accumulation of mutations and epimutations. Here, we first review current concepts regarding the relationship between DNA damage, repair, and mutation, as well as the data regarding genome alterations as a function of age. We then describe a model for how randomly induced DNA sequence and epigenomic variants in the somatic genomes of animals can result in functional decline and disease in old age. Finally, we discuss the genetics of genome instability in relation to longevity to address the importance of alterations in the somatic genome as a causal factor in aging and to underscore the opportunities provided by genetic approaches to develop interventions that attenuate genome instability, reduce disease risk, and increase life span.
The germline mutation rate has been extensively studied and has been found to vary greatly between species, but much less is known about the somatic mutation rate in multicellular organisms, which ...remains very difficult to determine. Here, we present data on somatic mutation rates in mice and humans, obtained by sequencing single cells and clones derived from primary fibroblasts, which allows us to make the first direct comparison with germline mutation rates in these two species. The results indicate that the somatic mutation rate is almost two orders of magnitude higher than the germline mutation rate and that both mutation rates are significantly higher in mice than in humans. Our findings demonstrate both the privileged status of germline genome integrity and species-specific differences in genome maintenance.
Cancer researchers have traditionally used the mouse and the rat as staple model organisms. These animals are very short-lived, reproduce rapidly and are highly prone to cancer. They have been very ...useful for modelling some human cancer types and testing experimental treatments; however, these cancer-prone species offer little for understanding the mechanisms of cancer resistance. Recent technological advances have expanded bestiary research to non-standard model organisms that possess unique traits of very high value to humans, such as cancer resistance and longevity. In recent years, several discoveries have been made in non-standard mammalian species, providing new insights on the natural mechanisms of cancer resistance. These include mechanisms of cancer resistance in the naked mole rat, blind mole rat and elephant. In each of these species, evolution took a different path, leading to novel mechanisms. Many other long-lived mammalian species display cancer resistance, including whales, grey squirrels, microbats, cows and horses. Understanding the molecular mechanisms of cancer resistance in all these species is important and timely, as, ultimately, these mechanisms could be harnessed for the development of human cancer therapies.
Accumulation of mutations in somatic cells has been implicated as a cause of aging since the 1950s. However, attempts to establish a causal relationship between somatic mutations and aging have been ...constrained by the lack of methods to directly identify mutational events in primary human tissues. Here we provide genome-wide mutation frequencies and spectra of human B lymphocytes from healthy individuals across the entire human lifespan using a highly accurate single-cell whole-genome sequencing method. We found that the number of somatic mutations increases from <500 per cell in newborns to >3,000 per cell in centenarians. We discovered mutational hotspot regions, some of which, as expected, were located at Ig genes associated with somatic hypermutation (SHM). B cell–specific mutation signatures associated with development, aging, or SHM were found. The SHM signature strongly correlated with the signature found in human B cell tumors, indicating that potential cancer-causing events are already present even in B cells of healthy individuals. We also identified multiple mutations in sequence features relevant to cellular function (i.e., transcribed genes and gene regulatory regions). Such mutations increased significantly during aging, but only at approximately one-half the rate of the genome average, indicating selection against mutations that impact B cell function. This full characterization of the landscape of somatic mutations in human B lymphocytes indicates that spontaneous somatic mutations accumulating with age can be deleterious and may contribute to both the increased risk for leukemia and the functional decline of B lymphocytes in the elderly.
Nuclear Genomic Instability and Aging Niedernhofer, Laura J; Gurkar, Aditi U; Wang, Yinsheng ...
Annual review of biochemistry,
06/2018, Letnik:
87, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The nuclear genome decays as organisms age. Numerous studies demonstrate that the burden of several classes of DNA lesions is greater in older mammals than in young mammals. More challenging is ...proving this is a cause rather than a consequence of aging. The DNA damage theory of aging, which argues that genomic instability plays a causal role in aging, has recently gained momentum. Support for this theory stems partly from progeroid syndromes in which inherited defects in DNA repair increase the burden of DNA damage leading to accelerated aging of one or more organs. Additionally, growing evidence shows that DNA damage accrual triggers cellular senescence and metabolic changes that promote a decline in tissue function and increased susceptibility to age-related diseases. Here, we examine multiple lines of evidence correlating nuclear DNA damage with aging. We then consider how, mechanistically, nuclear genotoxic stress could promote aging. We conclude that the evidence, in toto, supports a role for DNA damage as a nidus of aging.
Mutation analysis in single-cell genomes is prone to artifacts associated with cell lysis and whole-genome amplification. Here we addressed these issues by developing single-cell multiple ...displacement amplification (SCMDA) and a general-purpose single-cell-variant caller, SCcaller (https://github.com/biosinodx/SCcaller/). By comparing SCMDA-amplified single cells with unamplified clones from the same population, we validated the procedure as a firm foundation for standardized somatic-mutation analysis in single-cell genomics.
Mammals have evolved a remarkable diversity of ageing rates. Within the single order of Rodentia, maximum lifespans range from 4 years in mice to 32 years in naked mole rats. Cancer rates also differ ...substantially between cancer-prone mice and almost cancer-proof naked mole rats and blind mole rats. Recent progress in rodent comparative biology, together with the emergence of whole-genome sequence information, has opened opportunities for the discovery of genetic factors that control longevity and cancer susceptibility.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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