| NSF Org: |
IOS Division Of Integrative Organismal Systems |
| Recipient: |
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| Initial Amendment Date: | March 29, 2018 |
| Latest Amendment Date: | July 1, 2020 |
| Award Number: | 1755242 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Joanna Shisler
jshisler@nsf.gov (703)292-5368 IOS Division Of Integrative Organismal Systems BIO Directorate for Biological Sciences |
| Start Date: | April 1, 2018 |
| End Date: | March 31, 2022 (Estimated) |
| Total Intended Award Amount: | $148,992.00 |
| Total Awarded Amount to Date: | $148,992.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
11 W JONES ST RALEIGH NC US 27601-1029 (919)707-9847 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
11 W Jones Street Raleigh NC US 27601-1029 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): | Symbiosis Infection & Immunity |
| Primary Program Source: |
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| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.074 |
ABSTRACT
The ability of an organism to recognize invading pathogens, infected cells, or cancerous cells and kill them without causing excessive damage to itself is essential for survival. From fish to frogs to humans, all of the ~60,000 vertebrate species on earth use sophisticated immune cells to "inspect" every other cell in their body to determine if it is friend or foe. These immune cells possess a large number of protein receptors on their surface that work to maintain the peace. Many of these receptors are designed to recognize specific types of pathogens, forming a front line of defense. However, pathogens typically reproduce quickly, allowing them to evolve or change faster than most vertebrates and thereby develop ways to escape detection. In response, vertebrates have evolved a complex immune system that includes large groups of receptors that evolve faster than most other proteins and are specialized for anticipated as well as unanticipated pathogens. Fish represent half of all vertebrates and, as a group, are a great model for studying the genetic basis of these defenses. This project will use new and existing genomic data from numerous fish species to determine the origins of these receptors and study how these receptors have evolved to achieve the diversity observed today. Using fish as a model, this work will reveal fundamental aspects of immunity in all vertebrates. Data collected from this project will be incorporated into multiple new exhibits at the North Carolina Museum of Natural Sciences.
Ray-finned fish (Actinopterygii) constitute over half of the extant vertebrates on earth, making them a powerful system for understanding the genetic and functional evolution of immune genes. Fish not only share certain immune gene families with mammals, but also encode a number of highly diverse "fish-specific" immune gene families. Understanding the factors that underlie the diversification of gene families involved in immunity is critical for explaining the origins and sub-/neo-functionalization of new genes and for understanding the molecular basis of pathogen recognition and resistance. In order to provide an in-depth understanding of the origins of vertebrate immune gene families and their diversification dynamics, this project will integrate a phylogenetic comparative framework with new and existing transcriptome and genomic sequence data from multiple ray-finned fish lineages to determine how genomic architecture impacts the rate and mechanism of gene family evolution. This project will also evaluate the interdependence between genetically encoded markers of self and their candidate receptors. In total, this project will illuminate the evolution of recognition mechanisms that delineate self from non-self in all ray-finned fish, and reveal novel insight into both conserved and divergent means of accomplishing this critical immune function. Finally, this project will enable the creation of media content and interactive exhibits at the North Carolina Museum of Natural Sciences including a virtual reality and augmented reality video-game that teaches visitors fundamental aspects of how immune systems function.
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.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
The overall aim of this project was to understand the mechanisms and functional consequences of immune gene family diversification in ray-finned fishes. Comprising over half of all living vertebrates, ray-finned fishes are an excellent model for investigating the evolution of the innate immune system. However, studies of the ray-finned fish immune system have been largely restricted to a group of highly diverse fishes called teleosts, that contain over 99% of living fishes including pufferfish, clownfish, tuna, and seahorses. In this project, we established the evolutionary origins of two innate immune gene families previously thought to be limited to teleost fish species. We demonstrated that the evolutionary origins of these receptors, which include a family analogous to mammalian natural killer cell receptors, have an ancestry well before the rise of teleosts. Rather than being restricted to teleosts, we identified novel immune-type receptors (NITRs) and diverse immunoglobulin domain-containing proteins (DICPs) in more ancient fish lineages such as gars, bowfin and bichirs. Many immune receptor gene families like NITRs and DICPs are organized in clusters, whereas other immune receptor families are dispersed throughout the genome. Focusing on these innate immune receptor families, we hypothesized that gene clusters experienced more rapid evolution than dispersed gene families. Our work revealed that in ancient fishes, the NITR and DICP families of innate immune receptors are as diverse as sequences found in teleosts. Through a comparison of the dispersed Toll-Like Receptor immune receptor families, we found that the clustered nature of NITRs and DICPs likely contribute to their sequence diversity. We further reveal that the genome of bowfin, which diverged prior to teleosts, possesses a continuous major histocompatibility complex locus (MHC - which encodes a multitude of immune-related genes). The MHC complex in bowfin has a large degree of similarity to that in the human genome. As teleost MHC regions are more fragmented than bowfin and human, this finding provides a critically needed missing link for translating comparative immunogenetic research from research models such as zebrafish and medaka to humans. Additionally, by partnering with the North Carolina Museum of Natural Sciences, we developed several exhibits and special events that included interactive LED based games, science cafes, live-streamed talks, and behind the scenes tours, allowing us to illuminate often misunderstood topics such as human genetic diversity and herd immunity. Collectively, the results of our work have allowed us to engage with a diverse range of audiences that span K-12 students, young adults, and members of the scientific community, while filling critical knowledge gaps concerning the molecular evolution of clustered gene families within the innate immune system during the early history of vertebrates.
Last Modified: 05/02/2022
Modified by: Alex Dornburg
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