Krisen Hopperstad (North Carolina State University)
Quantil Melendez (North Carolina Central University)
Temini Ajayi (Duke University)
Nicholas Brazeau (University of North Carolina, Chapel Hill)
Katie Barrett (University of North Carolina, Chapel Hill)
Jeremy Ash (North Carolina State University)
Jordan Anderson (Duke University)
The Effects of Early Adversity on T-cell Receptor Diversity in Wild Baboons
The experience of adversity during early life can powerfully shape an organism’s life course. For example, in humans, low early life socioeconomic status (SES) predicts increased rates of heart disease, even in individuals who later attain high SES. Early life adversity also predicts longevity in other animals, suggesting that some responses to early life insults are rooted in our evolutionary history. The “extrinsic mortality cue” hypothesis proposes that early life adversity serves as a cue for a harsh external environment, which predicts a shorter life and selects for reduced investment in specific immune defenses (e.g. those that defend against specific pathogen strains). I propose to test this hypothesis using a recently developed genomic method for characterizing T-cell receptor (TCR) diversity, an important component of recognizing and responding to individual pathogens. To do so, I will take advantage of a long-term study population of wild baboons in which both genomic data and extensive information on early life experiences are available and early adversity has been shown to predict higher mortality rates. I predict that early adversity will be linked to reduced TCR diversity, reflecting a reduction in specific immune defenses. By focusing on a primate that is closely related to humans, my results will further our understanding of the evolutionary and biological mechanisms linking early adversity to later life health.
Using Molecular Modeling and Machine Learning to Study Dynamic ERK-ligand Interactions
Kinase inhibitors represent the new generation of highly promising bioactive molecules for combating various types of cancer. With compounds already on the market and even more currently in clinical trials, the research community is on the path to developing a large collection of kinase-mediating drugs and chemical probes. However, drug resistance is the “Achilles heel” of kinases inhibitors. As members of signaling pathways that are critical to an array of cellular processes, kinase inhibition gives rise to strong selection pressure for drug resistance conferring mutations in patients. In this project, we focus on studying the ERK1 and ERK2 kinase, especially the dynamic interactions small molecule inhibitors undergo within the ERK binding site. To do so, we will rely on our novel modeling approach that integrates several state-of-the-art cheminformatics methods (molecular docking, molecular dynamics, and machine learning). We posit this analysis will deepen the understanding of why certain inhibitors interact differently with these two isoforms. This will help identify residues where the selection pressure driving drug resistance is different, and inform chemists of strategies to design new ERK inhibitors with greater efficacy. At last, our analysis of ERK-ligand dynamic interactions that confer specificity to ERK1, ERK2, or both will aide in the development of new chemical probes capable of more selective
The Developmental Roles of Leptin and Ghrelin: Mammalian Comparisons
Human metabolism is programmed during the gestation and the first two years of postnatal life. The reasons for this are rooted in our evolutionary history. This metabolic programming influences our risk of obesity and other chronic diseases, and the hormones leptin and ghrelin may play an important role both in our early development and later disease risk. Our understanding of the roles of leptin and ghrelin in human appetites and disease risk are constantly improving, but there is still a need to understand how our evolutionary history has influenced those roles. This project will compare studies in rodents and non-human primates with human studies in order to explore how human evolution and the roles of leptin and ghrelin in human development may be linked.
The Evolutionary Origins and Global Dispersal of Plasmodium vivax
Malaria in humans is caused by several different parasites. One in particular, Plasmodium vivax, is believed to have evolved in African non-human apes prior to the parasite making the zoonotic leap and infecting their closest cousin, us! Humans then transported the parasite to Asia and Latin America, where today the disease afflicts millions. Although originating in central Africa, vivax malaria has been considered absent in these areas due to the high prevalence of a mutation that confers the Duffy-negative phenotype, offering protection against P. vivax infection. However, recent evidence has begun to ove rturn this view, as P. vivax has been found in several African countries among individuals with the supposed protective mutation. Through a large, representative population study of the Democratic Republic of the Congo, our group h as identified several P. vivax cases infecting Duffy-negative (“protected”) individuals. I am studying these new cases to determine what has caused their reemergence and their evolutionary origins by comparing them to the potentially ancestral African non-human ape sequences. Determining the evolutionary origins of P. vivax will help us to better understand drug resistance and to devise better malaria control and elimination interventions.
Investigating a modern era role for IRGM in chronic obstructive pulmonary disease (COPD)
Evolutionary mismatch – the idea that populations living in rapidly changing environments differ radically from their ancestral environments – has been proposed to explain declining infectious disease trends and concomitant rising non-infectious chronic disease trends over time. Genetic variants formerly evolutionarily selected for or against by infectious pressures may in the modern era modify risk for non-infectious chronic diseases such as Crohn’s disease and chronic obstructive pulmonary disease (COPD), potentially through the same mechanisms involved in host defense. In this project, we use a genetic association study to explore a potential modern era role in COPD for the gene Immune Related GTPase Family M (IRGM). IRGM encodes a protein that plays a key role in autophagy, a process that degrades pathogens that invade host cells as well as damaged components of the host cell itself.
Phylogenic studies suggest that IRGM was pseudogenized ~40 million years ago and recently “resurrected” with an alu retrotransposon insertion. IRGM is involved in autophagy-dependent suppression of M. tuberculosis in human cells and IRGM polymorphisms have been firmly linked to increased tuberculosis (TB) risk. Defective autophagy has also been implicated in the pathogenesis of chronic diseases including Crohn’s disease (CD) and COPD. IRGM single nucleotide polymorphisms (SNPs) have been associated with increased risk for CD,7 but have not to our knowledge been examined in relation to COPD. We hypothesize that minor (TB/CD-associated) IRGM alleles at rs10065172 and rs13361189 will associate with increased risk for COPD, as well with worsened disease severity (cough, dyspnea) in patients with COPD.
Epigenetic regulation of PCSK9 and the onset of metabolic diseases in diverse ethnic groups
A well-known disease affecting ~ 74 million Americans is high cholesterol, as of March 2015 according to CDC reports. Of those, over 64% are African-American adults . The large percentage of citizens affected by hypercholesterolemia, that leads to the most deadly disease called atherosclerosis, creates the need for a deep investigation to determine easier and faster ways to deal with the problem. To understand why a specific group of patients are affected by a serious disease, we will investigate their DNA and identify differences via DNA sequence analysis when compared to the DNA of other common patient groups. More specifically, DNA differences between AA and CA patients in the NC Triangle area will be analyzed. Identifying these key differences in the DNA could help us discover personalized ways to prevent and treat specific diseases.
A population genetic and genomic approach to estimate the evolutionary potential of Aedes aegypti
The yellow fever mosquito, Aedes aegypti, is a vector of devastating human diseases. This mosquito can transmit dengue, also known as breakbone fever, and Zika, which can cause critical birth defects in infants. Understanding how this mosquito species is currently evolving can help us more effectively reduce mosquito populations and subsequent disease spread. I will use molecular techniques to investigate how yellow fever mosquito populations in the U.S. are related to each other. This tells us how genes are flowing across landscapes and if some populations are potentially evolving differently than others. These differences may have implications for disease transmission, pesticide resistance, and how mosquitoes can adapt to new environments. Further, I will also use environmental factors in analyses to look for potential drivers of genetic patterns. Finally, I will combine my data with a global dataset, and identify potential corridors and barriers to mosquito movement into and out of the U.S.
Achsah Dorsey (University of North Carolina, Chapel Hill)
An exploration of iron deficiency and morbidity in Peru
While iron is essential for many biological processes in living organisms, iron deficiency is common worldwide. Explanations and solutions for the high rates of iron deficiency remain elusive. The relationship between iron levels and health is not simple; too much iron and too little iron cause negative health outcomes with lasting effects but there is little consensus on what constitutes as too high or too low. An evolutionary perspective may help address this problem. The Optimal Iron Hypothesis states that an individual’s best iron status is related to the environment that they live in. When individuals live in environments with high rates of disease, lower levels of iron will protect them from infection while higher levels of iron will be beneficial to individuals living in an environment with low rates of disease. This project will investigate iron deficiency and its relationship to health in families, specifically grandmothers, mothers, and children in Lima, Peru, an area that suffers from severe rates of iron deficiency.
Kayleigh O’Keeffe (University of North Carolina-Chapel Hill)
Joshua K. Hughey (North Carolina Central University)
Matthew T. Biegler (Duke University School of Medicine)
Clarifying Promoter and Cell-Type Homologies Across Avian and Mammalian Taxa
Our project is aimed towards harnessing genetic tools used in mice for studying vocal learning and human speech disorders in songbirds. Songbirds are unparalleled models for understanding the neurobiology of human language acquisition, maintenance, and production. Songbirds, more so than mice and non-human primates, share similar anatomical and genetic properties with humans to execute this complex behavior. However, no current techniques exist in birds to allow for a robust understanding of vocal learning behavior at the molecular-cellular level. By exploiting the nature of cell type conservation and convergent evolution across species, we will assess well-characterized, mammalian promoters in the avian brain to isolate the functional properties of specific cell populations. With the right promoters, it will be possible to dissect and manipulate the brain circuits responsible for vocal learning in birds, using a variety of genetic tools. We can then extrapolate mechanisms to human brain regions responsible for speech and language, and provide insight into how genes are similarly regulated in distantly related species.
Yersinia pseudotuberculosis to Yersinia pestis – Evolution of the deadliest pathogen in history
, as the causative agent for plague, is responsible for over 250 million deaths throughout human history. Of plague’s three manifestations, bubonic, pneumonic, and septicemic, the pneumonic iteration has the highest rate of mortality (~99%), and is the only one spread easily from human to human, via respiratory droplets. Due to its greater virulence and relative ease of transmission, pneumonic plague has remained a persistent threat, particularly in less developed nations. Pneumonic plague’s increased virulence may be attributed to its unique ability to remain undetected in the lungs of infected persons for approximately 36 hours post infection. Termed the pre-inflammatory phase, this time window gives the pathogen time to achieve a critical mass, giving it a foothold in overcoming host defenses. Recent research by lab and others indicates that this “immune inactivation” that characterizes the pre-inflammatory phase may be attributed, at least in part, to Y. pestis
‘s ability to induce expressions of IL-1RA, a recepter antagonist for IL-1ß, a pro-inflammatory cytokine that plays a crucial role in mitigating acute bacterial infection.
Y. pestis evolved from a comparatively harmless soil bacterium, Yersinia pseudotuberculosis, approximately 15,000-22,000 years ago. In tracing the evolutionary lineage from Y. pseudotuberculosis to Y. pestis, the question my research asks is whether Y. pestis‘s ability to induce IL-1RA expression in immune cells is inherited from its evolutionary forebear, or if it is unique to the organism. The hope is that this understanding will provide insight into exactly when and how Y. pestis acquired this lethal adaptation.
How Microbial Interactions Affect Infection & Gene Expression of a Plant Pathogen
Caroline Amoroso (Duke University)
Kendra Smyth (Duke University)
Microorganisms, like bacteria and fungi, are found in many host organisms like humans, animals, and plants. These microorganisms can have different effects on their host and on each other. In disease ecology and evolution, there is rising interest in how interactions among microbial species influence disease… how do they affect pathogen transmission and infections, how do they affect genetic patterns within population of pathogens. These interactions have the potential to profoundly influence both host and pathogen populations. Plants and their pathogens are easily-manipulated systems that would facilitate studies of these microbial interactions that could clarify their effects on disease in general. This study will examine the influence of microbial interactions on pathogen infection and genetic patterns following transmission. I will address these questions experimentally by studying responses of the focal plant pathogen, Rhizoctonia solani
, to microbial interactions within its grass host, tall fescue (Schedonorus arundinaceus
). I will focus specifically on its interactions with Epichloë coenophiala
, a fungal species that lives within plants without causing disease, and Puccinia coronata
, another fungal pathogen.
Cody S. Nelson (Duke University School of Medicine)
Cytomegalovirus (CMV) Evolution to Evade Vaccine-Elicited Antibody Responses
The CDC estimates that a child is born every hour in the United States with permanent neurologic disability resulting from congenital cytomegalovirus (CMV) infection. Indeed, CMV is the most common cause of infection in newborn infants worldwide, causing deafness and neurologic disease in afflicted children. CMV infection is passed from mother to infant in the womb. Our laboratory is working to develop a vaccine to stop women from becoming infected with CMV while pregnant, and thus to prevent them from subsequently passing that infection on to their unborn child. Previous CMV vaccines have demonstrated only modest success in clinical trials. We suggest that vaccine failure occurs because of CMV evolution in response to the immune response mounted against the virus in vaccinated individuals. Therefore, in the this project, we will attempt to identify changes in the viral structure that occur following vaccination. These changes indicate locations of viral mutation, which allow the virus to evade the host immune system. Identification of these locations of virus evolution will enable the rational design of a vaccine such that the virus is not able to mutate to avoid the vaccine-induced immune response.
Reversing Evolutionary Mismatch Using Biome Enrichment: The Next Step
The concept of ‘evolutionary mismatch’ is a fundamental principle of evolutionary medicine and explains how recent changes in Western culture have led to increases in a variety of inflammation-associated diseases. These diseases include allergies, autoimmune conditions, and certain neuropsychiatric disorders including migraine headaches, anxiety, and depression. Foremost among the mismatches that lead to these diseases is a loss of biodiversity from the ecosystem of the human body. Originally attributed to hygiene, this mismatch involves the disappearance of symbiotic organisms, most notably the virtual absence of symbiotic worms, called helminths, which previously inhabited our bodies. The work proposed herein is the next critical step for testing the hypothesis that enriching the ecosystem of the human body with helminths, essentially reversing a key evolutionary mismatch, will alleviate inflammatory disease. Findings from numerous experimental animal studies and a few studies in humans support the reversibility of this mismatch. Nevertheless, helminthic therapy remains inaccessible to the public at large; the studies that would bring this innovative evolution-based medical treatment into mainstream medicine are not currently in progress due to a lack of FDA-approved helminths. Thus, the goal of this project is the develop a protocol that will meet FDA guidelines for producing helminths for human use. I expect that this protocol will be widely used to produce helminths for enriching the ecosystem of the human body and alleviating a range of inflammatory diseases.
Mercy Akinyi (Duke University)
Co-infections in wild primate populations
My research aims at quantifying disease prevalence and identifying the sources of disease variance among natural populations of baboons. Research on the ecology, behavior, and genetics of nonhuman primates significantly contributes to understanding the evolution of humans because of the comparative perspective these studies provide on humans traits (Jurmain et al. 2012). Studies of disease variance in nonhuman primates are also important; by increasing our understanding of disease dynamics and how diseases affect hosts, we can gain insight into the ways in which human ancestors were affected by disease during evolution, and eventually understand how humans diverged from nonhuman primate in our response to disease.
Are humans exceptionally parasitized?
Humans have a lot of parasites – 1,415 to be exact. But is that number more than you would expect given the vast human population that stretches to the ends of the globe? We do live in very high densities and in very close contact with domestic animals, which are the source of many of our diseases. Or do we have fewer parasites than you would expect? We have medicine and other cultural practices that might shield us from parasites. This project aims to use statistical methods to compare the number of human parasites to the parasites of our closest relatives, wild primates, in order to see how we measure up. How many parasites should humans have if we were “just another primate,” and how does that prediction compare to reality? (website
Yuantong Ding (Duke University)
Cancer Evolutionary model shedding light on clinical tumor sampling strategies
Cancer is a major cause of death throughout the world and, despite an extraordinary amount of effort and money spent, the eradication or control of advanced disease has not been achieved. Recently, researchers have started to view cancer as an evolutionary process, and this has profound clinical implications for neoplastic progression, cancer prevention and cancer therapy. Several evolutionary models have been proposed to model the evolution of cancer. However, less effort has focused on how to apply these models to clinical practice. In this project, I will use an evolutionary model to guide the practical sampling strategies of tumor, the first step to bridge the gap between a theoretical cancer model and clinical practice.
Amanda Lea (Duke University)
Social effects on the baboon epigenome: critical periods or lifelong plasticity?
Humans and other primates live in complex social environments. Within these societies, some individuals frequently engage in social interactions, while others do not; similarly, only some individuals achieve high social status. Research across primate species suggests that this variation in social experiences can have profound effects on physiology, reproduction, and survival; yet, despite strong evidence that adverse social conditions (e.g., social isolation or low social status) negatively affect health, we do not understand how they do so. To address this gap, my project tests the hypothesis that social conditions influence health-related traits by altering the way genes are regulated. Specifically, it asks whether low social status and/or social isolation (in both early life and adulthood) lead to changes in DNA methylation, an environmentally sensitive modifier of gene regulation. To do so, I will combine behavioral data from wild female baboons in the Amboseli ecosystem of Kenya with measures of genome-wide DNA methylation levels. The resulting analyses will shed new light on (i) which genes and biological pathways are affected by social challenges and (ii) when in an individual’s lifetime social experiences matter most. Together, these results will inform our understanding of how primate sociality shapes our epigenomes, including how we might best focus intervention efforts to offset the consequences of social adversity. (website
Yuxiang Liu (University of North Carolina-Chapel Hill)
Parallel evolution of gene molecular mechanisms underlying evolution of hippocampal function
The hippocampus is a brain region that plays an essential role in human memory and has been linked to mental disorders such as Alzheimer’s and depression. Homologs of the human hippocampus have been proposed for all vertebrate groups and, within each group, some species have evolved specializations of the hippocampus that enable advanced learning abilities. I hypothesize that the evolution of hippocampal function within different vertebrate groups depends on the evolution of the same gene molecular mechanism. In order to address my hypothesis, I will draw upon expertise from three labs at two universities to generate computational programs and use them to compare hippocampus and whole brain gene expression profiles among 14 vertebrates, across 10 families and three classes. The results will further verify the homology of vertebrate hippocampus and test whether parallel evolution really occurred across vertebrate hippocampal specializations at the scale of gene-regulatory level. Comparing evolution of hippocampal gene expression profiles across vertebrates could enable us to infer the fundamental gene-regulation rules underlying the hippocampal specializations, which could, in turn, aid our understanding of human hippocampal specialization and its pathology underlying mental diseases.
Sasha Makohon-Moore (Duke University)
Co-infections in wild primate populations
Understanding the underpinnings of uniquely human traits is critical to understanding our evolutionary origins as well as our disease risks. We, as humans, have a much higher risk of many diseases compared with other primates. The use of induced pluripotent stem cells from humans and chimpanzees provides samples and experimental controls that were previously unavailable. Utilizing genome-wide epigenetic profiling, gene expression measurements and regulatory region sequencing, we can identify genes that have changed expression due to genetic modifications, epigenetic modifications, or a combination of both. This will allow us to identify changes that may have had profound impacts on our evolutionary history as well as our susceptibility to disease. (website
Jennifer Niemuth (North Carolina State University)
An Evolutionary Model of Physiologic Adaptations to Hypothermia and Reperfusion
This study will evaluate whether understanding the physiology of sea turtles can provide insight into the evolution of how animals and humans respond to sudden exposure to cold environmental conditions. We will compare results of metabolomic data already gathered from sea turtles naturally exposed suddenly to cold ocean conditions in the wild, and with normal unaffected individuals, to findings in the scientific literature on the physiologic responses of humans and other animals to exposure to cold and rewarming. We hope to identify metabolic changes that are either highly conserved or extremely divergent across the broad evolutionary history of the ancient sea turtles and mammals. Such findings could help us understand the best ways to reduce the harm of exposure to sudden extreme cold and recovery from such exposure. (website
Jaymin Patel (University of North Carolina-Chapel Hill)
Understanding the Genetic Diversity and Identification of Pathogenic Variants of Malaria in Pregnancy
Globally, malaria in pregnancy (MiP) remains a significant public health problem. Each year, placental malaria imperils millions of pregnant women and is associated with several adverse birth outcomes, largely owing to Plasmodium falciparum sequestration in the placenta. Currently, efforts are underway to develop a vaccine against MiP by targeting a protein (VAR2CSA) that is critical in this sequestration process. However, there is a lot of genetic diversity in this gene probably as a result of balancing evolutionary selection by the host immune system. To this end, investigations of the causes and consequences of genetic diversity of var2csa can help on-going vaccine development efforts. We will investigate the genetic diversity of var2csa using next-generation deep- sequencing technology, targeting a large 1.5 kb fragment of var2csa in cohorts of Beninese and Malawian pregnant women. We will compare alpha (within group) and beta (between group) diversity among women with and without adverse birth outcomes and look for signatures of balancing selection. Further, we will identify pathogenic variants by estimating their relative effect on fetal growth. This study will integrate new molecular technologies and analytic approaches; the results will help elucidate the role of VAR2CSA in the pathogenesis of MiP and directly inform on- going vaccine development efforts.
Laura Sligar (University of North Carolina-Chapel Hill)
Evolution of mitochondrial heteroplasmy in Drosophila
Dustin Wcisel (North Carolina State University)
Evolutionary medicine strives to understand why human disorders occur. My research will use existing fruit fly genomic data to analyze mitochondrial DNA in Drosophila fruit flies. Mitochondria are small organelles that exist within the cells of our bodies, and they produce the energy we use for life: everything from running a marathon to digesting lunch. Mitochondria are different from other types of organelles because each mitochondria contains its own DNA genome. Therefore, different parts of your body could have mitochondria with different DNA: a phenomenon called heteroplasmy. This is important to understand because if two patients come to the doctor with mitochondrial disorder symptoms in different organs, they may have the same mitochondrial DNA mutation but simply have broken mitochondria in different cells. The goal of my research is to understand how heteroplasmy has evolved and how it varies within and between populations of Drosophila. (website
Transcriptional response of immunoglobulin domain-containing innate immune receptors
Differences in genomic sequence between and within species are often manifested at chromosomal regions that encode gene families which function in the recognition of pathogens. The zebrafish has proven to be a highly useful model for the study of human disease; however, differences between the number and combinations of immune related genes between each individual’s genome are commonly disregarded. The goal of this project is to use these differences to identify conserved and diversified immune genes in the zebrafish genome. A vast wealth of information on zebrafish genes and their expression differences is available via public databases, but because of the complexity of comparing large datasets, little effort has gone into describing their differences. In this project, we will select and analyze numerous publicly available zebrafish gene expression studies with a focus on cataloging highly conserved and diverse immune receptors that respond to infection. By combining datasets, we will be able to differentiate conserved responses from biased responses observed on the single experiment level. Through this project, a novel publicly available database will be created that links zebrafish gene sequence to functional response as measured by infection-induced changes in gene expression. Furthering our understanding of immune genes in zebrafish will facilitate our ability to test hypotheses regarding the evolutionary pressures and processes that shape immune gene diversity within any species, including human.
Qinglong Zeng (Duke University)
Ecological and Evolutionary Models of Short Term Microbiome Dynamics
Microbial communities associated with human are implicated in the day-to- day functioning of their hosts. However, we do not yet know how these host-microbiome associations evolve. In this project, I will develop a computational framework for modelling the short term evolution of microbiomes. I expect these models to provide a framework for studying the dynamics of microbiome assembly. In doing so, we hope to show how patterns of microbiome composition are related to processes that may influence health outcomes and how these processes may be ameliorated. (website
Kelly Houck (University of North Carolina, Chapel Hill)
Life History Theory (LHT) models the evolutionary tradeoffs in allocating energy between the costs of maintaining immunocompetence and linear growth. Studies have examined these tradeoffs during childhood in high pathogenic environments with low nutritional resources (McDade et al. 2008). However, as developing countries transition to high-fat, low-fiber diets and are continually plagued with heavy infectious disease burdens, a new paradoxical relationship between stunting and obesity has emerged (Frisancho 2003). Children now exhibit simultaneous signs of both under-and over-nutrition. In this dual burden environment, the energetic costs of pathogenic and obesogenic immunocompetence must be considered for their novel evolutionary implications. Due to the role of intestinal commensal bacteria in the development and function of human metabolism and immune function, study of the gut microbiome provides an innovative pathway of exploring synergetic effects of nutritional and pathogenic environments. This project integrates immune function biomarkers, fecal microbiota, anthropometric and survey data I collected and analyzed from 180 children ages two to ten years for my dissertation on intestinal health in Galapagos, Ecuador. This project develops and tests a new application of childhood LHT modified for the dual burden environment that examines the energetic costs of pathogenic- and dietary-induced gut immunodysregulation on child growth restrictions and adiposity gains after six months. Synthesizing concepts from evolutionary medicine, the dual burden framework and the study of gut microbiome, this project will provide original insight into the impacts of gut immune function on childhood growth and obesity relevant to the Galapagos, Ecuador and other populations undergoing transition.