ABSTRACT
Nonhuman primates provide unique evolutionary and comparative insight into the human phenotype. Genome assemblies are now available for nearly half of the species in the primate order, expanding our understanding of genetic variation within and between species and making important contributions to evolutionary biology, evolutionary anthropology, and human genetics.
Subject(s)
Genetic Variation , Genome , Primates , Animals , Humans , Biological Evolution , Genome/genetics , Genomics , Primates/geneticsABSTRACT
Individuals from different populations vary considerably in their susceptibility to immune-related diseases. To understand how genetic variation and natural selection contribute to these differences, we tested for the effects of African versus European ancestry on the transcriptional response of primary macrophages to live bacterial pathogens. A total of 9.3% of macrophage-expressed genes show ancestry-associated differences in the gene regulatory response to infection, and African ancestry specifically predicts a stronger inflammatory response and reduced intracellular bacterial growth. A large proportion of these differences are under genetic control: for 804 genes, more than 75% of ancestry effects on the immune response can be explained by a single cis- or trans-acting expression quantitative trait locus (eQTL). Finally, we show that genetic effects on the immune response are strongly enriched for recent, population-specific signatures of adaptation. Together, our results demonstrate how historical selective events continue to shape human phenotypic diversity today, including for traits that are key to controlling infection.
ABSTRACT
The early-life environment can profoundly shape the trajectory of an animal's life, even years or decades later. One mechanism proposed to contribute to these early-life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early-life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early-life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early-life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early-life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early-life effects on fitness-related traits.
Subject(s)
Adverse Childhood Experiences , DNA Methylation , Animals , Nucleotide Motifs , Biological Assay , Papio/geneticsABSTRACT
Dominance is a primary determinant of social dynamics and resource access in social animals. Recent studies show that dominance is also reflected in the gene regulatory profiles of peripheral immune cells. However, the strength and direction of this relationship differs across the species and sex combinations investigated, potentially due to variation in the predictors and energetic consequences of dominance status. Here, we investigated the association between social status and gene expression in the blood of wild meerkats (Suricata suricatta; n = 113 individuals), including in response to lipopolysaccharide, Gardiquimod (an agonist of TLR7, which detects single-stranded RNA in vivo) and glucocorticoid stimulation. Meerkats are cooperatively breeding social carnivores in which breeding females physically outcompete other females to suppress reproduction, resulting in high reproductive skew. They therefore present an opportunity to disentangle the effects of social dominance from those of sex per se. We identify a sex-specific signature of dominance, including 1045 differentially expressed genes in females but none in males. Dominant females exhibit elevated activity in innate immune pathways and a larger fold-change response to LPS challenge. Based on these results and a preliminary comparison to other mammals, we speculate that the gene regulatory signature of social status in the immune system depends on the determinants and energetic costs of social dominance, such that it is most pronounced in hierarchies where physical competition is important and reproductive skew is large. Such a pattern has the potential to mediate life history trade-offs between investment in reproduction versus somatic maintenance.
ABSTRACT
Humans harbor diverse communities of microorganisms, the majority of which are bacteria in the gastrointestinal tract. These gut bacterial communities in turn host diverse bacteriophage (hereafter phage) communities that have a major impact on their structure, function, and, ultimately, human health. However, the evolutionary and ecological origins of these human-associated phage communities are poorly understood. To address this question, we examined fecal phageomes of 23 wild nonhuman primate taxa, including multiple representatives of all the major primate radiations. We find relatives of the majority of human-associated phages in wild primates. Primate taxa have distinct phageome compositions that exhibit a clear phylosymbiotic signal, and phage-superhost codivergence is often detected for individual phages. Within species, neighboring social groups harbor compositionally and evolutionarily distinct phageomes, which are structured by superhost social behavior. Captive nonhuman primate phageome composition is intermediate between that of their wild counterparts and humans. Phage phylogenies reveal replacement of wild great ape-associated phages with human-associated ones in captivity and, surprisingly, show no signal for the persistence of wild-associated phages in captivity. Together, our results suggest that potentially labile primate-phage associations have persisted across millions of years of evolution. Across primates, these phylosymbiotic and sometimes codiverging phage communities are shaped by transmission between groupmates through grooming and are dramatically modified when primates are moved into captivity.
Subject(s)
Bacteriophages/pathogenicity , Gastrointestinal Microbiome , Hominidae/virology , Virome , Animals , Bacteriophages/genetics , Environment , Evolution, Molecular , Hominidae/classification , Hominidae/genetics , Hominidae/microbiology , Phylogeny , Social BehaviorABSTRACT
AbstractOver the past 50 years, a wealth of testable, often conflicting hypotheses have been generated about the evolution of offspring sex ratio manipulation by mothers. Several of these hypotheses have received support in studies of invertebrates and some vertebrate taxa. However, their success in explaining sex ratios in mammalian taxa-especially in primates-has been mixed. Here, we assess the predictions of four different hypotheses about the evolution of biased offspring sex ratios in the baboons of the Amboseli basin in Kenya: the Trivers-Willard, female rank enhancement, local resource competition, and local resource enhancement hypotheses. Using the largest sample size ever analyzed in a primate population (n=1,372 offspring), we test the predictions of each hypothesis. Overall, we find no support for adaptive biasing of sex ratios. Offspring sex is not consistently related to maternal dominance rank or biased toward the dispersing sex, nor is it predicted by group size, population growth rates, or their interaction with maternal rank. Because our sample size confers power to detect even subtle biases in sex ratio, including modulation by environmental heterogeneity, these results suggest that adaptive biasing of offspring sex does not occur in this population.
Subject(s)
Papio cynocephalus , Sex Ratio , Animals , Female , Papio , Primates , MammalsABSTRACT
Affiliative social bonds are linked to fitness components in many social mammals. However, despite their importance, little is known about how the tendency to form social bonds develops in young animals, or if the timing of development is heritable and thus can evolve. Using four decades of longitudinal observational data from a wild baboon population, we assessed the environmental determinants of an important social developmental milestone in baboons-the age at which a young animal first grooms a conspecific-and we assessed how the rates at which offspring groom their mothers develops during the juvenile period. We found that grooming development differs between the sexes: female infants groom at an earlier age and reach equal rates of grooming with their mother earlier than males. We also found that age at first grooming for both sexes is weakly heritable (h2 = 0.043, 95% CI: 0.002-0.110). These results show that sex differences in grooming emerge at a young age; that strong, equitable social relationships between mothers and daughters begin very early in life; and that age at first grooming is heritable and therefore can be shaped by natural selection.
Subject(s)
Mothers , Social Behavior , Humans , Animals , Female , Male , Papio , Sexual Behavior , Sex Characteristics , Grooming , MammalsABSTRACT
In humans and other long-lived species, harsh conditions in early life often lead to profound differences in adult life expectancy. In response, natural selection is expected to accelerate the timing and pace of reproduction in individuals who experience some forms of early-life adversity. However, the adaptive benefits of reproductive acceleration following early adversity remain untested. Here, we test a recent version of this theory, the internal predictive adaptive response (iPAR) model, by assessing whether accelerating reproduction following early-life adversity leads to higher lifetime reproductive success. We do so by leveraging 48 y of continuous, individual-based data from wild female baboons in the Amboseli ecosystem in Kenya, including prospective, longitudinal data on multiple sources of nutritional and psychosocial adversity in early life; reproductive pace; and lifetime reproductive success. We find that while early-life adversity led to dramatically shorter lifespans, individuals who experienced early adversity did not accelerate their reproduction compared with those who did not experience early adversity. Further, while accelerated reproduction predicted increased lifetime reproductive success overall, these benefits were not specific to females who experienced early-life adversity. Instead, females only benefited from reproductive acceleration if they also led long lives. Our results call into question the theory that accelerated reproduction is an adaptive response to both nutritional and psychosocial sources of early-life adversity in baboons and other long-lived species.
Subject(s)
Papio/physiology , Papio/psychology , Adaptation, Physiological , Animals , Animals, Wild/growth & development , Animals, Wild/physiology , Animals, Wild/psychology , Female , Kenya , Longevity , Longitudinal Studies , Male , Papio/growth & development , Prospective Studies , ReproductionABSTRACT
Social experience is an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent proinflammatory pathways and lower expression of genes involved in the antiviral response and type I IFN signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB- and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are linked not only to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Taken together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history-in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.
Subject(s)
Bacterial Infections/veterinary , Primate Diseases/genetics , Primate Diseases/psychology , Virus Diseases/veterinary , Animals , Bacterial Infections/genetics , Bacterial Infections/immunology , Bacterial Infections/psychology , Behavior, Animal , Female , Gene Expression , Gene Expression Regulation , Hierarchy, Social , Immunity, Innate , Macaca mulatta/genetics , Macaca mulatta/immunology , Macaca mulatta/psychology , Male , NF-kappa B/genetics , NF-kappa B/immunology , Primate Diseases/immunology , Primate Diseases/microbiology , Social Stigma , Virus Diseases/genetics , Virus Diseases/immunology , Virus Diseases/psychologyABSTRACT
Low social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health outcomes remain elusive. Here, we used an in vitro GC challenge to investigate the consequences of experimentally manipulated social status (i.e., dominance rank) for immune cell gene regulation in female rhesus macaques, using paired control and GC-treated peripheral blood mononuclear cell samples. We show that social status not only influences immune cell gene expression but also chromatin accessibility at hundreds of regions in the genome. Social status effects on gene expression were less pronounced following GC treatment than under control conditions. In contrast, social status effects on chromatin accessibility were stable across conditions, resulting in an attenuated relationship between social status, chromatin accessibility, and gene expression after GC exposure. Regions that were more accessible in high-status animals and regions that become more accessible following GC treatment were enriched for a highly concordant set of transcription factor binding motifs, including motifs for the GC receptor cofactor AP-1. Together, our findings support the hypothesis that social status alters the dynamics of GC-mediated gene regulation and identify chromatin accessibility as a mechanism involved in social stress-driven GC resistance. More broadly, they emphasize the context-dependent nature of social status effects on gene regulation and implicate epigenetic remodeling of chromatin accessibility as a contributing factor.
Subject(s)
Chromatin Assembly and Disassembly/drug effects , Chromatin/drug effects , Chromatin/genetics , Gene Expression Regulation/drug effects , Glucocorticoids/pharmacology , Animals , Binding Sites/drug effects , Chromatin Assembly and Disassembly/genetics , Epigenomics/methods , Female , Leukocytes, Mononuclear/drug effects , Macaca mulatta , Receptors, Glucocorticoid/genetics , Transcription Factors/geneticsABSTRACT
Despite the promise of ecological epigenetics, there remain few cases that clearly link epigenetic variation in wild animal populations to evolutionary change. In this issue of Molecular Ecology, Sun et al. provide such an example in white-throated sparrows-a fascinating system in which a large chromosomal rearrangement generates a "supergene" polymorphism linked to plumage colour, aggression and parenting behaviour. By combining whole genome bisulphite sequencing with RNA-sequencing and chromatin accessibility data, they show that the two alleles of this chromosomal polymorphism also exhibit substantial differences in DNA methylation levels, with implications for gene expression and transposable element activity. Their results provide a compelling case study for how genetic and epigenetic evolution proceed in concert. They also demonstrate the importance of integrating multiple types of genomic information to understand how gene regulation evolves, providing a model for future work in nonmodel species.
Subject(s)
Sparrows , Aggression , Alleles , Animals , Chromosomes , Epigenesis, Genetic , Sparrows/geneticsABSTRACT
In North American gray wolves, black coat color is dominantly inherited via a 3 base pair coding deletion in the canine beta defensin 3 (CBD103) gene. This 3 base pair deletion, called the KB allele, was introduced through hybridization with dogs and subsequently underwent a selective sweep that increased its frequency in wild wolves. Despite apparent positive selection, KBB wolves have lower fitness than wolves with the KyB genotype, even though the 2 genotypes show no observable differences in black coat color. Thus, the KB allele is thought to have pleiotropic effects on as-yet unknown phenotypes. Given the role of skin-expressed CBD103 in innate immunity, we hypothesized that the KB allele influences the keratinocyte gene expression response to TLR3 pathway stimulation and/or infection by canine distemper virus (CDV). To test this hypothesis, we developed a panel of primary epidermal keratinocyte cell cultures from 24 wild North American gray wolves of both Kyy and KyB genotypes. In addition, we generated an immortalized Kyy line and used CRISPR/Cas9 editing to produce a KyB line on the same genetic background. We assessed the transcriptome-wide responses of wolf keratinocytes to the TLR3 agonist polyinosinic:polycytidylic acid (polyI:C), and to live CDV. K locus genotype did not predict the transcriptional response to either challenge, suggesting that variation in the gene expression response does not explain pleiotropic effects of the KB allele on fitness. This study supports the feasibility of using cell culture methods to investigate the phenotypic effects of naturally occurring genetic variation in wild mammals.
Subject(s)
Distemper Virus, Canine , Wolves , Alleles , Animals , Distemper Virus, Canine/genetics , Dogs , Gene Expression , Toll-Like Receptor 3/genetics , Wolves/geneticsABSTRACT
In humans and other hierarchical species, social status is tightly linked to variation in health and fitness-related traits. Experimental manipulations of social status in female rhesus macaques suggest that this relationship is partially explained by status effects on immune gene regulation. However, social hierarchies are established and maintained in different ways across species: While some are based on kin-directed nepotism, others emerge from direct physical competition. We investigated how this variation influences the relationship between social status and immune gene regulation in wild baboons, where hierarchies in males are based on fighting ability but female hierarchies are nepotistic. We measured rank-related variation in gene expression levels in adult baboons of both sexes at baseline and in response to ex vivo stimulation with the bacterial endotoxin lipopolysaccharide (LPS). We identified >2,000 rank-associated genes in males, an order of magnitude more than in females. In males, high status predicted increased expression of genes involved in innate immunity and preferential activation of the NF-κB-mediated proinflammatory pathway, a pattern previously associated with low status in female rhesus macaques. Using Mendelian randomization, we reconcile these observations by demonstrating that high status-associated gene expression patterns are precursors, not consequences, of high social status in males, in support of the idea that physiological condition determines who attains high rank. Together, our work provides a test of the relationship between social status and immune gene regulation in wild primates. It also emphasizes the importance of social context in shaping the relationship between social status and immune function.
Subject(s)
Hierarchy, Social , Papio/genetics , Social Dominance , Animals , Animals, Wild/genetics , Animals, Wild/immunology , Animals, Wild/physiology , Behavior, Animal , Female , Gene Expression , Immunity, Innate , Macaca mulatta , Male , Mendelian Randomization Analysis , Papio/immunology , Papio/physiology , Sex Factors , Social BehaviorABSTRACT
Changes in gene regulation have long been thought to play an important role in primate evolution. However, although a number of studies have compared genome-wide gene expression patterns across primate species, fewer have investigated the gene regulatory mechanisms that underlie such patterns, or the relative contribution of drift versus selection. Here, we profiled genome-scale DNA methylation levels in blood samples from five of the six extant species of the baboon genus Papio (4-14 individuals per species). This radiation presents the opportunity to investigate DNA methylation divergence at both shallow and deeper timescales (0.380-1.4 My). In contrast to studies in human populations, but similar to studies in great apes, DNA methylation profiles clearly mirror genetic and geographic structure. Divergence in DNA methylation proceeds fastest in unannotated regions of the genome and slowest in regions of the genome that are likely more constrained at the sequence level (e.g., gene exons). Both heuristic approaches and Ornstein-Uhlenbeck models suggest that DNA methylation levels at a small set of sites have been affected by positive selection, and that this class is enriched in functionally relevant contexts, including promoters, enhancers, and CpG islands. Our results thus indicate that the rate and distribution of DNA methylation changes across the genome largely mirror genetic structure. However, at some CpG sites, DNA methylation levels themselves may have been a target of positive selection, pointing to loci that could be important in connecting sequence variation to fitness-related traits.
Subject(s)
DNA Methylation , Evolution, Molecular , Papio/genetics , Animals , PhylogeographyABSTRACT
Gut microbiota in geographically isolated host populations are often distinct. These differences have been attributed to between-population differences in host behaviours, environments, genetics and geographical distance. However, which factors are most important remains unknown. Here, we fill this gap for baboons by leveraging information on 13 environmental variables from 14 baboon populations spanning a natural hybrid zone. Sampling across a hybrid zone allowed us to additionally test whether phylosymbiosis (codiversification between hosts and their microbiota) is detectable in admixed, closely related primates. We found little evidence of genetic effects: none of host genetic ancestry, host genetic relatedness nor genetic distance between host populations were strong predictors of baboon gut microbiota. Instead, gut microbiota were best explained by the baboons' environments, especially the soil's geologic history and exchangeable sodium. Indeed, soil effects were 15 times stronger than those of host-population FST, perhaps because soil predicts which foods are present, or because baboons are terrestrial and consume soil microbes incidentally with their food. Our results support an emerging picture in which environmental variation is the dominant predictor of host-associated microbiomes. We are the first to show that such effects overshadow host species identity among members of the same primate genus.
Subject(s)
Bacteria/classification , Gastrointestinal Microbiome , Papio anubis/microbiology , Papio cynocephalus/microbiology , Soil/chemistry , Animals , Bacterial Physiological Phenomena , Hybridization, Genetic , KenyaABSTRACT
In many social mammals, social adversity predicts compromised health and reduced fitness. These effects are thought to be driven in part by chronic social stress, but their molecular underpinnings are not well understood. Recent work suggests that chronic stress can affect mitochondrial copy number, heteroplasmy rates and function. Here, we tested the first two possibilities for the first time in non-human primates. We manipulated dominance rank in captive female rhesus macaques ( n = 45), where low rank induces chronic social stress, and measured mitochondrial DNA (mtDNA) copy number and heteroplasmy in five peripheral blood mononuclear cell types from each study subject. We found no effect of dominance rank on either mtDNA copy number or heteroplasmy rates. However, grooming rate, a measure of affiliative social behaviour predicted by high social status, was positively associated with mtDNA copy number in B cells, cytotoxic T cells and monocytes. Our results suggest that social interactions can influence mtDNA regulation in immune cells. Further, they indicate the importance of considering both affiliative and competitive interactions in investigating this relationship.
Subject(s)
DNA Copy Number Variations , DNA, Mitochondrial , Animals , Female , Leukocytes, Mononuclear , Macaca mulatta , MitochondriaABSTRACT
Identifying differentially expressed (DE) genes from RNA sequencing (RNAseq) studies is among the most common analyses in genomics. However, RNAseq DE analysis presents several statistical and computational challenges, including over-dispersed read counts and, in some settings, sample non-independence. Previous count-based methods rely on simple hierarchical Poisson models (e.g. negative binomial) to model independent over-dispersion, but do not account for sample non-independence due to relatedness, population structure and/or hidden confounders. Here, we present a Poisson mixed model with two random effects terms that account for both independent over-dispersion and sample non-independence. We also develop a scalable sampling-based inference algorithm using a latent variable representation of the Poisson distribution. With simulations, we show that our method properly controls for type I error and is generally more powerful than other widely used approaches, except in small samples (n <15) with other unfavorable properties (e.g. small effect sizes). We also apply our method to three real datasets that contain related individuals, population stratification or hidden confounders. Our results show that our method increases power in all three data compared to other approaches, though the power gain is smallest in the smallest sample (n = 6). Our method is implemented in MACAU, freely available at www.xzlab.org/software.html.
Subject(s)
Gene Expression Profiling/methods , Sequence Analysis, RNA , Algorithms , Bayes Theorem , Computer Simulation , Humans , Linear Models , Markov Chains , Models, Genetic , Monte Carlo Method , Poisson Distribution , SoftwareABSTRACT
DNA methylation is an epigenetic mark thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a live pathogenic bacteria is associated with rapid and active demethylation at thousands of loci, independent of cell division. We performed an integrated analysis of data on genome-wide DNA methylation, histone mark patterns, chromatin accessibility, and gene expression, before and after infection. We found that infection-induced demethylation rarely occurs at promoter regions and instead localizes to distal enhancer elements, including those that regulate the activation of key immune transcription factors. Active demethylation is associated with extensive epigenetic remodeling, including the gain of histone activation marks and increased chromatin accessibility, and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that active, rapid changes in DNA methylation in enhancers play a previously unappreciated role in regulating the transcriptional response to infection, even in nonproliferating cells.
Subject(s)
Bacterial Infections/genetics , DNA Methylation , Dendritic Cells/metabolism , Dendritic Cells/microbiology , Host-Pathogen Interactions/genetics , 5-Methylcytosine/analogs & derivatives , Bacterial Infections/immunology , Bacterial Infections/metabolism , CpG Islands , Cytosine/analogs & derivatives , Cytosine/metabolism , Dendritic Cells/immunology , Epigenesis, Genetic , Epigenomics/methods , Gene Expression Regulation , Host-Pathogen Interactions/immunology , Humans , Mycobacterium tuberculosis/immunology , Transcription Factors/metabolism , Tuberculosis/genetics , Tuberculosis/immunology , Tuberculosis/metabolism , Tuberculosis/microbiologyABSTRACT
Identifying sources of variation in DNA methylation levels is important for understanding gene regulation. Recently, bisulfite sequencing has become a popular tool for investigating DNA methylation levels. However, modeling bisulfite sequencing data is complicated by dramatic variation in coverage across sites and individual samples, and because of the computational challenges of controlling for genetic covariance in count data. To address these challenges, we present a binomial mixed model and an efficient, sampling-based algorithm (MACAU: Mixed model association for count data via data augmentation) for approximate parameter estimation and p-value computation. This framework allows us to simultaneously account for both the over-dispersed, count-based nature of bisulfite sequencing data, as well as genetic relatedness among individuals. Using simulations and two real data sets (whole genome bisulfite sequencing (WGBS) data from Arabidopsis thaliana and reduced representation bisulfite sequencing (RRBS) data from baboons), we show that our method provides well-calibrated test statistics in the presence of population structure. Further, it improves power to detect differentially methylated sites: in the RRBS data set, MACAU detected 1.6-fold more age-associated CpG sites than a beta-binomial model (the next best approach). Changes in these sites are consistent with known age-related shifts in DNA methylation levels, and are enriched near genes that are differentially expressed with age in the same population. Taken together, our results indicate that MACAU is an efficient, effective tool for analyzing bisulfite sequencing data, with particular salience to analyses of structured populations. MACAU is freely available at www.xzlab.org/software.html.