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Tung, J.

Publications and source records attributed to Tung, J..

At least 55 records · Page 3Linked to original sources

Synchrony and idiosyncrasy in the gut microbiome of wild primates

Human gut microbial dynamics are highly individualized, making it challenging to link microbiota to health and to design universal microbiome therapies. This individuality is typically attributed to variation in host genetics, diets, environments, and medications, but it could also emerge from fundamental ecological forces that shape microbiota more generally. Here we leverage extensive gut microbial time series from wild baboons--hosts who experience little interindividual dietary and environmental heterogeneity--to test whether gut microbial dynamics are synchronized across hosts or largely idiosyncratic. Despite their shared lifestyles, baboon microbiome dynamics were only weakly synchronized. The strongest synchrony occurred among baboons living in the same social group, likely because group members range over the same habitat and simultaneously encounter the same sources of food and water. However, this synchrony was modest compared to each hosts personalized dynamics. Indeed, host-specific factors, especially host identity, explained 10 times the deviance in longitudinal microbial dynamics, compared to factors shared across hosts. These results contribute to mounting evidence that highly idiosyncratic gut microbiomes are not an artifact of modern human environments, and that synchronizing forces in the gut microbiome (e.g., shared environments, diets, and microbial dispersal) are often not strong enough to overwhelm drivers of microbiome personalization, including host genetics, priority effects, horizontal gene transfer, and functional redundancy.

ecology↗

Selection against admixture and gene regulatory divergence in a long-term primate field study

Admixture has profoundly influenced evolution across the tree of life, including in humans and other primates1,2. However, we have limited insight into the genetic and phenotypic consequences of admixture in primates, especially during its key early stages. Here, we address this gap by combining 50 years of field observations with population and functional genomic data from yellow (Papio cynocephalus) and anubis (P. anubis) baboons in Kenya, in a longitudinally studied population that has experienced both historical and recent admixture3. We use whole-genome sequencing to characterize the extent of the hybrid zone, estimate local ancestry for 442 known individuals, and predict the landscape of introgression across the genome. Despite no major fitness costs to hybrids, we identify signatures of selection against introgression that are strikingly similar to those described for archaic hominins4-6. These signatures are strongest near loci with large ancestry effects on gene expression, supporting the importance of gene regulation in primate evolution and the idea that selection targeted large regulatory effects following archaic hominin admixture7,8. Our results show that genomic data and field observations of hybrids are important and mutually informative. They therefore demonstrate the value of other primates as living models for phenomena that we cannot observe in our own lineage.

evolutionary biology↗

Agonism and grooming behavior explain social status effects on physiology and gene regulation in rhesus macaques

Variation in social status predicts molecular, physiological, and life history outcomes across a broad range of species, including our own. Experimental studies indicate that some of these relationships persist even when the physical environment is held constant. Here, we draw on data sets from one such study--experimental manipulation of dominance rank in captive female rhesus macaques--to investigate how social status shapes the lived experience of these animals to alter gene regulation, glucocorticoid physiology, and mitochondrial DNA phenotypes. We focus specifically on dominance rank-associated dimensions of the social environment, including both competitive and affiliative interactions. Our results show that simple summaries of rank-associated behavioral interactions are often better predictors of molecular and physiological outcomes than dominance rank itself. However, while measures of immune function are best explained by agonism rates, glucocorticoid-related phenotypes tend to be more closely linked to affiliative behavior. We conclude that dominance rank serves as a useful summary for investigating social environmental effects on downstream outcomes. Nevertheless, the behavioral interactions that define an individuals daily experiences reveal the proximate drivers of social status-related differences, and are especially relevant for understanding why individuals who share the same social status sometimes appear physiologically distinct.

genomics↗

Distinct gene regulatory signatures of dominance rank and social bond strength in wild baboons

The social environment is a major determinant of morbidity, mortality, and Darwinian fitness in social animals. Recent studies have begun to uncover the molecular processes associated with these relationships, but the degree to which they vary across different dimensions of the social environment remains unclear. Here, we draw on a long-term field study of wild baboons to compare the signatures of affiliative and competitive aspects of the social environment in white blood cell gene regulation, under both immune stimulated and non-stimulated conditions. We find that the effects of dominance rank on gene expression are directionally opposite in males versus females, such that high-ranking males resemble low-ranking females, and vice-versa. Among females, rank and social bond strength are both reflected in the activity of cellular metabolism and proliferation genes. However, pronounced rank-related differences in baseline immune gene activity are near-absent for social bond strength, while only bond strength predicts the fold-change response to immune (lipopolysaccharide) stimulation. Together, our results indicate that the directionality and magnitude of social effects on gene regulation depend on the aspect of the social environment under study. This heterogeneity may help explain why social environmental effects on health and longevity can also vary between measures.

genomics↗

Experimental assessment of K locus effects on the gray wolf response to virus

In North American gray wolves, black coat color is dominantly inherited via a three base pair coding deletion in the canine beta defensin 3 (CBD103) gene. This three 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 significantly lower fitness than wolves with the KyB genotype, even though the two 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 gene regulatory response to viral infection. To test this hypothesis, we developed a panel of primary epidermal keratinocyte cell cultures from 24 wild North American gray wolves (both Kyy and KyB genotypes) and generated immortalized Kyy and CBD103 knockout lines. We assessed the transcriptome-wide responses of wolf keratinocytes to polyinosinic:polycytidylic acid (polyI:C), which mimics infection by a double-stranded RNA virus, and to live canine distemper virus. Keratinocytes with the KyB genotype and with the Kyy genotype had similar gene regulatory responses to viral infection, suggesting that this 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.

evolutionary biology↗

Genetic ancestry predicts male-female affiliation in a natural baboon hybrid zone

Opposite-sex social relationships are important predictors of fitness in many animals, including several group-living mammals. Consequently, understanding sources of variance in the tendency to form opposite-sex relationships is important for understanding social evolution. Genetic contributions are of particular interest due to their importance in long-term evolutionary change, but little is known about genetic effects on male-female relationships in social mammals, especially outside of the mating context. Here, we investigate the effects of genetic ancestry on male-female affiliative behavior in a hybrid zone between the yellow baboon (Papio cynocephalus) and the anubis baboon (P. anubis), in a population in which male-female social bonds are known predictors of lifespan. We place our analysis within the context of other social and demographic predictors of affiliative behavior in baboons. Genetic ancestry was the most consistent predictor of opposite-sex affiliative behavior we observed, with the exception of strong effects of dominance rank. Our results show that increased anubis genetic ancestry is associated with subtly, but significantly higher rates of opposite-sex affiliative behavior, in both males and females. Additionally, pairs of anubis-like males and anubis-like females were the most likely to socially affiliate, resulting in moderate assortativity in grooming and proximity behavior as a function of genetic ancestry. Our findings indicate that opposite-sex affiliative behavior partially diverged during baboon evolution to differentiate yellow and anubis baboons, despite overall similarities in their social structures and mating systems. Further, they suggest that affiliative behavior may simultaneously promote and constrain baboon admixture, through additive and assortative effects of ancestry, respectively. HIGHLIGHTSO_LIOpposite-sex social relationships can have important fitness consequences. C_LIO_LIIn hybrid baboons, genetic ancestry predicted male-female affiliative behavior. C_LIO_LIBoth an individuals genetic ancestry and that of its social partner mattered. C_LIO_LIMale-female affiliation was assortative with respect to genetic ancestry. C_LIO_LIDominance rank and group demography also influenced male-female social affiliation. C_LI

evolutionary biology↗

Morphological and genomic shifts in mole-rat 'queens' increase fecundity but reduce skeletal integrity

In some mammals and many social insects, highly cooperative societies are characterized by reproductive division of labor, in which breeders and nonbreeders become behaviorally and morphologically distinct. While differences in behavior and growth between breeders and nonbreeders have been extensively described, little is known of their molecular underpinnings. Here, we investigate the consequences of breeding for skeletal morphology and gene regulation in highly cooperative Damaraland mole-rats. By experimentally assigning breeding queen status versus nonbreeder status to age-matched littermates, we confirm that queens experience vertebral growth that likely confers advantages to fecundity. However, they also up-regulate bone resorption pathways and show reductions in femoral mass, which predicts increased vulnerability to fracture. Together, our results show that, as in eusocial insects, reproductive division of labor in mole-rats leads to gene regulatory rewiring and extensive morphological plasticity. However, in mole-rats, concentrated reproduction is also accompanied by costs to bone strength.

evolutionary biology↗

Caspases from Scleractinian Coral Show Unique Regulatory Features

Diseases affecting coral have led to massive decline and altered the community structure of reefs. In response to immune challenges, cnidaria activate apoptotic or autophagic pathways, and the particular pathway correlates with disease sensitivity (apoptosis) or resistance (autophagy). Although cnidaria contain complex apoptotic signaling pathways, similar to those in vertebrates, the mechanisms leading to cell death are largely unexplored. We identified and characterized two caspases each from Orbicella faveolata, a disease-sensitive stony coral, and Porites astreoides, a disease-resistant stony coral. The four caspases are predicted homologs of human caspases-3 and -7, but OfCasp3a and PaCasp7a contain an amino-terminal caspase activation and recruitment domain (CARD) similar to human initiator/inflammatory caspases. In contrast, OfCasp3b and PaCasp3 have short pro-domains, like human effector caspases. We show that OfCasp3a and PaCasp7a are DxxDases, like human caspases-3 and -7, while OfCasp3b and PaCasp3 are more similar to human caspase-6, with VxxDase activity. Our biochemical analyses suggest a mechanism in coral in which the CARD-containing DxxDase is activated on death platforms, but the protease does not directly activate the VxxDase. We also report the first X-ray crystal structure of a coral caspase, that of PaCasp7a determined at 1.57[A] resolution. The structure reveals overall conservation of the caspase-hemoglobinase fold in coral as well as an N-terminal peptide bound near the active site that may serve as a regulatory exosite. The binding pocket has been observed in initiator caspases of other species, suggesting mechanisms for the evolution of substrate selection while maintaining common activation mechanisms of CARD-mediated dimerization.

biochemistry↗

Primate phageomes are structured by superhost phylogeny and environment

The evolutionary origins of human-associated bacteriophage communities are poorly understood. To address this question, we examined fecal phageomes of 23 wild non-human primate taxa, including multiple representatives of all the major primate radiations, and find relatives of the majority of human-associated phages. Primate taxa have distinct phageome compositions that exhibit a clear phylosymbiotic signal, and phage-superhost co-divergence is detected for 44 individual phages. Within species, neighboring social groups harbor evolutionarily and compositionally distinct phageomes, structured by superhost social behavior. However, captive non-human primate phageomes are more similar to humans than their wild counterparts, revealing replacement of wild-associated phages with human-associated ones. Together, our results suggest that potentially labile primate-phage associations persisted across millions of years of evolution, potentially facilitated by transmission between groupmates. One Sentence SummaryRelatives of human-associated phages in wild primates reveal ancient but dynamic superhost-phage associations shaped by social transmission.

microbiology↗

The costs of competition: high social status males experience accelerated epigenetic aging in wild baboons

Aging, for virtually all life, is inescapable. However, within populations, biological aging rates vary. Understanding sources of variation in this process is central to understanding the biodemography of natural populations. We constructed a DNA methylation-based age predictor for an intensively studied wild baboon population in Kenya. Consistent with findings in humans, the resulting "epigenetic clock" closely tracks chronological age, but individuals are predicted to be somewhat older or younger than their known ages. Surprisingly, these deviations are not explained by the strongest predictors of lifespan in this population, early adversity and social integration. Instead, they are best predicted by male dominance rank: high-ranking males are predicted to be older than their true ages, and epigenetic age tracks changes in rank over time. Our results argue that achieving high rank for male baboons--the best predictor of reproductive success--imposes costs consistent with a "live fast, die young" life history strategy.

genomics↗

High-powered detection of genetic effects on DNA methylation using integrated methylation QTL mapping and allele-specific analysis

Identifying genetic variants that are associated with methylation variation - an analysis commonly referred to as methylation quantitative trait locus (mQTL) mapping -- is important for understanding the epigenetic mechanisms underlying genotype-trait associations. Here, we develop a statistical method, IMAGE, for mQTL mapping in sequencing-based methylation studies. IMAGE properly accounts for the count nature of bisulfite sequencing data and incorporates allele-specific methylation patterns from heterozygous individuals to enable more powerful mQTL discovery. We compare IMAGE with existing approaches through extensive simulation. We also apply IMAGE to analyze two bisulfite sequencing studies, in which IMAGE identifies more mQTL than existing approaches.

genomics↗

Intergenerational effects of early adversity on survival in wild baboons

In humans and nonhuman animals, early life adversity can affect an individuals health, survival, and fertility for many years after the adverse experience. However, whether early life adversity also imposes intergenerational effects on the exposed individuals offspring is not well understood. Here, we fill this gap by leveraging prospective, longitudinal data on a wild, long-lived primate. We find that juveniles whose mothers experienced early life adversity exhibit high mortality before age 4, and this effect is independent of the juveniles own experience of early adversity. Furthermore, our results point towards a strong role for classic parental effects in driving these effects: mothers that experienced early life adversity displayed reduced viability in adulthood, which in turn led to reductions in offspring survival. Importantly, these mothers juvenile offspring often preceded them in death by 1 to 2 years, indicating that, for high adversity mothers, the quality of maternal care declines near the end of life. While we cannot exclude direct effects of a parents environment on offspring quality (e.g., transgenerational epigenetic changes), our results are most consistent with a classic parental effect, in which the environment experienced by a parent affects its future phenotype and therefore its offsprings phenotype. Together, our findings demonstrate that adversity experienced by individuals in one generation can have strong effects on the survival of offspring in the next generation, even if those offspring did not themselves experience early adversity.

zoology↗

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

Social experiences are an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a pro-inflammatory 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-{kappa}B-dependent pro-inflammatory pathways and lower expression of genes involved in the antiviral response and type I interferon (IFN) signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-{kappa}B and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are not only linked 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. 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.

genomics↗

Social integration predicts mitochondrial DNA copy number in rhesus macaques

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 nonhuman primates. We manipulated dominance rank in captive female rhesus macaques (n=45), where low rank induces chronic social stress, and measured mitochondrial DNA 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 rates, a measure of affiliative social behavior 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.

animal behavior and cognition↗

Evolution of DNA methylation in Papio baboons

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 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 time scales (380,000 - 1.4 million years). 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.

genomics↗

Dominance rank-associated immune gene expression is widespread, sex-specific, and a precursor to high social status in wild male baboons

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 >2000 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 NFkB-mediated pro-inflammatory 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 the first 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.\n\nSIGNIFICANCESocial status predicts fitness outcomes in social animals, motivating efforts to understand its physiological causes and consequences. We investigated the relationship between social status and immune gene expression in wild baboons, where female status is determined by kinship but male status is determined by fighting ability. We uncover pervasive status-gene expression associations in males, but not females. High status males exhibit high levels of pro-inflammatory gene expression, in contrast to previous findings in hierarchies that are not competitively determined. Using Mendelian randomization, we show that this status-associated variation precedes dominance rank attainment: males who compete successfully for high status are already immunologically distinct. The nature of social hierarchies thus fundamentally shapes the relationship between social status and immune function.

evolutionary biology↗

Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques

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 glucocorticoid 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 post-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 glucocorticoid receptor co-factor 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.

genomics↗

Megaphage infect Prevotella and variants are widespread in gut microbiomes

Bacteriophage (phage) dramatically shape microbial community composition, redistribute nutrients via host lysis, and drive evolution through horizontal gene transfer. Despite their importance, much remains to be learned about phage in the human microbiome. We investigated gut microbiomes of humans from Bangladesh and Tanzania, two African baboon social groups, and Danish pigs, and report that many contain phage belonging to a clade with genomes >540 kb in length, the largest yet reported in the human microbiome and close to the maximum size ever reported for phage. We refer to these as Lak phage. CRISPR spacer targeting indicates that the Lak phage infect bacteria of the genus Prevotella. We manually curated to completion 15 distinct Lak phage genomes recovered from metagenomes. The genomes display several interesting features, including use of an alternative genetic code, large intergenic regions that are highly expressed, and up to 35 putative tRNAs, some of which contain enigmatic introns. Different individuals have distinct phage genotypes, and shifts in variant frequencies over consecutive sampling days reflect changes in relative abundance of phage sub-populations. Recent homologous recombination has resulted in extensive genome admixture of nine baboon Lak phage populations. We infer that Lak phage are widespread in gut communities that contain Prevotella species, especially in individuals in the developing world, and conclude that megaphage, with fascinating and underexplored biology, may be common but largely overlooked components of human and animal gut microbiomes.

microbiology↗