Living nonhuman primates generally inhabit tropical forests, and torpor is regarded as a strategy employed by cold-adapted organisms. Yet, some primates employ daily torpor or hibernation (heterothermy) under obligatory, temporary, or emergency circumstances. Though heterothermy is present in most mammalian lineages, there are only three extant heterothermic primate lineages: bushbabies from Africa, lorises from Asia, and dwarf and mouse lemurs from Madagascar. Here, we analyze their phenotypes in the general context of tropical mammalian heterothermy. We focus on Malagasy lemurs as they have been the most intensively studied and also show an unmatched range of flexibility in their heterothermic responses. We discuss the evidence for whether heterothermy should be considered an ancestral or derived condition in primates. This consideration is particularly intriguing given that an understanding of the underlying mechanisms for hibernation in lemurs opens the possibility for insight into genotype-phenotype interactions, including those with biomedical relevance for humans.

Tropical heterothermy is "cool": The expression of daily torpor and hibernation in primates

Mammals maintain a constant warm body temperature, facilitating a wide variety of metabolic reactions. Mammals that hibernate have the ability to slow their metabolism, which in turn reduces their body temperature and leads to a state of hypothermic torpor. For this metabolic rate reduction to occur on a whole-body scale, molecular interactions that change the physiology of cells, tissues and organs are required, resulting in a major departure from normal mammalian homeostasis. The aim of this Review is to cover recent advances in the molecular biology of mammalian hibernation, including the role of small molecules, seasonal changes in gene expression, cold-inducible RNA-binding proteins, the somatosensory system and emerging information on hibernating primates. To underscore the importance of differential gene expression across the hibernation cycle, mRNA levels for 14,261 ground squirrel genes during periods of activity and torpor are made available for several tissues via an interactive transcriptome browser. This Review also addresses recent findings on molecular interactions responsible for multi-day survival of near-freezing body temperatures, single-digit heart rates and a slowed metabolism that greatly reduces oxygen consumption. A better understanding of how natural hibernators survive these physiological extremes is beginning to lead to innovations in human medicine.

Molecular interactions underpinning the phenotype of hibernation in mammals.

Small hibernators are long-lived for their size because seasonal dormancy greatly reduces predation risk. Thus, within a year, hibernators switch between states of contrasting mortality risk (active season versus hibernation), making them interesting species for testing the predictions of life-history theory. Accordingly, we hypothesized that, with advancing age and hence diminishing reproductive potential, hibernators should increasingly accept the higher predation risk associated with activity to increase the likelihood of current reproductive success. For edible dormice (Glis glis) we show that age strongly affects hibernation/activity patterns, and that this occurs via two pathways: (i) with increasing age, dormice are more likely to reproduce, which delays the onset of hibernation, and (ii) age directly advances emergence from hibernation in spring. We conclude that hibernation has to be viewed not merely as an energy saving strategy under harsh climatic conditions, but as an age-affected life-history trait that is flexibly used to maximize fitness.

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Effects of aging on timing of hibernation and reproduction.

Madagascar's biodiversity is notoriously threatened by deforestation and climate change. Many of these organisms are rare, cryptic, and severely threatened, making population-level sampling unrealistic. Such is the case with Madagascar's dwarf lemurs (genus Cheirogaleus), the only obligate hibernating primate. We here apply comparative genomic approaches to generate the first genome-wide estimates of genetic diversity within dwarf lemurs. We generate a reference genome for the fat-tailed dwarf lemur, Cheirogaleus medius, and use this resource to facilitate analyses of high-coverage (~30×) genome sequences for wild-caught individuals representing species: C. sp. cf. medius, C. major, C. crossleyi, and C. sibreei. This study represents the largest contribution to date of novel genomic resources for Madagascar's lemurs. We find concordant phylogenetic relationships among the four lineages of Cheirogaleus across most of the genome, and yet detect a number of discordant genomic regions consistent with ancient admixture. We hypothesized that these regions could have resulted from adaptive introgression related to hibernation, indeed finding that genes associated with hibernation are present, though most significantly, that gene ontology categories relating to transcription are over-represented. We estimate levels of heterozygosity and find particularly low levels in an individual sampled from an isolated population of C. medius that we refer to as C. sp. cf. medius. Results are consistent with a recent decline in effective population size, which is evident across species. Our study highlights the power of comparative genomic analysis for identifying species and populations of conservation concern, as well as for illuminating possible mechanisms of adaptive phenotypic evolution.

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Conservation genomic analysis reveals ancient introgression and declining levels of genetic diversity in Madagascar’s hibernating dwarf lemurs

Identifying genetic variation involved in thermal adaptation is likely to yield insights into how species adapt to different climates. Physiological and behavioral responses associated with overwintering (e.g., torpor) are thought to serve important functions in climate adaptation. In this study, we use 2 isolated Peromyscus leucopus lineages on the northern margin of the species range to identify single nucleotide polymorphisms (SNPs) showing a strong environmental association and test for evidence of parallel evolution. We found signatures of clinal selection in each lineage, but evidence of parallelism was limited, with only 2 SNPs showing parallel allele frequencies across transects. These parallel SNPs map to a gene involved in protection against iron-dependent oxidative stress (Fxn) and to a gene with unknown function but containing a forkhead-associated domain (Fhad1). Furthermore, within transects, we find significant clinal patterns in genes enriched for functions associated with glycogen homeostasis, synaptic function, intracellular Ca2+ balance, H3 histone modification, as well as the G2/M transition of cell division. Our results are consistent with recent literature on the cellular and molecular basis of climate adaptation in small mammals and provide candidate genomic regions for further study.

Genomic Signatures of Selection along a Climatic Gradient in the Northern Range Margin of the White-Footed Mouse (Peromyscus leucopus).

Hibernation is a highly dynamic phenotype whose timing, for many mammals, is controlled by a circannual clock and accompanied by rhythms in body mass and food intake. When housed in an animal facility, 13-lined ground squirrels exhibit individual variation in the seasonal onset of hibernation, which is not explained by environmental or biological factors, such as body mass and sex. We hypothesized that underlying genetic architecture instead drives variation in this timing. After first increasing the contiguity of the genome assembly, we therefore employed a genotype-by-sequencing approach to characterize genetic variation in 153 13-lined ground squirrels. Combining this with datalogger records, we estimated high heritability (61-100%) for the seasonal onset of hibernation. After applying a genome-wide scan with 46,996 variants, we also identified 21 loci significantly associated with hibernation immergence, which alone accounted for 54% of the variance in the phenotype. The most significant marker (SNP 15, p=3.81x10−6) was located near prolactin-releasing hormone receptor (PRLHR), a gene that regulates food intake and energy homeostasis. Other significant loci were located near genes functionally related to hibernation physiology, including muscarinic acetylcholine receptor M2 (CHRM2), involved in the control of heart rate, exocyst complex component 4 (EXOC4) and prohormone convertase 2 (PCSK2), both of which are involved in insulin signaling and processing. Finally, we applied an expression quantitative loci (eQTL) analysis using existing transcriptome datasets, and we identified significant (q

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Cabral Gf

Papers

Genetic architecture drives seasonal onset of hibernation in the 13-lined ground squirrel