Brown adipose tissue (BAT) is a unique thermogenic tissue in mammals that rapidly produces heat via nonshivering thermogenesis. Small mammalian hibernators have evolved the greatest capacity for BAT ...because they use it to rewarm from hypothermic torpor numerous times throughout the hibernation season. Although hibernator BAT physiology has been investigated for decades, recent efforts have been directed toward understanding the molecular underpinnings of BAT regulation and function using a variety of methods, from mitochondrial functional assays to 'omics' approaches. As a result, the inner-workings of hibernator BAT are now being illuminated. In this Review, we discuss recent research progress that has identified players and pathways involved in brown adipocyte differentiation and maturation, as well as those involved in metabolic regulation. The unique phenotype of hibernation, and its reliance on BAT to generate heat to arouse mammals from torpor, has uncovered new molecular mechanisms and potential strategies for biomedical applications.
Changes in gene regulation have long been appreciated as a driving force of adaptive evolution, however the relative contributions of cis- and trans-acting changes to gene regulation over short ...evolutionary timescales remain unclear. Instances of recent, parallel phenotypic evolution provide an opportunity to assess whether parallel patterns are seen at the level of gene expression, and to assess the relative contribution of cis- and trans- changes to gene regulation in the early stages of divergence. Here, we studied gene expression in liver and brown adipose tissue in two wild-derived strains of house mice that independently adapted to cold, northern environments, and we compared them to a strain of house mice from a warm, tropical environment. To investigate gene regulatory evolution, we studied expression in parents and allele-specific expression in F1 hybrids of crosses between warm-adapted and cold-adapted strains. First, we found that the different cold-adapted mice showed both unique and shared changes in expression, but that the proportion of shared changes (i.e. parallelism) was greater than expected by chance. Second, we discovered that expression evolution occurred largely at tissue-specific and cis-regulated genes, and that these genes were over-represented in parallel cases of evolution. Finally, we integrated the expression data with scans for selection in natural populations and found substantial parallelism in the two northern populations for genes under selection. Furthermore, selection outliers were associated with cis-regulated genes more than expected by chance; cis-regulated genes under selection influenced phenotypes such as body size, immune functioning, and activity level. These results demonstrate that parallel patterns of gene expression in mice that have independently adapted to cold environments are driven largely by tissue-specific and cis-regulatory changes, providing insight into the mechanisms of adaptive gene regulatory evolution at the earliest stages of divergence.
Distinguishing between genetic, environmental, and genotype × environment effects is central to understanding geographic variation in phenotypic clines. Two of the best-documented phenotypic clines ...are Bergmann’s rule and Allen’s rule, which describe larger body sizes and shortened extremities in colder climates, respectively. Although numerous studies have found inter- and intraspecific evidence for both ecogeographic patterns, we still have a poor understanding of the extent to which these patterns are driven by genetics, environment, or both. Here, we measured the genetic and environmental contributions to Bergmann’s rule and Allen’s rule across introduced populations of house mice (Mus musculus domesticus) in the Americas. First, we documented clines for body mass, tail length, and ear length in natural populations and found that these conform to both Bergmann’s rule and Allen’s rule. We then raised descendants of wild-caught mice in the lab and showed that these differences persisted in a common environment and are heritable, indicating that they have a genetic basis. Finally, using a full-sib design, we reared mice under warm and cold conditions. We found very little plasticity associated with body size, suggesting that Bergmann’s rule has been shaped by strong directional selection in house mice. However, extremities showed considerable plasticity, as both tails and ears grew shorter in cold environments. These results indicate that adaptive phenotypic plasticity as well as genetic changes underlie major patterns of clinal variation in house mice and likely facilitated their rapid expansion into new environments across the Americas.
Various animals across the tree of life express some form of programmed dormancy (e.g. hibernation, diapause) to maximize fitness in highly seasonal environments. The integrated phenotype of animals ...undergoing programmed dormancy is strikingly similar among diverse groups; however, research on programmed dormancy has historically been phylogenetically siloed. A broad comparative approach could clarify new angles for answering fundamental questions about programmed dormancy evolution.
To advance this approach, we present a cross‐taxonomic framework describing dimensions that distinguish animal dormancies and provide a set of core traits that animals regulate as they progress through the eco‐physiological phases of deep, programmed dormancy.
We use this universal framework to explore the ultimate drivers and evolutionary consequences of dormancy across the tree of life. Deep, programmed dormancy appears to be a predictable and repeated adaptation to highly seasonal environments that draws on a conserved suite of ancestral traits. We highlight evidence for molecular convergence in signalling pathways coordinating environmental sensing and energy metabolism in the insect and mammal lineages, separated by 700 million years of evolution and representing independent colonizations of highly seasonal environments.
Lastly, we discuss the utility of this new framework and highlight opportunities and challenges for researchers to continue advancing our understanding of dormancy through a broad, comparative lens.
A free Plain Language Summary can be found within the Supporting Information of this article.
A free Plain Language Summary can be found within the Supporting Information of this article.
Changes in
-regulatory regions are thought to play a major role in the genetic basis of adaptation. However, few studies have linked
-regulatory variation with adaptation in natural populations. ...Here, using a combination of exome and RNA-seq data, we performed expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses to study the genetic architecture of regulatory variation in wild house mice (
) using individuals from five populations collected along a latitudinal cline in eastern North America. Mice in this transect showed clinal patterns of variation in several traits, including body mass. Mice were larger in more northern latitudes, in accordance with Bergmann's rule. We identified 17 genes where
-eQTLs were clinal outliers and for which expression level was correlated with latitude. Among these clinal outliers, we identified two genes (
and
) with
-eQTLs that were associated with adaptive body mass variation and for which expression is correlated with body mass both within and between populations. Finally, we performed a weighted gene co-expression network analysis (WGCNA) to identify expression modules associated with measures of body size variation in these mice. These findings demonstrate the power of combining gene expression data with scans for selection to identify genes involved in adaptive phenotypic evolution, and also provide strong evidence for
-regulatory elements as essential loci of environmental adaptation in natural populations.
The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for over a century. However, laboratory mice capture only a subset of the genetic ...variation found in wild mouse populations, ultimately limiting the potential of classical inbred strains to uncover phenotype-associated variants and pathways. Wild mouse populations are reservoirs of genetic diversity that could facilitate the discovery of new functional and disease-associated alleles, but the scarcity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently developed, sequenced, and phenotyped a set of 11 inbred strains derived from wild-caught Mus musculus domesticus. Each of these "Nachman strains" immortalizes a unique wild haplotype sampled from one of five environmentally distinct locations across North and South America. Whole genome sequence analysis reveals that each strain carries between 4.73-6.54 million single nucleotide differences relative to the GRCm39 mouse reference, with 42.5% of variants in the Nachman strain genomes absent from current classical inbred mouse strain panels. We phenotyped the Nachman strains on a customized pipeline to assess the scope of disease-relevant neurobehavioral, biochemical, physiological, metabolic, and morphological trait variation. The Nachman strains exhibit significant inter-strain variation in >90% of 1119 surveyed traits and expand the range of phenotypic diversity captured in classical inbred strain panels. These novel wild-derived inbred mouse strain resources are set to empower new discoveries in both basic and preclinical research.
Changes in gene expression are thought to play a major role in adaptive evolution. While it is known that gene expression is highly sensitive to the environment, very few studies have determined the ...influence of genetic and environmental effects on adaptive gene expression differences in natural populations. Here, we utilize allele-specific expression to characterize
cis
and
trans
gene regulatory divergence in temperate and tropical house mice in two metabolic tissues under two thermal conditions. First, we show that gene expression divergence is pervasive between populations and across thermal conditions, with roughly 5 to 10% of genes exhibiting genotype-by-environment interactions. Second, we found that most expression divergence was due to
cis
-regulatory changes that were stable across temperatures. In contrast, patterns of expression plasticity were largely attributable to
trans
-effects, which showed greater sensitivity to temperature. Nonetheless, we found a small subset of temperature-dependent
cis
-regulatory changes, thereby identifying loci underlying expression plasticity. Finally, we performed scans for selection in wild house mice to identify genomic signatures of rapid adaptation. Genomic outliers were enriched in genes with evidence for
cis
-regulatory divergence. Notably, these genes were associated with phenotypes that affected body weight and metabolism, suggesting that
cis-
regulatory changes are a possible mechanism for adaptive body size evolution between populations. Our results show that gene expression plasticity, largely controlled in
trans
, may facilitate the colonization of new environments, but that evolved changes in gene expression are largely controlled in
cis
, illustrating the genetic and nongenetic mechanisms underlying the establishment of populations in new environments.
During hibernation, thirteen-lined ground squirrels (
) regularly cycle between bouts of torpor and interbout arousal (IBA). Most of the brain is electrically quiescent during torpor but regains ...activity quickly upon arousal to IBA, resulting in extreme oscillations in energy demand during hibernation. We predicted increased functional capacity of brain mitochondria during hibernation compared with spring to accommodate the variable energy demands of hibernation. To address this hypothesis, we examined mitochondrial bioenergetics in the ground squirrel brain across three time points: spring (SP), torpor (TOR), and IBA. Respiration rates of isolated brain mitochondria through complex I of the electron transport chain were more than twofold higher in TOR and IBA than in SP (
< 0.05). We also found a 10% increase in membrane potential between hibernation and spring (
< 0.05), and that proton leak was lower in TOR and IBA than in SP. Finally, there was a 30% increase in calcium loading in SP brain mitochondria compared with TOR and IBA (
< 0.01). To analyze brain mitochondrial abundance between spring and hibernation, we measured the ratio of copy number in a mitochondrial gene (
) vs. a nuclear gene (
) in frozen cerebral cortex samples. No significant differences were observed in DNA copies between SP and IBA. These data show that brain mitochondrial bioenergetics are not static across the year and suggest that brain mitochondria function more effectively during the hibernation season, allowing for rapid production of energy to meet demand when extreme physiological changes are occurring.
Across species, many individuals carry one or more recessive lethal alleles, posing an evolutionary conundrum for their persistence. Using a population genomic approach, Amorim et al. studied the ...abundance of lethal disease-causing mutations in humans and found that, while appearing more common than expected, most may nonetheless persist at frequencies predicted by mutation–selection balance.
The brain of mammalian hibernators is naturally protected. Hibernating ground squirrels undergo rapid and extreme changes in body temperature and brain perfusion as they cycle between lengthy torpor ...bouts and brief periods of euthermia called interbout arousals (IBAs). Arousal from torpor to IBA occurs rapidly, but there is no evidence of brain injury accompanying this extreme physiological transition. Production of the hormone melatonin accompanies arousal, suggesting that it plays a protective role at this time. Here, we investigated mechanisms of melatonin receptor-mediated protection in the brain of the hibernating ground squirrel. We administered the competitive melatonin receptor antagonist luzindole (30 mg/kg ip) to ground squirrels at the predicted end of a torpor bout, triggering an arousal. We found that luzindole-treated animals exhibited caspase-3 activity two times higher than vehicle-treated animals in the hypothalamus at midarousal (P = 0.01), suggesting that melatonin receptor signaling is important for protection in this brain region. We also found a 30% decline in succinate-fueled mitochondrial respiration in luzindole-treated animals compared with vehicle-treated animals (P = 0.019), suggesting that melatonin receptor signaling is important for optimal mitochondrial function during arousal from torpor. The mitochondrial effects of luzindole treatment were seen only during the hibernation season, indicating that this effect is specifically important for arousal from torpor. These data provide evidence for the protective role of melatonin receptor signaling during the extreme physiological transition that occurs when a hibernating mammal arouses from torpor and provide further evidence for regional and seasonal changes in the hibernator brain.
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