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.

In the past we developed transgenic reporter systems in mouse and fruit fly, which allowed 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.

We are currently focused on single-cell genomics to assess mutation frequencies and spectra in human tissues during aging. To gain insight into the possible functional consequences of random somatic mutations we use single-cell multiomics assays to link specific mutations to transcriptional and translational end point. 

Projects

NIH Program Project

People

• Yolanne Blake
• Shixiang Sun
• Moonsook Lee
• Zhenqiu Huang
• Alex Maslov
• Johanna Heid
• Yujue Wang
• Julian Gingold
• Olivia Albert
• Ronald Cutler

• 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.
• Dong X, Zhang L, Milholland B, Lee M, Maslov AY, Wang T, Vijg J. Accurate identification of single-nucleotide variants in whole-genome-amplified single cells. Nat Methods 2017;14:491-493.
• Milholland B, Dong X, Zhang L, Hao X, Suh Y, Vijg J. Differences between germline and somatic mutation rates in humans and mice. Nat. Commun. 2017;8:15183.
• Zhang L, Vijg J. Somatic Mutagenesis in Mammals and Its Implications for Human Disease and Aging. Annu Rev Genet. 2018;52:397-419.
• Zhang L, Dong X, Lee M, Maslov AY, Wang T, Vijg J. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc Natl Acad Sci USA 2019;116:9014-9019.
• Brazhnik K, Sun S, Alani O, Kinkhabwala M, Wolkoff AW, Maslov AY, Dong X, Vijg J. Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver. Sci Adv. 2020;6:eaax2659.
• Vijg J, Dong X, Pathogenic Mechanisms of Somatic Mutation and Genome Mosaicism in Aging. Cell 2020;18:12-23.  

Books    

• Aging of the Genome, The dual role of DNA in life and death.  Vijg, Jan. Oxford University Press: 2007. ISBN13: 978-0-19-856923-7.
• The American Technological Challenge, Stagnation and Decline in the 21st Century. Vijg, Jan. Algora Publishing: 2011.  ISBN13:978-0-87586-886-8.