Jan Vijg, Ph.D.
Genome Instability in Aging and Disease
Genome instability, i.e., the tendency of the genome to acquire mutations and epimutations, underlies human genetic disease, causally contributes to cancer and has also been implicated in aging and age-related, degenerative conditions other than cancer. Little is known about the mechanisms that give rise to spontaneous changes in the genome or epigenome and how this may lead, in somatic cells, to increased cancer risk and loss of organ and tissue function with age. We study genome and epigenome instability as a function of age in various model organisms, including mouse and fruit fly, and its consequences in terms of alterations in tissue-specific patterns of gene regulation.
We developed transgenic reporter systems in mouse and fruit fly, which allow us to determine tissue-specific frequencies of various forms of genome instability, e.g., point mutations, deletions, translocations. By crossing the mutational reporter animals with mutants harboring specific defects in various genome maintenance pathways, the relevance of these pathways for the accumulation of specific forms of genome instability is assessed, in relation to the pathophysiology of aging. Similarly, by using knockdown approaches we assess the effect of specific genes implicated in longevity and healthy aging, e.g., SOD, FOXO, SIR2, on genome integrity.
More recently, we have begun to assess global gene mutation and epimutation loads in normal and disease tissues of both animal models and humans using massively parallel sequencing approaches.
- Carlos Morales
- Wenge Li
- Silvia Gravina
- Moonsook Lee
- Shireen Ganapathee
- Lola MacRae
- Brandon Milholland
- Francesca Faggioli
- Uitterlinden AG, Slagboom P, Knook DL, Vijg J. Two-dimensional DNA fingerprinting of human individuals. Proc Natl Acad Sci USA 1989;86:2742-2746. The first 2-dimensional electrophoretic DNA ‘fingerprint’ of a human genome.
- Gossen JA, de Leeuw WJF, Tan CHT, Lohman PHM, Berends F, Knook DL, Zwarthoff EC, Vijg J. Efficient rescue of integrated shuttle vectors from transgenic mice: A new model for studying mutations in vivo. Proc Natl Acad Sci USA 1989;86:7971-7975. The first mouse model for analyzing mutation frequencies and spectra in every organ and tissue, often referred to as an in vivo ‘Ames test’.
- Mullaart E, de Vos GJ, te Meerman GJ, Uitterlinden AG, Vijg J. Parallel genome analysis by two-dimensional DNA typing. Nature 1993;365:469-471. The first automated instrument for 2-dimensional analysis of DNA sequence variation.
- Boerrigter METI, Dollé MET, Martus H-J, Gossen JA, Vijg J. Plasmid-based transgenic mouse model for studying in vivo mutations. Nature 1995;377:657-659. A new mouse model for analyzing mutations, with the capability of detecting not only point mutations but also large genome rearrangements.
- Dollé MET, Giese H, Hopkins CL, Martus H-J, Hausdorff JM, Vijg J. Rapid accumulation of genome rearrangements in liver but not in brain of old mice. Nature Genetics 1997;17:431-434. The first demonstration that different types of mutations accumulate with age in an organ-specific manner.
- Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dollé MET, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J. Increased cell-to-cell variation in gene expression in aging mouse heart. Nature 2006;441:1011-1014. The application of single-cell global mRNA amplification in detecting an age-related increase in cell-to-cell variation in gene expression, i.e., the first demonstration of transcriptional noise in mammalian cells in vivo.
- Garcia AM, Derventzi A, Busuttil R, Calder RB, Perez E Jr, Chadwell L, Dollé ME,Lundell M, Vijg J. A model system for analyzing somatic mutations in Drosophila melanogaster. Nat Methods. 2007;4:401-3. A new reporter-based model for analyzing somatic mutations in Drosophila melanogaster.
- Vijg J, Campisi J. Puzzles, promises and a cure for ageing. Nature 454:1065-1071. A realistic evaluation of our prospects for extending healthy life span in humans.
- Garcia AM, Calder RB, Dollé ME, Lundell M, Kapahi P, Vijg J. Age- and temperature-dependent somatic mutation accumulation in Drosophila melanogaster. PLoS Genet. 2010;6:e1000950. A comparison of somatic mutation frequency and spectrum between mouse and fruit fly and an analysis of mutation accumulation in flies as a function of both age and temperature.
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