Publications by authors named "Jenny Tung"

60 Publications

Glucocorticoid exposure predicts survival in female baboons.

Sci Adv 2021 Apr 21;7(17). Epub 2021 Apr 21.

Department of Biology, Duke University, Durham, NC 27708, USA.

Are differences in hypothalamic-pituitary-adrenal (HPA) axis activation across the adult life span linked to differences in survival? This question has been the subject of considerable debate. We analyze the link between survival and fecal glucocorticoid (GC) measures in a wild primate population, leveraging an unusually extensive longitudinal dataset of 14,173 GC measurements from 242 adult female baboons over 1634 female years. We document a powerful link between GCs and survival: Females with relatively high current GCs or high lifelong cumulative GCs face an elevated risk of death. A hypothetical female who maintained GCs in the top 90% for her age across adulthood would be expected to lose 5.4 years of life relative to a female who maintained GCs in the bottom 10% for her age. Hence, differences among individuals in HPA axis activity provide valuable prognostic information about disparities in life span.
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http://dx.doi.org/10.1126/sciadv.abf6759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059933PMC
April 2021

Primate phageomes are structured by superhost phylogeny and environment.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

Epidemiology of Highly Pathogenic Organisms, Robert Koch Institute, 13353 Berlin, Germany;

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.
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http://dx.doi.org/10.1073/pnas.2013535118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053973PMC
April 2021

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

Elife 2021 Apr 12;10. Epub 2021 Apr 12.

Department of Evolutionary Anthropology, Duke University, Durham, United States.

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 upregulate 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.
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http://dx.doi.org/10.7554/eLife.65760DOI Listing
April 2021

High social status males experience accelerated epigenetic aging in wild baboons.

Elife 2021 Apr 6;10. Epub 2021 Apr 6.

Department of Evolutionary Anthropology, Duke University, Durham, United States.

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.
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http://dx.doi.org/10.7554/eLife.66128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087445PMC
April 2021

Accelerated reproduction is not an adaptive response to early-life adversity in wild baboons.

Proc Natl Acad Sci U S A 2020 10 21;117(40):24909-24919. Epub 2020 Sep 21.

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556;

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.
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http://dx.doi.org/10.1073/pnas.2004018117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547275PMC
October 2020

Broadening primate genomics: new insights into the ecology and evolution of primate gene regulation.

Curr Opin Genet Dev 2020 06 20;62:16-22. Epub 2020 Jun 20.

Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA; Department of Biology, Duke University, Durham, NC 27708, USA; Institute of Primate Research, National Museums of Kenya, Nairobi 00502, Kenya; Duke Population Research Institute, Duke University, Durham, NC 27708, USA. Electronic address:

Comparative analyses have played a key role in understanding how gene regulatory evolution contributes to primate phenotypic diversity. Recently, these studies have expanded to include a wider range of species, within-population as well as interspecific analyses, and research on wild as well as captive individuals. This expansion provides context for understanding genetic and environmental effects on gene regulation in humans, including the importance of the pathogen and social environments. Although taxonomic representation remains biased, inclusion of more species has also begun to reveal the evolutionary processes that explain whether and when gene regulation is conserved. Together, this work highlights how studies in other primates contribute to understanding evolution in our own lineage, and we conclude by identifying promising avenues for future work.
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http://dx.doi.org/10.1016/j.gde.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483836PMC
June 2020

Social determinants of health and survival in humans and other animals.

Science 2020 05;368(6493)

Social and Biological Determinants of Health Working Group, NC, USA.

The social environment, both in early life and adulthood, is one of the strongest predictors of morbidity and mortality risk in humans. Evidence from long-term studies of other social mammals indicates that this relationship is similar across many species. In addition, experimental studies show that social interactions can causally alter animal physiology, disease risk, and life span itself. These findings highlight the importance of the social environment to health and mortality as well as Darwinian fitness-outcomes of interest to social scientists and biologists alike. They thus emphasize the utility of cross-species analysis for understanding the predictors of, and mechanisms underlying, social gradients in health.
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http://dx.doi.org/10.1126/science.aax9553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398600PMC
May 2020

IMAGE: high-powered detection of genetic effects on DNA methylation using integrated methylation QTL mapping and allele-specific analysis.

Genome Biol 2019 10 24;20(1):220. Epub 2019 Oct 24.

Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.

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.
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http://dx.doi.org/10.1186/s13059-019-1813-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813132PMC
October 2019

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

Proc Natl Acad Sci U S A 2020 09 14;117(38):23317-23322. Epub 2019 Oct 14.

Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC, Canada H3T1C5;

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.
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http://dx.doi.org/10.1073/pnas.1820846116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519294PMC
September 2020

Intergenerational effects of early adversity on survival in wild baboons.

Elife 2019 09 24;8. Epub 2019 Sep 24.

Department of Biology, Duke University, Durham, United States.

Early life adversity can affect an individual's health, survival, and fertility for many years after the adverse experience. Whether early life adversity also imposes intergenerational effects on the exposed individual's offspring is not well understood. 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, independent of the juvenile's own experience of early adversity. These juveniles often preceded their mothers in death by 1 to 2 years, indicating that high adversity females decline in their ability to raise offspring near the end of life. While we cannot exclude direct effects of a parent's environment on offspring quality (e.g., inherited epigenetic changes), our results are completely consistent with a classic parental effect, in which the environment experienced by a parent affects its future phenotype and therefore its offspring's phenotype.
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http://dx.doi.org/10.7554/eLife.47433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759315PMC
September 2019

Social Status and Gene Regulation: Conservation and Context Dependence in Primates.

Trends Cogn Sci 2019 09 15;23(9):722-725. Epub 2019 Jul 15.

Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA; Department of Biology, Duke University, Durham, NC 27708, USA; Duke Population Research Institute, Duke University, Durham, NC 27708, USA; Institute of Primate Research, National Museums of Kenya, 00502 Nairobi, Kenya. Electronic address:

Current models suggest that low social status affects immune function by increasing inflammation and compromising antiviral defense. While this pattern appears to be somewhat conserved, recent studies argue that the gene regulatory signature of social status also depends on the local environment and the nature of social hierarchies.
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http://dx.doi.org/10.1016/j.tics.2019.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101489PMC
September 2019

Molecular footprint of Medawar's mutation accumulation process in mammalian aging.

Aging Cell 2019 08 6;18(4):e12965. Epub 2019 May 6.

Department of Biological Sciences, Middle East Technical University, Ankara, Turkey.

Medawar's mutation accumulation hypothesis explains aging by the declining force of natural selection with age: Slightly deleterious germline mutations expressed in old age can drift to fixation and thereby lead to aging-related phenotypes. Although widely cited, empirical evidence for this hypothesis has remained limited. Here, we test one of its predictions that genes relatively highly expressed in old adults should be under weaker purifying selection than genes relatively highly expressed in young adults. Combining 66 transcriptome datasets (including 16 tissues from five mammalian species) with sequence conservation estimates across mammals, here we report that the overall conservation level of expressed genes is lower at old age compared to young adulthood. This age-related decrease in transcriptome conservation (ADICT) is systematically observed in diverse mammalian tissues, including the brain, liver, lung, and artery, but not in others, most notably in the muscle and heart. Where observed, ADICT is driven partly by poorly conserved genes being up-regulated during aging. In general, the more often a gene is found up-regulated with age among tissues and species, the lower its evolutionary conservation. Poorly conserved and up-regulated genes have overlapping functional properties that include responses to age-associated tissue damage, such as apoptosis and inflammation. Meanwhile, these genes do not appear to be under positive selection. Hence, genes contributing to old age phenotypes are found to harbor an excess of slightly deleterious alleles, at least in certain tissues. This supports the notion that genetic drift shapes aging in multicellular organisms, consistent with Medawar's mutation accumulation hypothesis.
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http://dx.doi.org/10.1111/acel.12965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612638PMC
August 2019

Genes, geology and germs: gut microbiota across a primate hybrid zone are explained by site soil properties, not host species.

Proc Biol Sci 2019 04;286(1901):20190431

2 Department of Biology, University of Notre Dame , Notre Dame, IN 46556 , USA.

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 F 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.
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http://dx.doi.org/10.1098/rspb.2019.0431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501927PMC
April 2019

Social affiliation predicts mitochondrial DNA copy number in female rhesus macaques.

Biol Lett 2019 01;15(1):20180643

1 Department of Biology, Duke University , Durham, NC 27708 , USA.

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.
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http://dx.doi.org/10.1098/rsbl.2018.0643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371908PMC
January 2019

Generating RNA Baits for Capture-Based Enrichment.

Methods Mol Biol 2019 ;1963:107-120

Department of Evolutionary Anthropology, Duke University, Durham, NC, USA.

Capture-based enrichment techniques have revolutionized genomic analysis of species and populations for which only low-quality or contaminated DNA samples (e.g., ancient DNA, noninvasively collected DNA, environmental DNA) are available. This chapter outlines an optimized laboratory protocol for generating RNA "baits" for genome-wide capture of target DNA from a larger pool of DNA. This method relies on the in vitro transcription of biotinylated RNA baits, which has the dual benefit of eliminating the high cost of synthesizing custom baits and producing a bait set that targets the majority of regions genome-wide. We provide a detailed protocol for the three main steps involved in bait library construction: (1) making a DNA library from a high-quality DNA sample for the organism of interest or a closely related species; (2) using duplex-specific nuclease digestion to reduce the representation of repetitive regions in the DNA library; and (3) performing in vitro transcription of the repetitive region-depleted DNA library to generate biotinylated RNA baits. Where applicable, we include notes and recommendations based on our own experiences.
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http://dx.doi.org/10.1007/978-1-4939-9176-1_12DOI Listing
September 2019

The comparative genomics and complex population history of baboons.

Sci Adv 2019 01 30;5(1):eaau6947. Epub 2019 Jan 30.

Department of Neuroscience, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

Recent studies suggest that closely related species can accumulate substantial genetic and phenotypic differences despite ongoing gene flow, thus challenging traditional ideas regarding the genetics of speciation. Baboons (genus ) are Old World monkeys consisting of six readily distinguishable species. Baboon species hybridize in the wild, and prior data imply a complex history of differentiation and introgression. We produced a reference genome assembly for the olive baboon () and whole-genome sequence data for all six extant species. We document multiple episodes of admixture and introgression during the radiation of baboons, thus demonstrating their value as a model of complex evolutionary divergence, hybridization, and reticulation. These results help inform our understanding of similar cases, including modern humans, Neanderthals, Denisovans, and other ancient hominins.
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http://dx.doi.org/10.1126/sciadv.aau6947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401983PMC
January 2019

Megaphages infect Prevotella and variants are widespread in gut microbiomes.

Nat Microbiol 2019 04 28;4(4):693-700. Epub 2019 Jan 28.

Department of Earth and Planetary Science, University of California, Berkeley, Berkeley, CA, USA.

Bacteriophages (phages) 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 phages in the human microbiome. We investigated the gut microbiomes of humans from Bangladesh and Tanzania, two African baboon social groups and Danish pigs; many of these microbiomes contain phages belonging to a clade with genomes >540 kilobases in length, the largest yet reported in the human microbiome and close to the maximum size ever reported for phages. We refer to these as Lak phages. CRISPR spacer targeting indicates that Lak phages 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 transfer RNAs, some of which contain enigmatic introns. Different individuals have distinct phage genotypes, and shifts in variant frequencies over consecutive sampling days reflect changes in the relative abundance of phage subpopulations. Recent homologous recombination has resulted in extensive genome admixture of nine baboon Lak phage populations. We infer that Lak phages are widespread in gut communities that contain the Prevotella species, and conclude that megaphages, with fascinating and underexplored biology, may be common but largely overlooked components of human and animal gut microbiomes.
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http://dx.doi.org/10.1038/s41564-018-0338-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784885PMC
April 2019

Genome-wide quantification of the effects of DNA methylation on human gene regulation.

Elife 2018 12 21;7. Epub 2018 Dec 21.

Department of Biology, Duke University, North Carolina, United States.

Changes in DNA methylation are involved in development, disease, and the response to environmental conditions. However, not all regulatory elements are functionally methylation-dependent (MD). Here, we report a method, mSTARR-seq, that assesses the causal effects of DNA methylation on regulatory activity at hundreds of thousands of fragments (millions of CpG sites) simultaneously. Using mSTARR-seq, we identify thousands of MD regulatory elements in the human genome. MD activity is partially predictable using sequence and chromatin state information, and distinct transcription factors are associated with higher activity in unmethylated versus methylated DNA. Further, pioneer TFs linked to higher activity in the methylated state appear to drive demethylation of experimentally methylated sites. MD regulatory elements also predict methylation-gene expression relationships across individuals, where they are 1.6x enriched among sites with strong negative correlations. mSTARR-seq thus provides a map of MD regulatory activity in the human genome and facilitates interpretation of differential methylation studies.
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http://dx.doi.org/10.7554/eLife.37513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303109PMC
December 2018

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

Proc Natl Acad Sci U S A 2019 01 11;116(4):1219-1228. Epub 2018 Dec 11.

Department of Evolutionary Anthropology, Duke University, Durham, NC 27708;

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.
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http://dx.doi.org/10.1073/pnas.1811758115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347725PMC
January 2019

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

Proc Natl Acad Sci U S A 2018 12 11;115(52):E12163-E12171. Epub 2018 Dec 11.

Department of Biology, Duke University, Durham, NC 27708;

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.
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http://dx.doi.org/10.1073/pnas.1811967115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310778PMC
December 2018

Evolution of DNA Methylation in Papio Baboons.

Mol Biol Evol 2019 03;36(3):527-540

Department of Evolutionary Anthropology, Duke University, Durham, NC.

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.
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http://dx.doi.org/10.1093/molbev/msy227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389319PMC
March 2019

Developmental plasticity research in evolution and human health: Response to commentaries.

Evol Med Public Health 2017 27;2017(1):201-205. Epub 2018 Feb 27.

Department of Biology, Duke University, Durham, NC 27708, USA.

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http://dx.doi.org/10.1093/emph/eoy007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888464PMC
February 2018

Developmental plasticity: Bridging research in evolution and human health.

Evol Med Public Health 2017 5;2017(1):162-175. Epub 2018 Feb 5.

Department of Biology, Duke University, Durham, NC 27708, USA.

Early life experiences can have profound and persistent effects on traits expressed throughout the life course, with consequences for later life behavior, disease risk, and mortality rates. The shaping of later life traits by early life environments, known as 'developmental plasticity', has been well-documented in humans and non-human animals, and has consequently captured the attention of both evolutionary biologists and researchers studying human health. Importantly, the parallel significance of developmental plasticity across multiple fields presents a timely opportunity to build a comprehensive understanding of this phenomenon. We aim to facilitate this goal by highlighting key outstanding questions shared by both evolutionary and health researchers, and by identifying theory and empirical work from both research traditions that is designed to address these questions. Specifically, we focus on: (i) evolutionary explanations for developmental plasticity, (ii) the genetics of developmental plasticity and (iii) the molecular mechanisms that mediate developmental plasticity. In each section, we emphasize the conceptual gains in human health and evolutionary biology that would follow from filling current knowledge gaps using interdisciplinary approaches. We encourage researchers interested in developmental plasticity to evaluate their own work in light of research from diverse fields, with the ultimate goal of establishing a cross-disciplinary understanding of developmental plasticity.
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http://dx.doi.org/10.1093/emph/eox019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798083PMC
February 2018

Group Living and Male Dispersal Predict the Core Gut Microbiome in Wild Baboons.

Integr Comp Biol 2017 Oct;57(4):770-785

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.

The mammalian gut microbiome plays a profound role in the physiology, metabolism, and overall health of its host. However, biologists have only a nascent understanding of the forces that drive inter-individual heterogeneity in gut microbial composition, especially the role of host social environment. Here we used 178 samples from 78 wild yellow baboons (Papio cynocephalus) living in two social groups to test how host social context, including group living, social interactions within groups, and transfer between social groups (e.g., dispersal) predict inter-individual variation in gut microbial alpha and beta diversity. We also tested whether social effects differed for prevalent "core" gut microbial taxa, which are thought to provide primary functions to hosts, versus rare "non-core" microbes, which may represent relatively transient environmental acquisitions. Confirming prior studies, we found that each social group harbored a distinct gut microbial community. These differences included both non-core and core gut microbial taxa, suggesting that these effects are not solely driven by recent gut microbial exposures. Within social groups, close grooming partners had more similar core microbiomes, but not non-core microbiomes, than individuals who rarely groomed each other, even controlling for kinship and diet similarity between grooming partners. Finally, in support of the idea that the gut microbiome can be altered by current social context, we found that the longer an immigrant male had lived in a given social group, the more closely his gut microbiome resembled the gut microbiomes of the group's long-term residents. Together, these results reveal the importance of a host's social context in shaping the gut microbiome and shed new light onto the microbiome-related consequences of male dispersal.
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http://dx.doi.org/10.1093/icb/icx046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886331PMC
October 2017

Maximizing ecological and evolutionary insight in bisulfite sequencing data sets.

Nat Ecol Evol 2017 Aug 21;1(8):1074-1083. Epub 2017 Jul 21.

Department of Biology, Duke University, Durham, NC, 27708, USA.

Genome-scale bisulfite sequencing approaches have opened the door to ecological and evolutionary studies of DNA methylation in many organisms. These approaches can be powerful. However, they introduce new methodological and statistical considerations, some of which are particularly relevant to non-model systems. Here, we highlight how these considerations influence a study's power to link methylation variation with a predictor variable of interest. Relative to current practice, we argue that sample sizes will need to increase to provide robust insights. We also provide recommendations for overcoming common challenges and an R Shiny app to aid in study design.
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http://dx.doi.org/10.1038/s41559-017-0229-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656403PMC
August 2017

The contribution of admixture to primate evolution.

Curr Opin Genet Dev 2017 Dec 15;47:61-68. Epub 2017 Sep 15.

Department of Pediatrics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Canada.

Genome-wide data on genetic variation are now available for multiple primate species and populations, facilitating analyses of evolutionary history within and across taxa. One emerging theme from these studies involves the central role of admixture. Genomic data sets indicate that both ancient gene flow following initial taxonomic divergence and ongoing gene flow at current species boundaries are common. These findings are of particular interest given evidence for a complex history of admixture in our own lineage, including examples of ecologically driven adaptive introgression. Like other aspects of human biology, studies of nonhuman primates thus provide both comparative context and a living model for understanding admixture dynamics in hominins. We highlight several open questions that could be addressed in future work.
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http://dx.doi.org/10.1016/j.gde.2017.08.010DOI Listing
December 2017

Vasopressin and the Neurogenetics of Parental Care.

Neuron 2017 Jul;95(1):9-11

Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA; Department of Biology, Duke University, Durham, NC 27708, USA; Duke Population Research Institute, Duke University, Durham, NC 27708, USA; Institute of Primate Research, National Museums of Kenya, Nairobi 00502, Kenya. Electronic address:

Making robust connections between genetic variation, neurophysiology, and social behavior remains a challenge. A study by Bendesky et al. (2017) tackles this challenge by dissecting the genetic architecture of parental care in deer mice to discover an important contribution of vasopressin signaling to the evolution of nest building.
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http://dx.doi.org/10.1016/j.neuron.2017.06.027DOI Listing
July 2017

Differential expression analysis for RNAseq using Poisson mixed models.

Nucleic Acids Res 2017 Jun;45(11):e106

Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.

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.
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http://dx.doi.org/10.1093/nar/gkx204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499851PMC
June 2017

Ovarian cycling and reproductive state shape the vaginal microbiota in wild baboons.

Microbiome 2017 01 19;5(1). Epub 2017 Jan 19.

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.

Background: The vaginal microbiome is an important site of bacterial-mammalian symbiosis. This symbiosis is currently best characterized for humans, where lactobacilli dominate the microbial community and may help defend women against infectious disease. However, lactobacilli do not dominate the vaginal microbiota of any other mammal studied to date, raising key questions about the forces that shape the vaginal microbiome in non-human mammals.

Results: We used Illumina sequencing of the bacterial 16S rRNA gene to investigate variation in the taxonomic composition of the vaginal microbiota in 48 baboons (Papio cynocephalus), members of a well-studied wild population in Kenya. Similar to prior studies, we found that the baboon vaginal microbiota was not dominated by lactobacilli. Despite this difference, and similar to humans, reproductive state was the dominant predictor of baboon vaginal microbiota, with pregnancy, postpartum amenorrhea, and ovarian cycling explaining 18% of the variance in community composition. Furthermore, among cycling females, a striking 39% of variance in community composition was explained by ovarian cycle phase, with an especially distinctive microbial community around ovulation. Periovulatory females exhibited the highest relative abundance of lactic acid-producing bacteria compared to any other phase, with a mean relative abundance of 44%. To a lesser extent, sexual behavior, especially a history of shared sexual partners, also predicted vaginal microbial similarity between baboons.

Conclusions: Despite striking differences in their dominant microbes, both human and baboon vaginal microbiota exhibit profound changes in composition in response to reproductive state, ovarian cycle phase, and sexual behavior. We found major shifts in composition during ovulation, which may have implications for disease risk and conception success. These findings highlight the need for future studies to account for fine-scale differences in reproductive state, particularly differences between the various phases of the ovarian cycle. Overall, our work contributes to an emerging understanding of the forces that explain intra- and inter-individual variation in the mammalian vaginal microbiome, with particular emphasis on its role in host health and disease risk.
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http://dx.doi.org/10.1186/s40168-017-0228-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5248513PMC
January 2017

Social status alters immune regulation and response to infection in macaques.

Science 2016 11;354(6315):1041-1045

Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA.

Social status is one of the strongest predictors of human disease risk and mortality, and it also influences Darwinian fitness in social mammals more generally. To understand the biological basis of these effects, we combined genomics with a social status manipulation in female rhesus macaques to investigate how status alters immune function. We demonstrate causal but largely plastic social status effects on immune cell proportions, cell type-specific gene expression levels, and the gene expression response to immune challenge. Further, we identify specific transcription factor signaling pathways that explain these differences, including low-status-associated polarization of the Toll-like receptor 4 signaling pathway toward a proinflammatory response. Our findings provide insight into the direct biological effects of social inequality on immune function, thus improving our understanding of social gradients in health.
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http://dx.doi.org/10.1126/science.aah3580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498102PMC
November 2016