Gregory A. Wray, Biology - US grants

0073278
Wray & Abouheif

One of the great challenges to biology is understanding how genes are deployed during an organism's development to produce the astonishing variety of creatures on earth. A variety of biological phenomena can, if studied in detail, help us gain a better understanding of these genetic blueprints. One such phenomenon, morphological polymorphism, is widespread in nature, and has appeared independently in many different types of organisms. In ants, for example, depending on the environmental conditions an individual ant embryo experiences, it will either develop into a reproductive caste (male or a queen) with wings or develop into a sterile caste (worker or soldier) without wings. Where, when. and which genes are turned off or on during development to produce antomical differenes among siblings?

This study examines the genes involved in this morphological polymorphism in ants by integrating data from multiple biological levels and from multiple species. It will characterize the expression of several genes involved in wing development, cell growth, and hormonal regulation. The goals are to determine: (1) whether the genes involved in wing development are conserved in winged reproductive ants; (2) how the patterning, growth, and differentiation of wings in wingless non-reproductive ants is interrupted; and (3) whether the process of interruption in wingless non-reproductive ants has evolved. Understanding the genetic basis of this phenomenon will provide insights into the relationship between an organism's genes, the environment, and anatomy.

Dissertation Research: Evolution and Development of Left-Right Asymmetry in Echinoderms

Gregory Wray and Margaret Pizer

One of the most active areas of research in evolutionary biology today concerns the origin of the unique morphological features seen in the different animal phyla. The members of the phylum Echinodermata (sea urchins, sea stars, sea cucumbers and their relatives) exhibit a number of features whose evolutionary origin has been the topic of extensive speculation among biologists for over a century. Perhaps the most striking of these characteristics involve echinoderm body symmetry. Echinoderm larvae are bilaterally symmetrical, while the adults show five-fold radial symmetry. The transition between these very different body symmetries occurs when adult structures develop on the left side of the larva, producing a left-right asymmetrical intermediate stage. Several scenarios have been proposed to explain the developmental transitions from bilateral symmetry to left-right asymmetry to pentaradial symmetry that occur during the echinoderm life cycle, but little testing of the predictions of these theories has been done using developmental data.

This project involves a systematic study of the development of adult structures in echinoderms. The goals of this study are to investigate 1) the evolution of left-right asymmetry within echinoderms and 2) the developmental mechanism of left-right asymmetry in echinoderms and the evolutionary origin of this mechanism. To achieve these goals a variety of embryological techniques will be used, and results will be compared between different groups of echinoderms and between echinoderms and their relatives. A detailed study of the evolution and development of left-right asymmetry will result in a better understanding of the origin and evolution of echinoderm morphology. In addition, this study will provide insights into the evolution and development of left-right asymmetry in other phyla of animals and the evolution of metamorphosis in other marine invertebrates.

The sea urchin gene Endo16 will be used to examine molecular evolution in DNA sequences responsible for gene regulation, called promoters. The functional consequences of the observed evolutionary changes will be tested among several closely related species. These issues will be addressed using DNA sequence comparisons, gene expression localizations, and experimental tests of promoter function. The ability to perform analyses of promoter function in any sea urchin species will provide a detailed picture of how promoter sequence variation arises within populations and accumulates to create more extensive species-level differences in promoter sequence, organization, and regulatory mechanisms.

The widespread conservation of protein products across the animal kingdom and the evolutionary correlation of changes in gene expression with changes in morphology suggest that change in gene regulatory sequences is an important basis for phenotypic evolution. Previous studies of molecular evolution in gene regulatory sequences have been limited by incomplete knowledge of the structure and function of the promoter region and the inability to perform the necessary functional experiments in more than one species. This project will provide one of the first detailed pictures of genetic variation in promoter sequences, furthering our understanding of the genetic differences underlying phenotypic evolution between species.

The genomes of all organisms contain DNA sequences called promoters that control gene expression. The goal of this project is to understand how these regulatory sequences vary genetically within populations. We will survey variation in regulatory sequences from several genes in the purple sea urchin, an animal model system that is particularly favorable for such analyses. We will then test the function of variant sequences for their ability to bind specific proteins that regulate gene expression. Finally, we will screen for promoter sequence variants that alter the timing of gene expression.

Studies of human genetics have revealed extensive variation in promoter sequences and in their regulatory function. Our meta-analysis of this data, published earlier this year, was the first study to provide direct evidence that differences in regulatory sequences comprise a substantial fraction of the total functional genetic variation within a population. The current project will extend these studies in an organism where we can analyze an unbiased sample of genetic variation in regulatory sequences that has a functional impact. The results of these analyses will advance understanding of the population genetics of a portion of the genome that is functionally critical but understudied.

Heritable variation in gene expression is raw material for the evolution of development, yet almost nothing is known about the distribution of such variation in nature. This proposal outlines a plan to estimate the structure of heritable variation in developmental gene expression in a natural population of purple sea urchins, a model system for developmental biology. Through the use of quantitative genetic techniques, the pattern of heritable variation in the abundance of gene products will be estimated for 120 genes at each of four stages in embryonic development. The resulting estimates will help answer several outstanding questions: How much heritable variation exists for early developmental gene expression? What is the timecourse of genetic variation and covariation? How do maternal effects influence variation in gene expression? Finally, how do networks of regulatory gene interactions influence the architecture of developmental variation, and hence the possibilities for developmental evolution?

This research will contribute to the synthesis of evolutionary and developmental biology, validate a new approach to studying heritable trait variation, and introduce quantitative genetics into sea urchin research. In addition, a deeper understanding of the patterns of genetic correlations among developmental gene expression traits could have applications to animal breeding and medical association studies.

Summary

A workshop is proposed to discuss the scope and goals of developmental physiology, and to identify the scientific opportunities for investment in this emerging field at the interface of developmental biology and physiology. This workshop will be held on November 15 and 16, 2004, at the Holiday Inn, Arlington ,VA.

Intellectual Merit
Developmental biologists have, for many years, focused their efforts in understanding embryonic development by selecting a relatively few model organisms that are genetically tractable, and that can be used to study the fundamental processes of development at the genetic, molecular and cellular levels. These efforts have often led to a detailed understanding of the genetic mechanisms that are involved in the control of
many processes in embryonic development. Developmental physiologists, on the other hand, have focused on postembryonic development and have been reluctant to adopt use of a relatively few model species, in part because the physiological principles that bind the science cohesively, such as the regulation and control of function, are known to differ between species.

It is becoming increasingly clear that genetic and physiological approaches to development are complementary, and that a full understanding of development, arguably the most complex problem in biology, will require a research program that integrates both approaches. The workshop brings together biologists with acknowledged expertise in the area of developmental physiology with biologists who practice modern developmental genetics, and with biologists who work in evolutionary developmental biology. These
participants will help to identify and frame the current scope and future goals of the field of developmental physiology and to identify the opportunities for research in this important emerging field at the interface of developmental biology and physiology. The primary aim of this workshop will be to explore the many aspects of developmental physiology and to develop an organized and coherent set of goals for research in
developmental physiology.

Broader Impacts
This workshop will bring together researcher from many different disciplines to discuss the goals of developmental physiology and to determine how best to integrate developmental physiology with other approaches to understanding animal development. These discussions will result in the formulation of a broad and coherent set of recommendations for research in this rapidly growing field of biology. This workshop is
therefore expected to have a substantial impact on research at the interface of physiology and development, and will be an aid in developing an effective infrastructure for this rapidly growing field.

Transcription factors regulate gene expression by binding in a sequence-specific manner to double-stranded DNA and modulating the initiation of new transcripts. The unique binding specificities of transcription factors are critical components of their ability to regulate gene expression. Yet determining binding specificity is time-consuming and detailed information is available for only a fraction of transcription factors, even in well-studied organisms. The goal of this project is to develop and validate a rapid, simple, high-throughput assay to determine the full spectrum of binding specificities (or position weight matrix) for any transcription factor. The approach uses a microarray containing thousands of different dsDNA hairpin probes to assay relative binding of all permutations of seven base pairs. This method will be tested by comparing results to those obtained using existing, more laborious methods, and then refined, calibrated, and optimized for general use. This high-throughput method should be applicable to understanding the binding specificity of almost any protein:DNA interaction. It is expected that this approach will offer several distinct advantages over existing methods for determining position weight matrices: speed, simplicity, and comprehensive sampling of all potential binding sites. Successful validation of this method should benefit basic research on mechanisms of gene expression by providing detailed information about the binding specificities of many different transcription factors. Other aspects of basic research will also benefit, including automated annotation of genome sequences and evolutionary analyses of gene networks.

Regulatory sequences control timing, location and level of gene expression, and are predicted to play a key role in molecular and organismal evolution. Despite the importance of this regulation and the abundance of variation in gene expression, the effect this variation has on the organism is not known. We propose to explore how induced mutations within specific regulatory regions in brewer's yeast affect the expression of neighboring genes, and to what extent these differences influences organismal fitness. This type of information has not been acquired for any organism.

The scientific importance of this project is to provide a greater understanding of how variation within regulatory regions translates to gene expression and organismal fitness. There are two significant broader impacts of this work. First, high school students are involved with laboratory components of this project through the Howard Hughes Summer Program. Second, natural isolates have been collected from both local and Australian vineyards. This work is collaborative in that isolated strains are made available to their vineyard of origin, for future use in fermentation, and the agriculture community is exposed to the benefits of scientific research.

Evolutionary genetics of a sea urchin skeletogenic gene network

Intellectual merit. Genes interact with each other and with the environment to produce the organismal phenotypes upon which natural selection operates. These GxG and GxE interactions can influence responses to natural selection to a significant degree. This proposal outlines a project to measure the impact of genetic and environmental influences on phenotypic variation within an exceptionally welldefined network of interacting genes. The subject of these analyses is the skeletogenic gene network and resulting larval skeleton of the sea urchin Strongylocentrotus purpuratus. The impact of genetic and environmental variation will be assayed at different levels of biological organization: molecular phenotypes will be measured as allele-specific transcription and organismal phenotypes will measured through morphometric analyses of anatomy. The Specific Aims are as follows: 1. Measure the genetic basis for network phenotypes. An 8 x 8 cross will be used to estimate genetic contributions to phenotypic variation, to identify genes whose expression contributes the most to phenotypic variation, and to measure the degree to which anatomical variation is buffered from variation in underlying gene expression. 2. Measure gene network-by-environment interactions. Manipulation of food level will be used to characterize the response of the gene network to changes in a key environmental variable, to measure how much genetic variation influences this response, and to identify specific genes that mediate phenotypic plasticity. Together, the results of these analyses will provide detailed information about the origins of complex trait variation across a well defined gene network and its anatomical product in a wild population, and provide insights into how variation in developmental processes affects ecologically relevant organismal phenotypes.


Broader impacts. The influence of genetic and environmental factors on phenotypic variation has considerable general importance. This topic is a critical part of understanding evolutionary processes, but also has broad significance for medical and agricultural studies. Integrating an understanding of gene networks and gene expression into such studies represents a challenge, but also an area of significant opportunity. In addition, the proposed research will involve training young scientists in modern laboratory methods and analytical approaches. Training will continue to involve scholars at several levels of education, from high school students to post-doctoral researchers, as during prior funding.

Duke University's Institute for Genome Sciences & Policy (IGSP) offers undergraduates research involving Explorations in the Genome Sciences. The interdisciplinary program involves IGSP faculty from the Departments of Biology, Cell Biology, Biochemistry, Molecular Genetics & Microbiology, Biomedical Engineering, Statistics, and Biostatistics & Bioinformatics. The IGSP-wide emphasis on challenges represented by the Genome Revolution unifies faculty research interests and will create common themes for the individual student projects. Aside from an intensive research effort, student activities over the 10-week summer program include: (1) one-day orientation; (2) genome research ethics retreat; (3) weekly genome sciences research seminars; (4) weekly genome science career forums; (5) weekly student research discussion sessions; and (6) end of summer research forum for students to present their research results and conclusions. Facilities at Duke and the IGSP will provide students the necessary tools with which to engage and conceptualize their individual project within the developing area of genome sciences research. Undergraduates will be drawn from a national and diverse pool. Applications from women and under-represented minority students are encouraged. The integrated research experience will enable students from a broad range of disciplines to disseminate knowledge and appreciation of the interdisciplinary nature of genome sciences research. More information is available at http://www.genome.duke.edu/edexchange/programs/summerfellowships, or by contacting Dr. Huntington Willard at hunt.willard@duke.edu or Dr. Gregory Wray at gwray@duke.edu.

Advisory Committees; Area; Bp50; CD40; CDW40; Clinical Research; Clinical Study; Dental; Development; Disease; Disorder; Ensure; Environment; Fostering; Investigators; Laboratories; MGC9013; Pilot Projects; Research; Research Personnel; Research Resources; Researchers; Resources; Services; TNFRSF5; TNFRSF5 gene; Task Forces; Training; Tumor Necrosis Factor Receptor Superfamily Member 5 Gene; Work; craniofacial; craniofacies; design; designing; disease/disorder; p50; pilot study

One of the most exciting challenges in contemporary science is uncovering the genetic basis for the origin of uniquely human traits. Humans and other great apes are genetically very similar, yet diverse aspects of human anatomy, physiology, and behavior are markedly distinct. Recent technological developments provide the ability to begin identifying the specific genes that underlie these important trait differences. This project will focus on the evolution of human diet. Dietary traits are particularly interesting because the diet of early human ancestors and modern humans differ so markedly from those of the other great apes and because diet affects so many aspects of human health and disease. An interdisciplinary team of anthropologists and human geneticists will integrate genetic, organismal, and ecological information to better understand the genetic basis for the evolution of dietary traits in humans.

The primary intellectual goals of this project are to: (1) screen the human genome for relevant genes using two approaches, measuring gene expression across the entire genome from humans and chimpanzees in several tissues of dietary significance using ultra high-throughput sequencing and testing for adaptation in DNA sequences across the entire genome based on patterns of mutation; (2) conduct integrative case studies of diet-related genes implicated in trait changes during human origins through extensive DNA sequence comparisons among great ape species, detailed characterization of gene expression, experimental tests of functional differences, and associations between gene expression and specific dietary traits; and (3) conduct integrative case studies of diet-related genes among modern African human populations that are diverse with respect to diet and local climate, through detailed analyses of genetic variation, tests for natural selection, and genetic associations with specific dietary traits.

The broader impacts of this research include: collaborations and resource building with African scientists, recruitment and training of women and minority trainees, education outreach to grade school students, building two novel and informative databases that will be easily accessible through the web, and developing software for comparative analysis of primate genome sequences and gene expression.

Changes in genes affecting the development of embyros play an important role in the evolution of differences between species. However, because genes interact in complex networks during development, the relationship between specific genetic changes affecting development and organismal changes is not straightforward. This study uses two closely related species of sea urchins, Strongylocentrotus purpuratus and S. droebachiensis, to understand how genetic interactions during development evolve. By examining patterns of gene expression within the well-characterized network of genes underlying the development of the larval skeleton in these two species, and in the hybrid offspring between these species, the investigators will identify specific genetic interactions within the network that have evolved between the species. These results will inform where in the network changes accumulate and how specific interactions have evolved between species.

Complex genetic networks are a common feature of biological systems, including pathways and processes involved in human disease. Insight into the ways networks respond to genetic variation are important for understanding human disease as well as engineering biological systems. This sea urchin network is also known to be affected by changes in CO2 levels associated with global warming. This project will provide an important resource to many laboratories working to understand the ways in which global change affect the health of marine organisms. The project places high priority on involvement of undergraduate students and dissemination to the broader scientific community of the computational and analytical tools that will be developed during this study.

Understanding the expression and evolution of complex traits requires, among other things, measuring the genetic variation that underlies these traits. This in turn requires an understanding of the interplay between genes, the environment, and the traits an organism displays, specifically the nature of gene by environment interactions (GEIs). GEIs arise when two different genotypes respond differently to a change in the environment. Surprisingly little is known about GEIs in natural populations, although GEIs are pervasive in all known organisms, including humans. This project will address this gap by examining multiple aspects of GEIs in a wild mammal population. The project takes advantage of a long-term field study of wild baboons in the Amboseli basin in southern Kenya, in which individually known animals have been under continuous observation for 38 years. The investigators will test hypotheses about the ways in which GEIs influence variation in traits of adult baboons, and the manner in which GEIs affect standing genetic variation.

The proposed project will continue and extend the investigators' long history of training American and Kenyan students. The project will generate several unique data sets that will be of interest to the wider scientific community, and which are available for no other natural primate population. In addition, PIs have shared the design and implementation of their comprehensive long term database (BABASE) with a number of other scientists, and have also developed a website for the research project (www.princeton.edu/~baboon) which serves as a vehicle for providing information and data to the public.

Echinoderms include familiar animals such as starfishes, sea urchins, and a wide array of extinct forms stretching back to the Cambrian Period, circa 500 million years ago. Echinoderms share a common ancestor with backboned animals and thus provide a crucial link to understanding a huge portion of the entire tree of life as well as the history of our species. This project, the Echinoderm Tree of Life Project, will resolve the phylogenetic placement of Echinoderms within the tree of life and clarify important unresolved relationships among major echinoderm lineages using data from genetic sequencing and anatomy.

Echinoderms are fascinating, and their unique features, such as mutable ligaments and novel means of detecting light, have biomedical engineering applications. Because research on such marine animals and their adaptations is naturally attractive to young people, excellent students are expected to be recruited and the importance of science will be communicated to a broad audience. Long-term impacts, embodied by scientific publications, textbooks, anatomical and genomic data, and extensive pages in the Tree of Life and Encyclopedia of Life web projects, will provide resources to researchers and educators. Outreach will include videos and broadcasts about marine exploration and applications of fundamental biological research across the biomedical sciences.

DESCRIPTION (provided by applicant): A new generation of ultra high-throughput DNA sequencers is transforming biomedical research. These instruments provide a wide range of applications to basic and clinical research, including SNP discovery, analysis of transcriptome profiles, identification of protein:DNA interactions and hypersensitive sites, and characterization of methylation and chromatin marks at the whole-genome scale. This proposal seeks funds to expand instrumentation within Duke University's Genome Sequencing & Analysis Core Facility by adding a HiSeq 2000 System next-generation DNA sequencer manufactured by Illumina. Existing next-generation capabilities within the Core Facility include four short-read instruments (three Illumina GAII and one Applied Biosystems SOLiD 4) and one long-read instrument (Roche GS-FLX). We acquired our first GAII three years ago and replacing this instrument with the new HiSeq 2000 would substantially expand capacity to meet growing demand and extend the range of services that the Core Facility provides to researchers. The HiSeq platform offers both a substantially larger throughput and a faster run time. Access to this instrument will therefore save some research projects time and cost, and provide others with expanded information. This instrument will be primarily utilized by eight identified Duke investigators for diversity of ongoing projects. Because of a pre-existing strong Illumina user base in the Core Facility and the HiSeq versatility, we anticipate that this new instrument will enable a wide range of additional projects over its lifetime. Efficient utilization of the instrument is ensured y placement in a Core Facility with a proven record of accomplishment of more than a decade of support for research projects. Since this new instrument would replace an older Illumina instrument, its integration to an established workflow would be easily achieved and no additional ancillary equipment, staff, and computing infrastructure would be required. The Core Facility provides start-to- finish partnership with investigators that includes consultation, sample preparation, library construction, DNA sequencing, post-run quality control, and in-depth bioinformatics and statistical analyses. A team of technicians and bioinformaticians with strong experience in operating various next-generation DNA sequencers would support the new instrument, allowing non-specialists to take immediate advantage of its capabilities. A HiSeq 2000 DNA sequencer would provide substantial benefit to several ongoing NIH-funded projects and serve as a valuable catalyst for additional projects throughout Duke University's vibrant biomedical research community.

DESCRIPTION: We propose a data commons to provide data storage for seven core facilities that produce or analyze large and complex datasets for biomedical researchers at Duke University and their collaborators worldwide. With data storage requirements already counting in hundreds of terabytes the core facilities continue to adopt new technologies that will further increase the flows of data by orders of magnitude, a looming challenge for data retention and analysis. Our proposal seeks to turn this excess of data from a challenge to strength for life sciences researchers. Equipment purchased with the NIH SIG grant will use a mixture of disc arrays (~450 usable terabytes) and tape library with initial uncompressed data capacity of 1 petabyte to create a scalable data storage resource with features that protect and preserve data and manage data efficiently. Disc arrays will be configured to serve up data to existing computational servers for analysis either by researchers or by staff in Duke's Omics Analysis Core Facility, which was created in 2012 to provide support to researchers unfamiliar with using genomic data sets. The disc arrays and tape library will function in a coordinated fashion in a Quantum Stornext file system, and data management policies and system usage data collection will allow for fine-grained optimization of system performance and economy. The Quantum systems have been widely deployed in data-intensive industry and research, including in the genome sciences. From the outset, the core facilities will use the equipment to enhance their integration. Data provenance and management features of the Duke's Express Data Repository - used by the proteomics and microarray core facilities since 2006 - will be attached to the proposed storage equipment so that services can be expanded to include sequence data, RNAi screening data, microscopy images, and results from the analysis core. Thus, the proposed data commons will function in a manner allowing for efficient and, in many cases, automatic data hand-offs within a protected storage framework. This integration removes logistical impediments for data integration, reduces chances for accidental (or malicious) data corruption, and enhances the scope of automation for large-scale research projects. The storage will be connected via the cores to data-producing equipment and to computational servers run by the 'omics analysis core and to storage on a high-performance analysis cluster. All IT assets, including the proposed equipment, are administered by professional IT staff with particular strength in infrastructure required for large-scale research in the genome sciences. While increase in efficiency of data management will be an immediate benefit, the more important goal of the project is to enable researchers to speed their use of integrated and complex data to explore the complexity of human health and disease.

This project examines how changes in gene regulation contribute to modifications in key life history traits, such as fecundity, lifespan, and age-specific mortality. Knowing more about how life history traits vary within populations, and how they change over evolutionary time will elucidate fundamental biological processes. The approach involves a detailed analysis of gene interactions during key stages of the life cycle in three species of sea urchins. The experiments involve manipulating the operation of key regulatory genes with known functions during the early phase of the life cycle. The impact of these experimental manipulations will then be assayed using several 'big data' approaches that measure the expression of tens of thousands of genes and thousands of proteins and metabolites during subsequent stages of the life history. These results will reveal how differences in the function of key genes impact the function of other genes, thereby influencing anatomy and health. The broader impacts from this project fall into four areas. First, the novel computational methods for analysis of the very large gene expression datasets will have broad utility for basic and applied research. Second, the large datasets will be made freely available to other researchers who work with the same species. Third, there will be significant contributions to the training young scientists, including undergraduate and graduate students. Finally, this project will extend an innovative educational outreach program to middle school students developed by the PI in partnership with the North Carolina Museum of Science.

The objective of this project is to identify evolutionary changes in a well defined gene regulatory network (GRN) that contribute to an ecologically significant shift in developmental mode from planktotrophic (feeding) to lecithotrophic (nonfeeding) larvae in sea urchins. The project is identifing maternal changes underlying GRN activation and egg provisioning, and identify zygotic changes in GRN sub-circuits and assess their impact on larval traits. Changes in the energy content of eggs are essential for the evolution of lecithotrophy. The eggs of H. erythrogramma are larger than those of H. tuberculata and other planktotrophs and are packed with prominent lipid droplets. Interestingly, the amount of vitellogenin (yolk protein) per egg is not elevated, but triglycerides and long chain fatty acids are vastly more abundant. Thus, this project focuses on changes in lipid metabolism that may have contributed to the evolution of lecithotrophy in H. erythrogramma to identify specific metabolites that support lecithotrophic development and to understand how those changes might have evolved.

NRT: Integrative Bioinformatics for Investigating and Engineering Microbes (IBIEM)

Microbes play a vital role in shaping almost every ecosystem on the planet. Understanding the capabilities of microbes and their microbial communities (microbiomes) is the foundation for a range of transformative discoveries essential for sustaining life and the environment. However, the numerous disciplines studying and working with microbes often operate in silos resulting from the lack of a shared knowledge base and common analytical processes, thus limiting the potential to develop novel applications. This National Science Foundation Research Traineeship (NRT) award will bring together biologists, engineers, computer scientists and biostatisticians at Duke University and North Carolina Agricultural and Technology State University to fill this gap. The traineeship anticipates preparing one hundred (100) doctoral students, including forty-five (45) funded trainees across the two institutions, to solve both current and the next generation of challenges in data-enabled science and engineering microbiome research.

Metagenomic and metatranscriptomic (meta?omic) analyses in combination with advanced bioinformatic tools present a powerful approach for obtaining key insights into the complex microbial interactions underlying microbiome composition and function. Academic institutions have often struggled to keep pace with the growing and diverse meta?omics training demands of their students. This traineeship will address these training gaps by creating a novel and replicable education model where microbiologists, engineers, statisticians, and other empirical scientists will be cross-trained with theorists, model builders, and computational scientists. Trainees will learn to effectively work in interdisciplinary teams, engage in exciting research in environmental engineering and science, biomedical engineering, microbial genetics, biostatistics, and bioinformatics, and share discoveries within their cohort. Targeted interactions with practitioners will provide trainees with an understanding of real world challenges, competencies in various communication tools, collaborative skills utilized in the workforce, and an exposure to a wide range of careers. By instilling breadth of knowledge and cross-disciplinary awareness, the traineeship will foster creative integration and ultimately acceleration of discovery while helping to provide the nation?s workforce with students equipped with interdisciplinary skills to address global challenges including restoring ecosystems, developing innovative metabolic engineering pathways and engineering the next generation of therapies. Finally, through immersion of trainees in an array of outreach activities, a community will be developed with the motivation and skills to promote science and engineering to the broader population with goals of broad and substantial engagement of underrepresented groups in science, technology, engineering, and mathematics fields.

The NSF Research Traineeship (NRT) Program is designed to encourage the development and implementation of bold, new, potentially transformative, and scalable models for STEM graduate education training. The Traineeship Track is dedicated to effective training of STEM graduate students in high priority interdisciplinary research areas, through the comprehensive traineeship model that is innovative, evidence-based, and aligned with changing workforce and research needs.

Humans differ from other living primates in terms of diet, metabolic traits, and disease susceptibilities, yet little is known about how these differences arose or the genetic mechanisms underlying these differences. This doctoral dissertation project will use a comparative primate model to investigate how gene expression in fat cells has changed during human evolution and the role of diet in these gene expression differences. The research will contribute to our growing understanding of important relationships among human evolutionary origins, uniquely human traits, and health and disease risks in modern humans, and will be relevant to evolutionary anthropology and clinical research on nutrition and metabolism. The project will support graduate and undergraduate student training and mentoring in STEM research, as well as public science outreach activities and dissemination of novel data and techniques.

Metabolic traits and diet were of particular importance during human evolution and play a role in many common human diseases and chronic conditions today. This project utilizes several state-of-the-art techniques to address evolutionary questions about the evolution of diet and metabolism in humans. The investigators will use induced pluripotent stem cells from humans and other primate species to investigate regulatory regions controlling gene expression in adipocytes. A massively parallel reporter assay will be used to determine the activity of these regulatory regions. Changes in gene expression in response to different dietary components such as omega-3 and omega-6 fatty acids will also be measured.

The overarching goal of this application is to provide a high quality mentored research experience for promising students in the rapidly growing area of genome sciences and precision medicine. Students interested in pursuing a career in genome sciences and medicine research will require a strong foundation of core genome sciences technology and inter-disciplinary training. We propose a 10-week summer program that will include a mentored research project in genome sciences and medicine, didactic and interactive training, and interaction with academic and industry scientists. The program will be open to undergraduate students, particularly under-represented minorities (URM), at North Carolina Central University (NCCU) and Duke University. Students will have a range of research opportunities to select from the pool of 34 mentors working on projects in applied genome sciences, data sciences, translational genomic medicine, bioinformatics and computational biology, engineering, and statistics. The summer program builds upon our rich experience in undergraduate mentorship and training by the former Duke Institute of Genome Sciences & Policy (IGSP) and currently administered by the Duke Center for Genomic and Computational Biology (GCB) and past partnership with NCCU. Through these programs, we have accepted more than 150 students, 22% of whom are from under-represented minorities and more than half of whom are women; several have successfully continued their research throughout their undergraduate career and been accepted into leading graduate programs and medical schools around the country. The research experience will be complemented by a series of training lectures and interactive learning activities from the core GCB facilities (proteomics/ metabolomics, sequencing, microarrays, and biostatistics), visits to NCCU and companies using genome sciences technologies or data in their research in nearby Research Triangle Park, and science-related community service activities. In addition, students will have the opportunity to consider broader issues impacted by their research through a weekly discussion on the ethical, legal, social, and policy issues and gain important skills such as critical reading a scientific paper, leading a discussion group, conducting literature reviews, and making formal presentations. All students will be required to present their research at the conclusion of the program. If needed to ensure a diverse student group each summer, we will expand our recruitment to other schools in the region, including several Historically Black Universities and Colleges (HBUCs) and establish partnerships with other local institutions during the course of the award to expand the student pool. In summary, students in this program will benefit from the rich and highly interdisciplinary resources available at Duke for genome sciences and medicine research.

ABSTRACT? INTEGRATED CANCER GENOMICS SHARED RESOURCE The Integrated Cancer Genomics shared resource (ICG) is committed to providing state-of-the-art instrumentation and protocol support to Duke Cancer Institute (DCI) researchers as these technologies evolve over time. The ICG expanded to meet DCI needs that encompass microbiome, epigenetic and increase single cell services provided by three institutionally designated core facilities: Sequencing and Genomic Technologies Core (SGT), the recently established Microbiome Shared Resource (MSR), and the Molecular Genomics Core (MGC). By unifying these existing resources for DCI members, the ICG meets its objective to provide one-stop access to all of the major research protocols and instrumentation platforms used in contemporary cancer genomics research, including genomics, transcriptomics, microbial studies, and epigenetics. For over a decade, the ICG has maintained a record of providing updated, state-of-the-art genomic and transcriptomic services to DCI members. The ICG includes services that are performed by three Duke School of Medicine (SOM) core facilities. The Sequencing and Genomic Technologies (SGT) and Microbiome Shared Resource (MSR) perform services within the Duke Center for Genomics and Computational Biology; the Molecular Genomics Core (MGC) performs services within the Duke Molecular Physiology Institute. The ICG unifies all of the cancer genomic technologies on campus, providing one-stop access to all of the major research protocols and instrumentation platforms used in contemporary cancer genomics research. The ICG supports a wide range of projects from DCI investigators, by providing expert consultation, project management and training to facilitate access to approaches including SNP discovery, mapping chromatin modifications, single-cell sequencing, measuring mRNA levels at several scales (single genes, cancer panels, entire transcriptome), sequencing exomes, identifying DNA methylation, microbiome profiling, and mapping transcription factor binding sites. By offering the full range of technological platforms, the ICG allows investigators to choose the optimal solution for their cancer related projects and assists investigators with data quality control, versioning, statistical analysis, and dissemination for all of these services. In addition, the ICG works with DCI investigators to explore and establish new technologies which catalyzes the advancement of cancer research. In 2018, the ICG shared resource provided services to 290 investigators, 29% of whom were DCI members, accounting for 25% of total usage, from all 8 DCI Research Programs. Use of this shared resource by DCI Members contributed to 216 publications over the project period, 80 of which were in high impact journals. The shared resource operates primarily on a cost-recovery basis, with institutional support for a portion of the operating costs and instrument purchases. Support from the Cancer Center Support Grant allows ICG to provide DCI members with consultations, assistance with grant and manuscript preparation, and scheduling priority. User fees for other activities follow School of Medicine guidelines.

Animal structures are made of combinations and arrangements of distinct cell types, the product of complex cell decision-making during development. But how do cells, which contain identical genetic information, decide their fate? This research addresses this fundamental biological question in a simple, yet spectacularly diverse animal structure–the color patterns on the wings of Heliconius butterflies. Although Heliconius wing patterns are highly diverse, they are created by altering the distribution of just three cell types (red, black and yellow wing scales) across the wing surface. Unlike in a complex organ, the cell decisions that create these patterns unfold on a flat canvas of non-migrating cells. This attribute greatly simplifies the process of understanding the interactions among genes and how these interactions change throughout development to create a specific pattern. This research capitalizes on this fact and emerging genomic tools to characterize the molecular decisions that determine how a developing wing cell becomes specified into one of the three different scale cell types. The project is strengthened by a 6-month internship program that targets traditionally underrepresented groups and offers an in-depth research experience and hands-on professional development. Moreover, through partnerships with science museums, this project will create bilingual (English and Spanish) experiential learning resources that harness the potential of butterflies to educate a variety of audiences (school children, teachers, and life-long learners) about genes, development, natural selection, and the role that interactions among them play in generating Earth’s biodiversity.

Evolutionary processes constantly generate and rearrange specialized cell types, forging the morphological dimension of biodiversity. Research is starting to connect changes in gene expression and open chromatin to cell fate decisions. However, this research has mostly focused on early embryonic development or on the developmental trajectories of complex organs in a few species. Although powerful, these studies do not have an explicit goal of linking changes in cell fate decisions to phenotypic change. This research fills this important knowledge gap by characterizing the rules governing cell specification– from signals, to reception, transduction, transcriptional activation, and fate determination during the critical developmental period when the wing patterns of Heliconius butterflies are established. Here, extensive knowledge of the ecological and evolutionary significance of wing color patterns, experimental tractability, and fantastic diversity make Heliconius a powerful experimental system for understanding how the processes of cell specification are modified by natural selection to produce diversity. By casting single-cell transcriptomics, open chromatin profiling and CRISPR loss-of-function experiments within an evolutionary framework that includes replicated cases of the independent evolution of identical wing patterns, this project will determine the rules that govern how cells communicate and acquire a specialized fate during development, and how those rules are applied to generate diversity.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.