1999 — 2003 |
Besansky, Nora J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Species Boundaries in the Anopheles Gambiae Complex @ University of Notre Dame
It is children living in Africa south of the Sahara that bear the brunt of morbidity and mortality caused by Plasmodium falciparum. Here, traditional methods of vector control have been least effective, and the mitigating role of permethrin-impregnated bednets is threatened by emergence of permethrin resistance in the primary vector, Anopheles gambiae. Effective strategies for monitoring and managing the spread of insecticide resistance will depend upon detailed information about the genetic structure of vector populations. This same information is essential for future genetic control strategies aimed at the replacement of vector by nonvector populations. In this context, it is important to address the hypothesis that different chromosomal forms of An. gambiae are reproductively isolated, using independent molecular markers. It is also a premise of this proposal that the requisite information extends beyond An. gambiae to a second vector of major importance, its sibling species An. arabiensis. The possibility that An. gambiae may be hybridizing productively with An. arabiensis suggests that undesirable traits such as insecticide resistance could be exchanged between species. Past efforts to conclusively demonstrate gene flow between these vectors ahve been complicated by the confounding explanation of recent common ancestry and the contadictory evidence concerning their status as sister taxa within the species complex known as the An. gambia complex. The Y chromosome provides a powerful tool to attack questions at the population level and above, not only because it is nonrecombining and paternally transmitted, but also because it cannot cross barriers since male hybrids are sterile. The main goal of this proposal is the development and application of DNA sequence markers on the Y chromosome (microsatellites, insertion-deletions, and base substitutions) that, in combination with other markers, will help solve three interrelated questions: (1) Are An. gambiae and An. arabiensis sister taxa? (2) How much gene flow is occurring between them, and which genomic regions are susceptible? (3) How much gene flow is occurring between chromosomal forms of An. gambiae?
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1 |
2001 — 2005 |
Besansky, Nora J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetics of Anopheles Funestus Populations @ University of Notre Dame
DESCRIPTION (provided by the applicant): Together with Anopheles gambiae and An. arabiensis, An. funestus is among the most important malaria vectors in the world. With sporozoite rates as high as 9 percent in parts of Africa, it is clear that An. funestus cannot be ignored in any comprehensive plan to control or eradicate malaria from this continent. Whatever control strategy is implemented against An. gambiae s.l. must be integrated with control against An. funestus. Because it is currently impossible to maintain colonies of An. funestus in the laboratory, neither classical genetic control schemes nor transgenic strategies can be developed. However, the importance of a detailed understanding of vector population structure transcends genetic control programs, as this knowledge is also pivotal to the successful use of insecticides in vector control, given limited financial and human resources. This knowledge allows predictions to be made about the response of vector populations to human interventions or genetic changes, e.g., the potential for spread of mutations conferring insecticide resistance. Unfortunately, the population genetics structure of An. funestus is poorly understood and relatively unstudied to date. Very few molecular genetic markers have been developed for this species. The experiments outlined in this proposal will employ cytogenetically mapped molecular markers that we have developed to address fundamental questions about gene flow within and between An. funestus populations. What is the size of a deme and what is the effect of distance and habitat on gene flow between demes? Are carries of alternative chromosomal inversion arrangements reproductively isolated? Do they have epidemiologically relevant differences in biting and resting behavior? Information gained from the use of these markers will enable us to more efficiently manage the currently available tools for vector control and will lay the necessary foundation if genetis strategies against An. funestus become possible
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1 |
2005 — 2009 |
Besansky, Nora Jessie |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Ecological Genomics of Anopheles Gambiae @ University of Notre Dame
DESCRIPTION (provided by applicant): Anopheles gambiae s.s. is subject to an ongoing speciation process which has resulted in increased malaria transmission spatially and temporally. Ecological adaptation associated with the speciation process has allowed exploitation of environments that formerly excluded A. gambiae: arid seasons and zones subject to irrigation for agriculture. It has been assumed that the arid-adapted incipient species (A. gambiae form M) shifted larval habitats from rain-dependent pools and puddles characteristic of A. gambiae form S to anthropogenic breeding sites associated with irrigation. However, the relevant ecological features used by the M and S forms to partition their environment at different spatial scales and developmental stages have not been established. We aim to study ecological adaptation at phenotypic and genotypic levels because we believe that this phenomenon is central to what makes A. gambiae the most efficient vector of malaria, and that an understanding of how it works will expose novel targets for control. We will complement ecological field studies of A. gambiae M and S at different spatial scales with a population genomic examination of adaptation based on the completed A. gambiae genome sequence and high throughput screening techniques. Toward the ultimate goal of identifying genes underlying complex ecophenotypes, we will apply a "topdown" approach in which key ecological differences between M and S will be carefully defined, and a "bottom-up" approach involving multilocus genome scans for candidate regions likely to be associated with ecological divergence of M and S. Within this framework, we propose the following specific aims: (1) Validate the hypothesis that M and S partition their habitat, and characterize the realized niche of each form at different spatial scales;(2) Define the spatial and temporal patterns of chromosomal polymorphism within M and S in relation to environmental heterogeneities;and (3) Identify genomic regions potentially associated with differential adaptations of M and S.
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2005 — 2012 |
Lodge, David (co-PI) [⬀] Lodge, David (co-PI) [⬀] Feder, Jeffrey [⬀] Lamberti, Gary (co-PI) [⬀] Fuentes, Agustin Besansky, Nora |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Igert: Global Linkages of Biology, Environment, and Society (Globes) @ University of Notre Dame
This Integrative Graduate Education and Research Training (IGERT) award supports the establishment of a new interdisciplinary graduate program in Global Linkages of Biology, Environment and Society (GLOBES) at the University of Notre Dame. The program integrates research, training, and educational activities among complementary faculty in ecology, evolution and environment, infectious disease, and social science, ethics, law and economics. The goal of the program is to train a new generation of Ph.D. scientists capable of designing and implementing sound scientific solutions to environmental problems within the framework of human culture, economics, policy, and law. Human practices and activities affecting environmental and global health have interrelated causes and feedbacks. These feedbacks are both biological and social, and exacerbate environmental degradation and the spread of invasive species and disease. Consequently, solutions to increasingly linked environmental and health problems require the coordinated interaction of biological and social scientists with expertise in ecology, evolution, infectious disease, anthropology, ethics, law, policy, and economics. The intellectual merit of this IGERT consists of the integration of the research and education activities of life and social scientists at the University of Notre Dame in a concerted effort to understand and find solutions to five specific problems: (1) invasive species in the Great Lake and their cascading effects on ecosystems (2) interactions of human land-use change and malaria transmission in West Africa; (3) cross-primate exchange of disease on the island of Bali, (4) resurgence of schistosomiasis in China driven by changes in water- and land-use patterns, and (5) impacts of invasive Sudden Oak Death as it spreads across the U.S. Without interdisciplinary thinking, relatively simple and effective measures to reduce environmental damage and disease transmission can go unrecognized. Most analyses suffer from concentrating on only one aspect of the question (e.g., ecology, culture, or disease). This IGERT will foster cross-disciplinary conversation and guide research directed at developing prevention and control responses to invasive species and disease that are scientifically sound, culturally acceptable, and cost-effective. The IGERT will use a coordinated set of approaches ranging from team-based research projects to outreach service activities to provide students with the interdisciplinary skills and knowledge they need to tackle the increasingly complex environmental and global health problems of our nation and the planet. The broader impacts of this proposal include finding solutions to these environmental and health problems. IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.
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0.915 |
2009 — 2013 |
Besansky, Nora Jessie |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Functional Genomics of Inversion 2la in Anopheles Gambiae @ University of Notre Dame
DESCRIPTION (provided by applicant): Malaria caused by Plasmodium falciparum claims the lives of three million children per year, mainly in Africa. A vaccine is not available and chemoprophylaxis alone is unlikely to significantly reduce transmission. Aside from the threat of insecticide resistance, existing vector control strategies that focus on indoor use of insecticides may not reach all of the disease-transmitting population or may induce a behavioral shift, given underlying population heterogeneities in vector resting and biting behavior-- even in vectors considered to be primarily endophilic and endophagic (indoor resting and biting) such as Anopheles gambiae. In Africa, A. gambiae is the most important vector. This mosquito has adapted rapidly to climatically diverse and anthropogenic environments. Instrumental to its adaptive flexibility are polymorphic chromosomal inversions. Of particular relevance are alternative arrangements on the left arm of chromosome 2 (2La or +a) that are preferentially associated with contrasting environments (arid and humid) through entirely unknown physiological and/or behavioral mechanisms. Based on frequency distribution maps of 2La, this arrangement reaches 100% in arid savannas while in humid rainforests only the alternative arrangement (2L+a) is found. Thus without the benefit of 2La, A. gambiae would be limited to rainforest areas where this mosquito is not necessarily the most abundant or even the best malaria vector. At a local level, 2La reaches its highest frequency during the dry season and in samples captured resting indoors at night where the nocturnal saturation deficit is higher. Thus 2La influences a key epidemiological trait-- the probability of vector-human contact-- as well as the likelihood of vector exposure to insecticide-treated walls and bed nets, through its effect on indoor biting and resting behavior. The ultimate goal of this project is to identify the genes and gene networks in 2La that confer resistance to aridity-- a phenotype or suite of phenotypes that leads to increased vector-human contact and malaria transmission at both local and geographic scales. To achieve this goal, we propose a multidisciplinary and integrative approach that combines phenotypic and molecular analysis to begin to tease apart the functional genomics of 2La through three specific aims: (1) Identify phenotypic traits associated with alternative arrangements of 2La; (2) Identify sequence differences between arrangements that may contribute to phenotypic differences; (3) Associate genotypic and phenotypic differences by comparing patterns of gene expression. The short-term outcome of this program will be linkages between adaptive phenotypes and underlying candidate genes, leading to specific hypotheses about how 2La confers resistance to aridity and impacts the probability of vector-human contact. The longer term benefits are two-fold. The first is improved implementation, evaluation and design of vector control, based on a mechanistic understanding of what we now call adaptive flexibility. In other words, gaining a detailed understanding of genetic, physiological and behavioral attributes of 2La that are linked to aridity tolerance and indoor resting behavior will significantly improve our ability to predict the epidemiological impact of existing and novel vector control strategies, and can lead to the design of more comprehensive strategies resistant to evasion by components of the vector population. The second benefit is that a successful outcome in the study of functional genomics of aridity resistance in 2La will serve as a general model for studying the functional genomics of many other medically important traits in A. gambiae.
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2012 — 2013 |
Besansky, Nora Jessie |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Genetic Basis of Salt Tolerance in Anopheles Gambiae S.L. @ University of Notre Dame
DESCRIPTION (provided by applicant): About 800,000 people die each year from malaria. While the currently available vector control tools-mainly bed nets and indoor insecticide spraying-are substantially reducing malaria cases and deaths, this public health success is fragile due to the threat of resistance. Moreover, even without resistance, existing tools are insufficient to interrupt malaria transmission where it is high and stable, as in many parts of Africa. The development of new vector-targeted tools is imperative, but depends on an understanding of mosquito ecology and behavior that is currently lacking. Here we study saltwater tolerance, a trait found in numerous important malaria vectors that plays a key role in determining habitat use and ecological distribution of mosquitoes, and thus their contribution to malaria transmission. Our objective is to dissect the genetic basis of saltwater tolerance in the African malaria vector An. merus, a close relative of the primary vector An. gambiae. We will dissect saltwater tolerance in An. merus through two complementary specific aims: 1. Genetically map QTLs that contribute to salinity tolerance in An. merus Using multiple colonies of An. merus and An. gambiae, we have shown that An. merus can be distinguished from An. gambiae and their F1 hybrids by survival in 50% seawater. We will apply a novel Illumina-based genotyping approach to map recombination breakpoints in individual backcross progeny that do/do not survive exposure to 50% seawater, to localize QTL regions that control salinity tolerance. 2. Identify differential gene expression associated with development in fresh vs. saltwater We have shown that the ability of An. merus to survive in 50% seawater is dependent upon developmental timing of exposure, and that the localization of an ion transporting protein (Na/K ATPase) in the rectum differs in fresh vs. saltwater-reared larvae. We hypothesize that these observations are due to differential expression triggered by exposure to saltwater. We will test this hypothesis and identify candidate genes by comparing global gene expression between fresh vs. saltwater-reared larvae. At the end of the two-year project, combined evidence from QTL mapping and differential gene expression will lead us to candidate genes and/or candidate gene regions that contribute to salinity tolerance in the malaria vector An. merus. Unlike other complex ecological, behavioral and life history traits of epidemiological importance that are probably polygenic, saltwater tolerance is relatively tractable, likely governed by a few major loc with large effects, and simple to assay. The ability to dissect the genetic basis of this adaptive trait using next generation genomic tools lays the groundwork for future efforts to understand the mechanisms by which these vector mosquitoes adapt to a heterogeneous and changing environment, opening up new avenues of vector control. PUBLIC HEALTH RELEVANCE: Currently available tools to combat malaria are insufficient to interrupt disease transmission where it is high and stable, as in many parts of Africa. The development of new vector-targeted tools is imperative, but depends on an understanding of mosquito ecology and behavior that is currently lacking. Here we study saltwater tolerance, a trait found in numerous important malaria vectors that plays a key role in determining habitat use and ecological distribution, and hence malaria transmission in coastal regions.
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1 |
2014 — 2015 |
Besansky, Nora Jessie |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Anchoring and Uniting the An. Funestus Assembly For Improved Vector Analysis @ University of Notre Dame
DESCRIPTION (provided by applicant): Anchoring and uniting the An. funestus assembly for improved vector analysis. Anopheles funestus is one of the three most important and widespread vectors of human malaria in tropical Africa, but unlike An. gambiae with which it broadly co-occurs, it is a relatively neglected species. It shares with An. gambiae not only a broad sub-Saharan distribution and major vector status, but also abundant chromosomal inversion polymorphism and apparently shallow population structure across much of Africa. However, there are behavioral and genetic heterogeneities relevant to malaria transmission that remain poorly understood. In the savannas of West Africa, where application of residual insecticides in the 1960's was not as successful against An. funestus as elsewhere in Africa, there is strong cytogenetic evidence for cryptic, temporally stable assortatively mating populations co-occurring in the same villages. In apparent analogy to the chromosomal forms of An. gambiae, the chromosomally recognized forms of An. funestus, named Kiribina and Folonzo cytotypes, seem to differ in larval ecology. Importantly, they also differ in adult behaviors affecting vectorial capacity, most notably indoor/outdoor resting behavior. At present, there exist no rapid molecular identification assays to facilitate more in-depth field studies of their behavio and genetics; the cytotypes can only be distinguished by laborious chromosomal karyotyping. Our long-term goal is to understand the underlying genomic determinants of epidemiologically important phenotypic and behavioral traits in An. funestus and its cytotypes. The newly sequenced An. funestus genome begins to make possible this goal, but its fragmented state, unanchored to chromosomes, poses a barrier that hinders the identification of causal loci affecting traits of interest. The central goal of this R21 is to upgrade the draft An. funestus reference to a chromosome-based assembly in which the unanchored scaffolds are united, ordered and oriented on chromosome arms, enabling a preliminary assessment of genomic divergence between the cytotypes. Toward this end, we propose three specific Aims: 1. Integrate the assembly with the cytogenetic map by physical mapping. 2. Unite, order and orient unanchored scaffolds using single molecule sequencing. 3. Assess divergence between An. funestus cytotypes by genome scans. The innovative strategy of integrating a powerful new sequencing technology with traditional physical mapping to chromosomes will transform the draft reference into a chromosome-based assembly, and provide the means to uncover in An. funestus and its cytotypes the genetic basis of traits that affect disease transmission.
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1 |
2016 — 2017 |
Besansky, Nora Jessie |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Elucidating the An. Funestus Complex @ University of Notre Dame
? DESCRIPTION (provided by applicant): Elucidating the An. funestus species complex Since 2000, renewed international commitment to malaria control has led to a substantial increase in malaria intervention coverage globally. However, there are disturbing signs that this trend has slowed, stalled or even reversed in some regions due to failures in vector control. Even if all households had insecticidal bed nets, emerging insecticide resistance, behavioral changes and outdoor transmission by vectors raise concerns that existing tools are inadequate to eliminate or even interrupt intense malaria transmission. Near-term strategies to manage resistance have been outlined, but longer-term research into new anti-vector interventions to complement existing tools is imperative. Many basic aspects of anopheline biology that could contribute to more effective control remain poorly defined. Anopheles funestus is one of the three most important and widespread vectors of human malaria in tropical Africa, but unlike An. gambiae, it is understudied. This major vector conceals a group of close relatives that are morphologically similar or identical as adults. None of these species, with one exception, has been directly implicated as a secondary vector. However, they can rest indoors in large numbers and are considered important due to their impact on scarce resources available for vector control. They overlap with An. funestus, but their geographic distribution is largely unknown, and their actual or potential contribution to malaria transmission is also uncertain. Traditionally characterized as zoophilic and exophilic, their behavior is plastic and depends upon host availability and other (unknown) environmental factors. Moreover, the taxonomic complexity of this group is at least as high as the better- known An. gambiae complex; within each named (or unnamed) species are genetically heterogeneous clusters whose interrelationships have never been resolved, and additional cryptic diversity is being reported by vector control programs. The central goal of this R21 is to elucidate the An. funestus complex. Toward this end, we propose two specific Aims: (1) Generate reference genome assemblies for species in the An. funestus complex. Complete reference genome assemblies have the power necessary to elucidate taxonomic and phylogenetic relationships among closely related taxa. Traditional approaches to genome assembly are impractical, but our preliminary data establish that the DISCOVAR de novo algorithm represents a simple, rapid and low-cost solution. (2) Assess sequence divergence and speciation history in the An. funestus complex. Using the new reference assemblies and additional light whole genome sequencing (~12 samples/taxon), we will analyze genome-wide SNP data to construct an initial portrait of population genomic patterns and species relationships for five members of the An. funestus complex. This project will provide the necessary frame of reference for species delimitation, identification, and vector incrimination in the An. funestus complex to support sustainable control or elimination of malaria transmission in Africa.
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1 |
2017 — 2021 |
Besansky, Nora Jessie |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Empowering Functional Genomics of An. Gambiae Through Inversion Genotyping @ University of Notre Dame
In Africa, where Anopheles gambiae is the primary vector, the intensity of transmission and the spread of resistance in parasite and vector populations pose major challenges to malaria control. New insecticides and novel vector control strategies complementary to existing ones are badly needed. Foundational genomic resources for novel vector-based strategies are newly available for An. gambiae. Together, they enable detailed population genomics and genome-wide association studies (GWAS) aimed at understanding the genetic basis of epidemiologically important traits. However, An. gambiae is highly polymorphic for chromosomal inversions. Failing to account for inversions can mislead population genetic and genome-wide association studies and obscure relationships between inversions and epidemiologically relevant traits. Yet despite rapid advances in genome technology, cytogenetic determination of inversion status is the only method currently available. Inversion status is not obvious from genome re-sequencing data, as alleles are mapped to their position on a reference genome and not to their actual physical locations. Unfortunately, cytogenetic analysis is impractical or even prohibitive. Addressing this gap, the central goal of this R01 is to develop and validate computational and molecular inversion genotyping approaches, enabling a modern assessment of the association between inversions and epidemiologically relevant traits. Toward this end, we propose three specific Aims: (1) Develop a computational karyotyping approach applicable to SNP genotype data. Our preliminary data for two inversions, based on existing Ag1000G sequences, indicates that there are SNPs that can serve as surrogate markers for alternative orientations. Using field-collected mosquitoes of known karyotype and with sequencing support from Ag1000G, we will validate these results on wider geographic samples and extend them to additional inversions. (2) Develop a molecular karyotyping approach applicable without sequencing. Using an existing battery of karyotyped samples, we will develop simple and rapid molecular assays that eliminate the need to PCR amplify across variable breakpoint regions, and are accessible to any lab. (3) Assess the association between karyotype and malariologically important parameters. Leveraging existing An. gambiae samples, we will apply our computational and molecular karyotyping methods to test for a relationship between karyotype, indoor resting behavior, and parasite rate. Together, these tools will empower efforts to map and monitor epidemiologically important traits in vector populations.
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