Genomic variation in captive deer mouse (Peromyscus maniculatus) populations.

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 × 109 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.

Coordination Analysis of Gene Expression Points to the Relative Impact of Different Regulators During Endoplasmic Reticulum Stress.

Analysis of gene expression can be challenging, especially if it involves genetically diverse populations that exhibit high variation in their individual expression profile. Despite this variation, it is conceivable that in the same individuals a high degree of coordination is maintained between transcripts that belong to the same signaling modules and are associated with related biological functions. To explore this further, we calculated the correlation in the expression levels between each of ATF4, CHOP (DDIT3), GRP94, DNAJB9 (ERdj4), DNAJ3C (P58IPK), and HSPA5 (BiP/GRP78) with the whole transcriptome in primary fibroblasts from deer mice following induction of endoplasmic reticulum (ER) stress. Since these genes are associated with different transducers of the unfolded protein response (UPR), we postulated that their profile, in terms of correlation of transcripts, reflects distinct UPR branches engaged, and therefore different biological processes. Standard gene ontology analysis was able to predict major functions associated with the corresponding transcript, and of the UPR arm related to that, namely regulation of the apoptotic response by ATF4 (PERK arm) and the ER stress-associated degradation for GRP94 (IRE1). BiP, being a global regulator of the UPR, was associated with activation of ER stress in a rather global manner. Pairwise comparison in the correlation coefficients for these genes' associated transcriptome showed the relevance of selected genes in terms of expression profiles. Conventional assessment of differential gene expression was incapable of providing meaningful information and pointed only to a generic association with stress. Collectively, this approach suggests that by evaluating the degree of coordination in gene expression, in genetically diverse biological specimens, may be useful in assigning genes in transcriptome networks, and more importantly in linking signaling nodules to specific biological functions and processes.

Differential regulation of the unfolded protein response in outbred deer mice and susceptibility to metabolic disease.

Endoplasmic reticulum (ER) stress has been causatively linked to the onset of various pathologies. However, whether and how inherent variations in the resulting unfolded protein response (UPR) affect predisposition to ER-stress-associated metabolic conditions remains to be established. By using genetically diverse deer mice (Peromyscus maniculatus) as a model, we show that the profile of tunicamycin-induced UPR in fibroblasts isolated at puberty varies between individuals and predicts deregulation of lipid metabolism and diet-induced hepatic steatosis later in life. Among the different UPR targets tested, CHOP (also known as Ddit3) more consistently predicted elevated plasma cholesterol and hepatic steatosis. Compared with baseline levels or inducibility, the maximal intensity of the UPR following stimulation best predicts the onset of pathology. Differences in the expression profile of the UPR recorded in cells from different populations of deer mice correlate with the varying response to ER stress in altitude adaptation. Our data suggest that the response to ER stress in cultured cells varies among individuals, and its profile early in life might predict the onset of ER-stress-associated disease in the elderly.This article has an associated First Person interview with the first author of the paper.

Growth of human breast cancers in Peromyscus.

Modeling breast cancer in general and hormone-sensitive breast cancer, in particular in mice, has several limitations. These are related to the inbred nature of laboratory mice, and do not allow adequate appreciation of the contribution of the host's genetic heterogeneity in tumor growth. In addition, the naturally low estrogen levels of mice makes estradiol supplementation obligatory for tumor growth. Here, we show that Peromyscus californicus, following cyclosporine-mediated immunosuppression, supports the growth of both MDA-MB-231 estrogen-independent and MCF7 estrogen receptor-positive breast cancers without exogenous estradiol supplementation. Tumor growth was inhibited by fulvestrant or letrozole, confirming that MCF7 xenografts remain hormone dependent in vivo and suggesting that P. californicus can be used as an alternative to conventional mice for the study of hormone-sensitive breast cancer. The fact that Peromyscus stocks are outbred also facilitates the study of breast cancer in genetically heterogenous populations.

Peromyscus as a model of human disease.

Animals of the genus Peromyscus have been a particularly informative model for many areas of study, including behavior, evolution, anatomy, physiology and genetics. While their use in modeling human disease and pathology has been relatively restricted, certain qualities of Peromyscine mice may make them a good candidate for such studies. Pathophysiological conditions where Peromyscus may be of particular value involve aging, reactive oxygen species-associated pathologies, metabolism and detoxification, diabetes, and certain cancers. In this review article we will summarize pathological conditions where Peromyscus have been used effectively, we will discuss factors limiting the use of Peromyscus in studying pathology and we will indicate areas at which the use of this model may be of special value.