Genome maintenance capacity has long been implicated in the evolution of species-specific maximum life span. Thus far, this could not be directly tested due to the lack of techniques to comparatively analyze somatic mutations in different species. While ultra-high-throughput sequencing now allows determining germ line mutation rate by comparing parents and offspring after whole genome sequencing, the rate of somatic mutations cannot be measured in this way because each mutation occurs only in one or few cells. Low- abundance, somatic mutations could theoretically be revealed by ultra-deep sequencing of a DNA sample from tissue (i.e., at ~ lOVold coverage). However, true mutations cannot be distinguished from sequencing errors, which occur at frequencies of 0.1-1%. We recentiy developed a method that allows assessing somatic mutation frequencies and spectra using a single-cell genomic sequencing approach. When sequencing the genome of a single cell after whole genome amplification, each mutation in that cell will be amplified and shows up in 50% of the reads at a given locus (one allele only since random mutations are unlikely to hit the exact same basepair in two independent DNA molecules). We demonstrated that this can be done at a very low error rate of amplification. In Project 3 we will use this method to first compare somatic mutation frequencies and spectra in cells from different rodent species with extreme differences in life span, with a focus on the possible role of DNA double-strand break repair, then study the possible effect of several potential mutation rate suppressors and, finally, study age-related mutation accumulation in liver and spleen of a short- and long-lived rodent species.

Public Health Relevance

A major question in the science of aging is what underiies the often dramatic differences in species-specific life span, which even among closely related rodent species can vary at least 10-fold. In this project we will test the hypothesis that long-lived rodent species, such as naked mole rate, can live so much longer than short-lived rodents, such as mice, because of their capacity to better prevent DNA mutations accumulating in the genome of their somatic cells. This is relevant because it will give us insight in the factors that control longevity and cancer risk in mammals.

National Institute of Health (NIH)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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University of Rochester
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Van Meter, Michael; Kashyap, Mehr; Rezazadeh, Sarallah et al. (2014) SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nat Commun 5:5011
Fang, Xiaodong; Seim, Inge; Huang, Zhiyong et al. (2014) Adaptations to a subterranean environment and longevity revealed by the analysis of mole rat genomes. Cell Rep 8:1354-64
Gorbunova, Vera; Boeke, Jef D; Helfand, Stephen L et al. (2014) Human Genomics. Sleeping dogs of the genome. Science 346:1187-8