Genome Dynamics in Aging Mice

Dollé, Martijn E.T.; Vijg, Jan

doi:10.1101/gr.125502

Cited by 63 publications

(40 citation statements)

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“…These reporter genes are part of a lambda or plasmid construct that can be recovered from genomic DNA and tested in E. coli for mutational inactivation of the reporter gene. Since then, a plethora of data has been published on somatic mutation frequencies and spectra in these animals, both induced mutations after exposure to a variety of mutagenic agents and spontaneous mutations accumulating during the normal aging process[51–53]. Using transgenic reporter genes, it has been shown that mutation frequencies in most tissues, especially actively proliferating tissues, such as the epithelia in the small intestine, consistently show an age-dependent increase (Fig.…”

Section: Introductionmentioning

confidence: 99%

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

Gundry

Vijg

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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DNA mutations are the source of genetic variation within populations. The majority of mutations with observable effects are deleterious. In humans mutations in the germ line can cause genetic disease. In somatic cells multiple rounds of mutations and selection lead to cancer. The study of genetic variation has progressed rapidly since the completion of the draft sequence of the human genome. Recent advances in sequencing technology, most importantly the introduction of massively parallel sequencing (MPS), have resulted in more than a hundred-fold reduction in the time and cost required for sequencing nucleic acids. These improvements have greatly expanded the use of sequencing as a practical tool for mutation analysis. While in the past the high cost of sequencing limited mutation analysis to selectable markers or small forward mutation targets assumed to be representative for the genome overall, current platforms allow whole genome sequencing for less than $5,000. This has already given rise to direct estimates of germline mutation rates in multiple organisms including humans by comparing whole genome sequences between parents and offspring. Here we present a brief history of the field of mutation research, with a focus on classical tools for the measurement of mutation rates. We then review MPS, how it is currently applied and the new insight into human and animal mutation frequencies and spectra that has been obtained from whole genome sequencing. While great progress has been made, we note that the single most important limitation of current MPS approaches for mutation analysis is the inability to address low-abundance mutations that turn somatic tissues into mosaics of cells. Such mutations are at the basis of intra-tumor heterogeneity, with important implications for clinical diagnosis, and could also contribute to somatic diseases other than cancer, including aging. Some possible approaches to gain access to low-abundance mutations are discussed, with a brief overview of new sequencing platforms that are currently waiting in the wings to advance this exploding field even further.

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Section: Introductionmentioning

confidence: 99%

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

Gundry

Vijg

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…Since the occurrence of somatic copy number changes has been shown to increase with age in sev- eral tissues in mice (Dolle and Vijg 2002) and also in peripheral blood in cancer-free humans (Forsberg et al 2012;Jacobs et al 2012;Laurie et al 2012), we assumed that single nucleotide somatic mutations might also increase with age. Therefore, we chose a healthy person of extreme age as our subject, anticipating that during a long lifetime, mutations leading to the fittest HSCs might lead to clonal selection and thus the detectability of somatic mutations (Naylor et al 2005;Gibson et al 2009).…”

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confidence: 99%

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

et al. 2014

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The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

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“…Our own data obtained with the lacZ transgenic reporter mice, extensively cited by de Grey, indicate surprisingly high numbers of genome rearrangement mutations in organs such as liver and heart (Dollé et al, 2002). In our model genome rearrangements occur as a consequence of a breakpoint in a lacZ reporter gene and a second breakpoint elsewhere in the mouse genome, either on the same chromosome (in which case the event reflects a deletion or inversion) or on another chromosome (resulting in a translocation).…”

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confidence: 68%