Erik Andersen - US grants

DESCRIPTION (provided by applicant): Mutations in many genes interacting with each other and with the environment cause most common human diseases. However, these mutations are difficult to identify because the majority cause small phenotypic effects and genetic modifiers can alter the severity of a disease. Numerous genes of large effect are known, but the genes of modest effect that predispose certain individuals to disease are less well known and vary in populations. Therefore, the same mutation that causes a severe disease in one genetic background may not cause the same severity of disease in a different genetic background. Using the genetic background differences among individuals in a population, quantitative genetic studies can identify the genes that modify disease predisposition. Caenorhabditis elegans facilitates the identification of human disease genes because most cell-signaling pathways are conserved, especially the TGF-beta and insulin pathways. In this study, I will use C. elegans quantitative genetics coupled with classical genetic epistasis to identify the genes of both major and modest effects on conserved TGF-beta and insulin pathways. First, I will score a collection of recombinant inbred lines (RILs) created from the reference strain from England and a polymorphic strain from Hawaii for pathway phenotypes. These quantitative trait analyses will rapidly identify the major effect genes that control any phenotypic differences. Next, I will determine whether subtle genetic modifiers exist in other strain backgrounds by crossing extant mutations from the reference genetic background into the Hawaiian genetic background and scoring for suppression or enhancement of TGF-beta and insulin pathway phenotypes. Last, I will create sensitized RIL collections to facilitate the identification of modest-effect genes that alter TGF-beta and insulin pathway activities. Public Health Relevance: Common disease-causing mutations are time-consuming and costly to identify in humans. Because the TGF-beta and insulin pathways are similar in the simple nematode C. elegans as in humans, genes that modify these pathways can be rapidly and cheaply identified. These modifier genes will broaden our understanding of diseases associated with these pathways, like epithelia-derived cancers and diabetes, and suggest new therapeutics.

Project summary   Parasitic nematodes impose a massive health and economic burden across much of the developing world, infecting over one billion humans worldwide and conservatively resulting in the loss of 14 million disability- adjusted life years (DALYs) per annum. The morbidity and mortality inflicted by these devastating pathogens is partly curtailed by well-organized mass drug administration (MDA) programs that depend on the continued efficacy of a limited portfolio of anthelmintic drugs. Avermectins are a widely used (and recently lauded) class of broad-spectrum anthelmintics that are an indispensable component of this limited chemotherapeutic arsenal. The human-approved avermectin formulation, ivermectin, is a mainstay in the treatment of many parasitic nematode infections such as Lymphatic Filariasis (LF) and is considered an `Essential Medicine' by the WHO. The prospects of avermectin resistance pose a serious threat to the future success of nematode control programs. These prospects have been realized in the veterinary domain following intensive avermectin use, and are predicted to materialize in human medicine with increased selection pressures resulting from expanded MDA coverage. Early detection of avermectin resistance-associated alleles in nematode parasite populations is essential to the goal of slowing anthelmintic resistance and extending the lifespan of this critical drug class. Despite consensus on urgency, very little is known about the genetic and molecular determinants of avermectin resistance. The experimental intractability of human nematode parasites necessitates the development of new approaches to discover and validate relevant markers for resistance. We propose to utilize the powerful model nematode Caenorhabditis elegans to systematically interrogate the complex genetic determinants of avermectin resistance. This model was crucial towards understanding anthelmintic resistance in parasites, including identification of glutamate-gated chloride channels as the target of avermectins. Our central hypothesis is that C. elegans can be used to identify genetic loci that are predictive of avermectin resistance in medically important human parasites. To establish mechanistic conservation, putative genetic markers identified in C. elegans will be validated experimentally in the vector-borne human filarial parasite Brugia malayi, an etiological agent of LF. Upon completion, this project will make available a new statistical genetics toolkit and molecular pipeline for the discovery and validation of parasite-relevant anthelmintic resistance mechanisms. 

A key challenge in education is determining the optimal sequence of concepts to present to a student. This is particularly important for second language learning, where there is a huge amount of content to learn and it is difficult for learners to stay engaged. Although researchers in education and psychology have identified guiding principles for sequencing learning materials, there is a lack of pragmatic techniques that can apply these principles to build effective learning progressions automatically. To address this gap, this project will: (1) develop techniques for estimating the difficulty of language learning content, (2) identify important characteristics of various expert-crafted progressions, and (3) experiment to find optimal progressions for individual students. These progressions will enhance the effectiveness of online interactive learning tools that are freely accessible to the public. The anticipated discovery of general principles of pacing will benefit educators and provide the foundation for maximizing engagement in adaptive learning systems.

The project will conduct three investigations in order to build adaptive learning progressions. First, the project will build a library of language materials that are organized by difficulty. To do this, the PI will explore procedural models of target linguistic knowledge such as grammar, identify which procedural steps are necessary for understanding specific materials, and organize these materials into skill trees. Second, the project will develop a set of control parameters that capture key aspects of pacing and sequencing. This will allow the PI to extract pacing strategies from expert-crafted progressions, and map these strategies onto other progressions. Third, the project will optimize progressions for individual learners by conducting large-scale multivariate experiments in online interactive learning tools.

PROJECT SUMMARY A substantial fraction of the variation in aging can be explained by genetics, but little is known about what these genetic factors are and how they modulate healthy aging. Much of our fundamental understanding of mechanisms that modulate aging, including insulin signaling and proteostasis pathways, come from the study of the model nematode Caenorhabditis elegans. Nearly all C. elegans aging studies use a single laboratory- adapted strain with little connection to natural variation. In this project we aim to establish C. elegans as a model for natural variation in aging. First we will develop a system for multi-modal automated healthspan assays based on a previously developed `WorMotel' microfabricated multi-well imaging platform. Second, we will carry out longitudinal assays on 16 genotypically diverged wild-isolate C. elegans strains to determine traits correlated with healthspan decline. Our results will set the stage for comprehensive mechanistic analysis of genes underlying natural variation in aging. The combination of high-throughput healthspan analysis and quantitative genetics methods will be particularly powerful for delineating genetic causes of a complex healthspan phenotype, providing the first mechanistic understanding of natural variation in metazoan aging.

Project summary: Exposure to environmental chemicals is a major health risk. Unfortunately, the detrimental impacts of toxin exposure vary among individuals in a population because of unknown genetic differences. With a better understanding of how our genetics influence toxin response, we can more accurately predict detrimental health effects. It is difficult to identify these factors because human genome-wide association studies often lack the necessary statistical power and controlled toxin exposures. For this reason, we will use defined population-wide variation in the roundworm Caenorhabditis elegans to enable precise measurements of toxin responses at the scale and statistical power of single-cell organisms but with conserved molecular, cellular, and developmental properties of a metazoan. In Aim 1, we will identify genetic loci underlying variation in response to 30 diverse toxins, including metals/metalloids, mitochondrial toxins, pesticides, and flame retardants. We will define effective toxin doses across diverse individuals using low-cost, high-throughput, and high-accuracy assays of growth and fertility. Then, we will define the population-wide variation in response to these 30 toxins and use these data to map toxin-response differences to genes using two mapping panels: (1) CeNDR - the C. elegans Natural Diversity Resource, a set of 500 strains representing nearly all known genetic variation for the species, and (2) CeMEE - the C. elegans Multiparental Experimental Evolution panel, a set of 1000 recombinant inbred lines that enable mapping to the resolution of single genes. In Aim 2, we will identify specific genetic variants and pathways affecting toxin-response variation. We will define causal relationships between toxin response differences and genetic variants using state-of-the-art breeding and genome-editing techniques. Then, we will use gene expression analyses and hypothesis- directed experiments to determine the molecular basis of toxin-response variation. In Aim 3, we will elucidate conserved mechanisms of toxin-response variation by mapping toxin responses in two other Caenorhabditis species that are as genetically different from each other as mice and humans. An innovative comparative quantitative trait locus analysis will ensure identification of sources of toxin-response variation that arise convergently (and therefore predictably) in multiple evolutionary lineages. We will extend this approach by further comparing our mapping results to those from Drosophila, rodents, and humans, identifying conserved pathways responsible for toxin-response variation. Our Caenorhabditis genetic resources have levels of variation, allele frequencies, and phenotypic effects similar to humans, providing a framework to discover the characteristics of genes and variants that underlie differences in human toxin responses. Indeed, decades of research in C. elegans have identified countless examples of widely conserved molecular mechanisms underlying signaling, gene regulation, and metabolism, suggesting that the toxin-response mechanisms discovered here will extend to humans despite overt differences in life history and anatomy.

Project summary: Parasitic nematodes impose a massive health and economic burden across much of the developing world, infecting over one billion people worldwide. The morbidity and mortality inflicted by these devastating pathogens is partly curtailed by mass drug administration (MDA) programs that depend on the continued efficacy of a limited portfolio of anthelmintic drugs. Benzimidazole (BZ) compounds are a widely used class of broad-spectrum anthelmintics that are an indispensable component of this limited chemotherapeutic arsenal. The prospects of BZ resistance pose a serious threat to the future success of nematode control programs. These prospects have been realized in the veterinary domain following intensive BZ use and are predicted to materialize in human medicine with increased selection caused by expanded MDA. Early detection of resistance-associated alleles in nematode parasite populations is essential to the goal of slowing anthelmintic resistance and extending the lifespan of this critical drug class. Based on research in the free-living nematode Caenorhabditis elegans from thirty years ago, parasitic nematode researchers focus on one BZ target, a nematode-specific beta-tubulin. Despite this knowledge, it is still a complete mystery (1) whether any alleles cause resistance (i.e. go beyond correlation), (2) the nematode tissues that are sensitive to BZ poisoning, and (3) the drug-target interactions that cause resistance. In Haemonchus contortus, we have collected both validated sensitive and resistance samples, and longitudinal samples where resistance has developed over time. These samples are not available in any human parasitic nematode species. Using quantitative resistance assays on these resources, we have shown that BZ resistance goes well beyond this single beta- tubulin target. However, we do not know these independent resistance mechanisms in C. elegans or parasite species. In Aim 1, we will test explicitly whether alleles correlated with resistance in parasites actually cause resistance, test the fitness effects of these alleles, identify the tissues targeted by BZ, and characterize the molecular mechanism for how beta-tubulin in affected by benzimidazoles. In Aim 2, we will discover beta- tubulin independent mechanisms of resistance using the tractable C. elegans model nematode. In Aim 3, we will expand our results to H. contortus where genomic and validated strain resources enable discoveries of conserved resistance mechanisms. It is not possible in any parasitic nematode species to accomplish these goals. New discoveries are possible only through this interplay between the model nematode C. elegans and the tractable veterinary parasitic nematode H. contortus. Our results will have direct impacts on how treatments are administered and resistance is monitored in human parasitic nematodes.

Studies of conserved biological processes require model organisms that share attributes with humans. Most model organisms are easily grown in the laboratory and enable experimental manipulations. Over the last forty years, the nematode worm Caenorhabditis elegans has been instrumental in numerous fundamental advances in genetics, developmental biology, and neurobiology. However, all of these discoveries come from studies of a single genetic strain of the species. This limitation is similar to the argument that we can understand all of human biology by the study of a single person in our species. This project seeks to expand the C. elegans Natural Diversity Resource (CeNDR), which includes nearly 2,000 genetically distinct strains from across the world, and create the Caenorhabditis Natural Diversity Resource (CaeNDR), incorporating almost 2,000 C. briggsae and more than 700 C. tropicalis strains. This combined genetic diversity facilitates discoveries about the evolution of physiological and behavioral traits, including responses to chemical and biotic stresses. Because humans share many of the same genes and processes as this nematode species, studies using these organisms can teach us a great deal about how the human population varies and how evolution works.<br/><br/>CaeNDR has three major goals: (1) Collect, organize, and disseminate wild Caenorhabditis strains; (2) Organize and disseminate whole-genome sequence and variant data for wild strains; and (3) Provide a genetics portal to facilitate mappings and interpretations of results. The project will further increase the capacity of CaeNDR by expanding the set of strains and preparing them for easy dissemination to the community, adding new tools and extensibility to existing CaeNDR genomic resources, and releasing all of the data for the three Caenorhabditis species on an updated and redesigned website (CaeNDR.org) with critical improvements to security, infrastructure costs, and user interface and experience. The extensive CaeNDR user-base from C. elegans will be amplified by researchers using C. briggsae and C. tropicalis, allowing for novel comparative approaches across the Caenorhabditis genus. Most research groups do not have the combination of experimental, computational, and statistical training to easily perform studies of natural variation. This project will make these tools available and usable by a large number of research laboratories across diverse model organism communities.<br/><br/>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.