Biology subjects

Tung, J.

Publications and source records attributed to Tung, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Social and environmental predictors of gut microbiome age in wild baboons

Mammalian gut microbiomes are highly dynamic communities that shape and are shaped by host aging, including age-related changes to host immunity, metabolism, and behavior. As such, gut microbial composition may provide valuable information on host biological age. Here we test this idea by creating a microbiome-based age predictor using 13,563 gut microbial profiles from 479 wild baboons collected over 14 years. The resulting "microbiome clock" predicts host chronological age. Deviations from the clocks predictions are linked to some demographic and socio-environmental factors that predict baboon health and survival: animals who appear old-for-age tend to be male, sampled in the dry season (for females), and have high social status (both sexes). However, an individuals "microbiome age" does not predict the attainment of developmental milestones or lifespan. Hence, in our host population, gut microbiome age largely reflects current, as opposed to past, social and environmental conditions, and does not predict the pace of host development or host mortality risk. We add to a growing understanding of how age is reflected in different host phenotypes and what forces modify biological age in primates.

evolutionary biology↗

bioRxiv2024

When is microbial strain sharing evidence for transmission?

In humans and other social animals, social partners have more similar microbiomes than expected by chance, suggesting that social contact transfers microorganisms. Yet, social microbiome transmission can be difficult to identify based on compositional data alone. To overcome this challenge, recent studies have used information about microbial strain sharing (i.e., the shared presence of highly similar microbial sequences) to infer transmission. However, the degree to which strain sharing is influenced by shared traits and environments among social partners, rather than transmission per se, is not well understood. Here, we first use a fecal microbiota transplant dataset to show that strain sharing can recapitulate true transmission networks under ideal settings when donor-recipient pairs are unambiguous and recipients are sampled shortly after transmission. In contrast, in gut metagenomes from a wild baboon population, we find that demographic and environmental factors can override signals of strain sharing among social partners. We conclude that strain-level analyses provide useful information about microbiome similarity, but other facets of study design, especially longitudinal sampling and careful consideration of host characteristics, are essential for inferring the underlying mechanisms.

microbiology↗

bioRxiv2024

Testing frameworks for early life effects: the developmental constraints and adaptive responsehypotheses do not explain key fertility outcomes in wild female baboons

In evolutionary ecology, two classes of explanations are frequently invoked to explain "early life effects" on adult outcomes. Developmental constraints (DC) explanations contend that costs of early adversity arise from limitations adversity places on optimal development. Adaptive response (AR) hypotheses propose that later life outcomes will be worse when early and adult environments are poorly "matched." Here, we use recently proposed mathematical definitions for these hypotheses and a quadratic-regression based approach to test the long-term consequences of variation in developmental environments on fertility in wild baboons. We evaluate whether low rainfall and/or dominance rank during development predict three female fertility measures in adulthood, and whether any observed relationships are consistent with DC and/or AR. Neither rainfall during development nor the difference between rainfall in development and adulthood predicted any fertility measures. Females who were low-ranking during development had an elevated risk of losing infants later in life, and greater change in rank between development and adulthood predicted greater risk of infant loss. However, both effects were statistically marginal and consistent with alternative explanations, including adult environmental quality effects. Consequently, our data do not provide compelling support for either of these common explanations for the evolution of early life effects.

evolutionary biology↗

bioRxiv2024

Infant spatial relationships with adult males in a wild primate: males as mitigators or magnifiers of intergenerational effects of early adversity?

Adult male mammals can provide infants with protection and enhance their access to resources. They can also pose a risk to infants, either directly through infanticide or other aggression, or indirectly by placing infants at increased risk of conspecific or heterospecific conflict. Both benefits and costs may be especially important for offspring born to mothers in poor condition. Here we present the most detailed analysis to date of the influence of adult non-human primate males on a wide range of infant behaviors, and a description of the predictors of individual infants proximity to adult males. We show that the number of adult males near an infant predicts many infant behavioral traits, including aspects of the mother-infant relationship, infant activity budgets, and the frequency of social interactions with non-mothers. Infant exposure to adult males is statistically significantly repeatable over time (R = 0.16). This repeatability is partially explained by whether the infants mother experienced early life adversity: offspring of high-adversity mothers spent time in close proximity to more males during the first months of life. Our results are consistent with the possibility that the effects of maternal early life adversity can be mitigated or magnified by relationships with adult males.

ecology↗

bioRxiv2024

A genome wide CRISPR/Cas9 screen identifies calreticulin as a selective repressor of ATF6

Activating transcription factor 6 (ATF6) is one of three endoplasmic reticulum (ER) transmembrane stress sensors that mediate the unfolded protein response (UPR). Despite its crucial role in long-term ER stress adaptation, regulation of ATF6 alpha () signalling remains poorly understood, possibly because its activation involves ER-to-Golgi and nuclear trafficking. Here, we generated an ATF6/IRE1 dual UPR reporter CHO-K1 cell line and performed an unbiased genome-wide CRISPR/Cas9 mutagenesis screen to systematically profile genetic factors that specifically contribute to ATF6 signalling in the presence and absence of ER stress. The screen identified both anticipated and new candidate genes that regulate ATF6 activation. Among these, calreticulin (CRT), a key ER luminal chaperone, selectively repressed ATF6 signalling: Cells lacking CRT constitutively activated a BiP::sfGFP ATF6-dependent reporter, had higher BiP levels and an increased rate of trafficking and processing of ATF6. Purified CRT interacted with the luminal domain of ATF6 in vitro and the two proteins co-immunoprecipitated from cell lysates. CRT depletion exposed a negative feedback loop implicating ATF6 in repressing IRE1 activity basally and overexpression of CRT reversed this repression. Our findings indicate that CRT, beyond its known role as a chaperone, also serves as an ER repressor of ATF6 to selectively regulate one arm of the UPR.

cell biology↗

bioRxiv2024

Taking identity-by-descent analysis into the wild: Estimating realized relatedness in free-ranging macaques

Biological relatedness is a key consideration in studies of behavior, population structure, and trait evolution. Except for parent-offspring dyads, pedigrees capture relatedness imperfectly. The number and length of DNA segments that are identical-by-descent (IBD) yield the most precise estimates of relatedness. Here, we leverage novel methods for estimating locus-specific IBD from low coverage whole genome resequencing data to demonstrate the feasibility and value of resolving fine-scaled gradients of relatedness in free-living animals. Using primarily 4-6x coverage data from a rhesus macaque (Macaca mulatta) population with available long-term pedigree data, we show that we can call the number and length of IBD segments across the genome with high accuracy even at 0.5x coverage. The resulting estimates demonstrate substantial variation in genetic relatedness within kin classes, leading to overlapping distributions between kin classes. They identify cryptic genetic relatives that are not represented in the pedigree and reveal elevated recombination rates in females relative to males, which allows us to discriminate maternal and paternal kin using genotype data alone. Our findings represent a breakthrough in the ability to understand the predictors and consequences of genetic relatedness in natural populations, contributing to our understanding of a fundamental component of population structure in the wild.

ecology↗

bioRxiv2023

A female-biased gene expression signature of dominance in cooperatively breeding meerkats

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 dominant status. To test this possibility, we investigated the association between social status and gene expression in the blood of wild meerkats (Suricata suricatta; n=113 unique individuals), including in response to lipopolysaccharide, Gardiquimod, 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 1,045 differentially expressed genes in females but none in males. Dominant females exhibit elevated activity in innate immune pathways and an exacerbated response to LPS challenge. In this respect, female meerkats resemble wild male baboons (for which similar data are available), where physical competition is also central to determining rank hierarchies and mating effort is high. However, they differ from female primates in which social status is nepotistically determined. Our results support the hypothesis that the gene regulatory signature of social status depends on the determinants and energetic costs of social dominance. They also support potential life history trade-offs between investment in reproduction versus somatic maintenance.

animal behavior and cognition↗

bioRxiv2023

DNA methylation signatures of early life adversity are exposure-dependent in wild baboons

The early life environment can profoundly shape the trajectory of an animals 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. Significance statementThe environment animals face when young can affect how they function throughout life. Long-lasting changes in DNA methylation--a chemical mark deposited on DNA that can affect gene activity--have been hypothesized to contribute to early life effects. But evidence for persistent, early environment-associated differences in DNA methylation is lacking in wild animals. Here, we show that early life adversity in wild baboons predicts DNA methylation levels in adulthood, especially for animals born in low resource environments and drought conditions. We also show that some of the changes we observe in DNA methylation have the capacity to influence gene activity levels. Together, our results support the idea that early experiences can become biologically embedded in the genomes of wild animals.

genomics↗

bioRxiv2023

DNA methylation-environment interactions in the human genome

Previously we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al., 2018). Here we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures--one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance.

genomics↗

bioRxiv2023

A randomized multiplex CRISPRi-Seq approach for the identification of critical combinations of genes

Identifying virulence-critical genes from pathogens is often limited by functional redundancy. To rapidly interrogate the contributions of combinations of genes to a biological outcome, we have developed a multiplex, randomized CRISPR interference sequencing (MuRCiS) approach. At its center is a new method for the randomized self-assembly of CRISPR arrays from synthetic oligonucleotide pairs. When paired with PacBio long-read sequencing, MuRCiS allowed for near-comprehensive interrogation of all pairwise combinations of a group of 44 Legionella pneumophila virulence genes encoding highly conserved transmembrane proteins for their role in pathogenesis. Both amoeba and human macrophages were challenged with L. pneumophila bearing the pooled CRISPR array libraries, leading to the identification of several new virulence-critical combinations of genes. lpg2888 and lpg3000 were particularly fascinating for their apparent redundant functions during L. pneumophila human macrophage infection, while lpg3000 alone was essential for L. pneumophila virulence in the amoeban host Acanthamoeba castellanii. Thus, MuRCiS provides a method for rapid genetic examination of even large groups of redundant genes, setting the stage for application of this technology to a variety of biological contexts and organisms.

genetics↗

bioRxiv2023

Early life drought predicts components of adult body size in wild female baboons

ObjectivesIn many taxa, adverse early-life environments are associated with reduced growth and smaller body size in adulthood. However, in wild primates, we know very little about whether, where, and to what degree trajectories are influenced by early adversity, or which types of early adversity matter most. Here, we use parallel-laser photogrammetry to assess inter-individual predictors of three measures of body size (leg length, forearm length, and shoulder-rump length) in a population of wild female baboons studied since birth. Materials and MethodsUsing >2,000 photogrammetric measurements of 127 females, we present a cross-sectional growth curve of wild female baboons (Papio cynocephalus) from juvenescence through adulthood. We then test whether females exposed to three important sources of early-life adversity - drought, maternal loss, or a cumulative measure of adversity - were smaller for their age than females who experienced less adversity. Using the animal model, we also test whether body size is heritable in this study population. ResultsProlonged early-life drought predicted shorter limbs but not shorter torsos (i.e., shoulder-rump lengths). Our other two measures of early-life adversity did not predict any variation in body size. Heritability estimates for body size measures were 36%-58%. Maternal effects accounted for 13%-22% of the variance in leg and forearm length, but no variance in torso length. DiscussionOur results suggest that baboon limbs, but not torsos, grow plastically in response to maternal effects and energetic early-life stress. Our results also reveal considerable heritability for all three body size measures in this study population.

ecology↗

bioRxiv2022

A generalizable epigenetic clock captures aging in two nonhuman primates.

Epigenetic clocks generated from DNA methylation array data provide important insights into biological aging, disease susceptibility, and mortality risk. However, these clocks cannot be applied to high-throughput, sequence-based datasets more commonly used to study nonhuman animals. Here, we built a generalizable epigenetic clock using genome-wide DNA methylation data from 493 free-ranging rhesus macaques. Using a sliding-window approach that maximizes generalizability across datasets and species, this model predicted age with high accuracy ({+/-} 1.42 years) in held-out test samples, as well as in two independent test sets: rhesus macaques from a captive population (n=43) and wild baboons in Kenya (n=271). Our model can also be used to generate insight into the factors hypothesized to alter epigenetic aging, including social status and exposure to traumatic events. Our results thus provide a flexible tool for predicting age in other populations and species and illustrate how connecting behavioral data with the epigenetic clock can uncover social influences on biological age.

evolutionary biology↗

bioRxiv2022

Heritable and sex-specific variation in the development of social behavior in a wild primate

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 development of social behavior 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 mother-offspring grooming reciprocity develops during the juvenile period. We found that grooming development differs between the sexes: female infants groom at an earlier age and reach reciprocity in grooming with their mother earlier than males. Using the quantitative genetic animal model, we also found that age at first grooming behavior for both sexes is weakly heritable (h2 = 4.3%). These results show that sex differences in grooming emerge at a young age; that strong, reciprocal 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.

animal behavior and cognition↗

bioRxiv2022

Early life adversity and adult social relationships have independent effects on survival in a wild animal model of aging

Does social isolation in adulthood predict survival because socially isolated individuals are already unhealthy due to adversity earlier in life (health selection)? Or do adult social environments directly cause poor health and increased mortality risk ("social causation")? These alternative hypotheses are difficult to disentangle in humans because prospective data on survival and the environment for both early life and adulthood are rarely available. Using data from the baboon population of Amboseli, Kenya, a model for human behavior and aging, we show that early adversity and adult social isolation contribute independently to reduced adult survival, in support of both health selection and social causation. Further, strong social bonds and high social status can buffer some negative effects of early adversity on survival. These results support a growing change in perspective, away from "either-or" hypotheses and towards a multi-causal perspective that points to multiple opportunities to mitigate the effects of social adversity. TeaserEarly life environments and adult social bonds have strong, but largely independent effects on survival in wild baboons.

animal behavior and cognition↗

bioRxiv2022

Ecology and age, but not genetic ancestry, predict fetal loss in a wild baboon hybrid zone

ObjectivesPregnancy failure and fetal loss represent a major fitness cost for any mammal, particularly those with slow life histories such as primates. Here, we quantified the risk of fetal loss in wild hybrid baboons, including genetic, ecological, and demographic sources of variance. We were particularly interested in testing the hypothesis that hybridization imposes a cost by increasing fetal loss rates. Such an effect would help explain how baboons maintain taxonomic integrity despite interspecific gene flow. Materials and MethodsWe analyzed pregnancy outcomes for 1,020 pregnancies observed over 46 years in a natural yellow baboon-anubis baboon hybrid zone. Fetal losses and live births were scored based on near-daily records of female reproductive state and the appearance of live neonates. We modeled the probability of fetal loss as a function of a females genetic ancestry (based on whole-genome resequencing data), age, number of previous fetal losses, dominance rank, group size, climate, and habitat quality using binomial mixed effects models. ResultsFemale genetic ancestry did not predict the likelihood of fetal loss. Instead, the risk of fetal loss is elevated for very young and very old females. Fetal loss is most robustly predicted by ecological factors, including poor habitat quality and extreme heat during pregnancy. DiscussionOur results suggest that gene flow between yellow baboons and anubis baboons is not impeded by an increased risk of fetal loss for hybrid females. Instead, ecological conditions and female age are key determinants of this component of female reproductive success. Research HighlightsO_LIFemale baboons do not experience fetal loss as a cost of hybridization. C_LIO_LIHeat stress, poor habitat quality, and young and old age elevate the risk of fetal loss, emphasizing roles for ecology and life history in determining birth outcomes. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/505836v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@74dd64org.highwire.dtl.DTLVardef@7301b5org.highwire.dtl.DTLVardef@751e9dorg.highwire.dtl.DTLVardef@12ce924_HPS_FORMAT_FIGEXP M_FIG Neonate drawings by Emily Nonnamaker. C_FIG

evolutionary biology↗

bioRxiv2022

Genetic variance and indirect genetic effects for affiliative social behavior in a wild primate

Affiliative social behaviors are linked to fitness components in multiple species. However, the role of genetic variance in shaping affiliative social behaviors remains largely unknown, limiting our understanding of how these behaviors can respond to natural selection. Here, we employed the animal model to estimate both environmental and genetic sources of variance and covariance in grooming behavior in the well-studied Amboseli baboon population in Kenya. We found that grooming given, grooming received, and total grooming all are similarly heritable (h2=0.22, h2=0.16, and h2=0.26 respectively), and that rank and the presence of kin contribute to environmental variance. We detected small but measurable indirect genetic effects of partner identity on the amount of grooming given within dyadic grooming partnerships. The genetic correlation between grooming given and grooming received was exceptionally strong and positive (R=0.94 {+/-} 0.12), and the indirect and direct genetic effects for grooming given were also strongly positively correlated (R=0.86 {+/-} 0.06). Our results provide insight into the evolvability of affiliative behavior in wild animals, including the possibility for correlations between direct and indirect genetic effects to accelerate the response to selection. As such they provide novel information about the genetic architecture of social behavior in nature, with important implications for the evolution of cooperation and reciprocity.

evolutionary biology↗

bioRxiv2022

Five decades of data yield no support for adaptive biasing of offspring sex ratio in wild baboons (Papio cynocephalus)

Over 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, and 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 well-studied 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 = 1372 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 towards the dispersing sex, nor it is 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.

evolutionary biology↗

bioRxiv2022

Universal gut microbial relationships in the gut microbiome of wild baboons

Ecological relationships between bacteria mediate the services that gut microbiomes provide to their hosts. Knowing the overall direction and strength of these relationships within hosts, and their generalizability across hosts, is essential to learn how microbial ecology scales up to affect microbiome assembly, dynamics, and host health. Here we gain insight into these patterns by inferring thousands of correlations in bacterial abundance between pairs of gut microbiome taxa from extensive time series data (5,534 microbiome profiles from 56 wild baboon hosts over a 13-year period). We model these time series using a statistically robust, multinomial logistic-normal modeling framework and test the degree to which bacterial abundance correlations are consistent across hosts (i.e., "universal") or individualized to each host. We also compare these patterns to two publicly available human data sets. We find that baboon gut microbial relationships are largely universal: correlation patterns within each baboon host reflect a mixture of idiosyncratic and shared patterns, but the shared pattern dominates by almost 2-fold. Surprisingly, the strongest and most consistently correlated bacterial pairs across hosts were overwhelmingly positively correlated and typically belonged to the same family--a 3-fold enrichment compared to pairs drawn from the data set as a whole. The bias towards universal, positive bacterial correlations was also apparent in monthly samples from human infants, and bacterial families that had universal relationships in baboons also tended to be universal in human infants. Together, our results advance our understanding of the relationships that shape gut microbial ecosystems, with implications for microbiome personalization, community assembly and stability, and the feasibility of microbiome interventions to improve host health.

ecology↗