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.

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

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.

Vijg J, Campisi J. Puzzles, promises and a cure for ageing. Nature 2008;454: 1065.
White RR, Milholland B, de Bruin A, Curran S, Laberge RM, van Steeg H, Campisi J, Maslov AY, Vijg J. Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing. Nat Commun. 2015;6:6790.

Gravina S, Dong X, Yu B, Vijg J. Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol. 2016;17:150.

Dong X, Milholland B, Vijg J. Evidence for a limit to human lifespan. Nature 2016; 538:257–259. PMID:27706136.

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. PMC5408311

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. PMC650011

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. PMC6994209

Vijg J, Dong X. Pathogenic Mechanisms of Somatic Mutation and Genome Mosaicism in Aging. Cell 2020;18:12-23.

Zhang L, Dong X, Tian X, Lee M, Ablaeva J, Firsanov D, Lee S-G, Maslov AY, Gladyshev VN, Seluanov A, Gorbunova V, Vijg J. Maintenance of genome sequence integrity in long- and short-lived rodent species. Sci Adv 2021;7:eabj3284. PMC8550225

Huang Z, Sun S, Lee M, Maslov AY, Shi M, Waldman S, Marsh A, Siddiqui T, Dong X, Peter Y, Sadoughi A, Shah C, Ye K, Spivack SD, Vijg J. Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking. Nat. Genet. 2022;54:492-498.