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DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long-living rodents that have emerged as an informative model to study aging, adaptation to extreme environments, and monogamous behavior. In the present study, we have undertaken an exhaustive, genome-wide analysis of DNA methylation inPeromyscus, spanning different species, stocks, sexes, tissues, and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissues (tail, liver, and brain). Two human-Peromyscusclocks accurately measure age and relative age, respectively. We present CpGs and enriched pathways that relate to different conditions such as chronological age, high altitude, and monogamous behavior. Overall, this study provides a first step towards studying the epigenetic correlates of monogamous behavior and adaptation to high altitude inPeromyscus. The human-Peromyscusepigenetic clocks are expected to provide a significant boost to the attractiveness ofPeromyscusas a biological model.

 

People’s social interactions could influence their risk of developing various diseases, including cancer, according to population-level studies. In particular, studies have identified a so-called widowhood effect where a person’s risk of disease increases following the loss of a spouse. However, the cause of the widowhood effect remains debatable, as it can be difficult to separate the impact of lifestyle changes from biological changes in the individual following bereavement. It is not possible to use laboratory mice to identify a causal biological mechanism, because they do not form long-term relationships with a single partner (pair bonds). However, several species of deer mouse form pair bonds, and suffer from anxiety and stress if these bonds are broken. Naderi et al. used these mice to study the widowhood effect on the risk of developing cancer. First, Naderi et al. grew human lung cancer cells in blood serum taken from mice that were either in a pair bond or had been separated from their partner. The cancer cells grown in the blood of mice with disrupted pair bonds changed size and shape, indicating that these mice were more likely to develop cancer. This effect was not observed when the cells were grown in the blood of bonded deer mice or of another deer mouse species that does not form pair bonds. Naderi et al. also found that the activity of genes involved in the cancer cells’ ability to spread and to stick together was different in pair-bonded mice and in pair-separated mice. Next, Naderi et al. implanted lung cancer cells into the deer mice to study their effects on live animals. When cancer cells from the deer mice were transplanted into laboratory mice with a weakened immune system, the cells taken from pair-bonded deer mice were less likely to grow than the cells from deer mice with disrupted pair bonds. This suggests that the protective effects of pair bonding persist even after removal from the original mouse. These results provide evidence for a biological mechanism of the widowhood effect, where social experiences can alter gene activity relating to cancer growth. In the future, it will be important to determine whether the same applies to humans, and to find out if there are ways to mimic the effects of long-term bonds to improve cancer prognoses. 

Abstract Background Deer mice (genus Peromyscus ) are the most common rodents in North America. Despite the availability of reference genomes for some species, a comprehensive database of polymorphisms, especially in those maintained as living stocks and distributed to academic investigators, is missing. In the present study we surveyed two populations of P. maniculatus that are maintained at the Peromyscus Genetic Stock Center (PGSC) for polymorphisms across their 2.5 × 10 9 bp genome. Results High density of variation was identified, corresponding to one SNP every 55 bp for the high altitude stock (SM2) or 207 bp for the low altitude stock (BW) using snpEff (v4.3). Indels were detected every 1157 bp for BW or 311 bp for SM2. The average Watterson estimator for the BW and SM2 populations is 248813.70388 and 869071.7671 respectively. Some differences in the distribution of missense, nonsense and silent mutations were identified between the stocks, as well as polymorphisms in genes associated with inflammation (NFATC2), hypoxia (HIF1a) and cholesterol metabolism (INSIG1) and may possess value in modeling pathology. Conclusions This genomic resource, in combination with the availability of P. maniculatus from the PGSC, is expected to promote genetic and genomic studies with this animal model. 

Using DNA methylation profiles (n= 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels inHOXLsubclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.