NIH supports research on fish models for human disease because teleost fish, including zebrafish, allow the rapid and efficient use of resources to explore problems fundamental to the development and function of animals with backbones. This proposal describes resources to facilitate the translation of functional information from teleost medical models to human biology. Most teleost genes have a one-to-one relationship with human genes, but due to a genome duplication event, teleosts have two copies of many human genes, especially genes controlling developmental and physiological mechanisms. Teleost duplicates of human genes have often shared between them the functions of the corresponding mammalian single-copy gene (subfunctionalization) and have often evolved new functions (neofunctionalization) more rapidly than singletons. The problem is: Which functions of teleost genes are due to inheritance from the last common human/fish ancestor and which are due to evolution since the teleost genome duplication? Solutions to this problem are important because the connectivity of teleost and human genomes is crucial for translating teleost research to human biology. The most recently diverged unduplicated ray-fin fish provides a bridge to connect the duplicated teleost genome to the unduplicated human genome. Spotted gar (Lepisosteus oculatus) occupies an unduplicated recent outgroup to the teleost lineage and is a convenient system for genomic, gene expression, and gene function analyses.
Aim 1 is to construct a high-resolution genetic linkage map for spotted gar using an innovative next-generation sequence-based genotyping methodology.
Aim 2 is to construct a resource of expressed sequence tags (ESTs) for gar and to develop bioinformatics that assign ESTs to thousands of markers on the linkage map.
Aim 3 is to construct a resource of tiled BACs (bacterial artificial chromosomes) using a novel method that includes all markers on the genetic linkage map, and to develop bioinformatics to associate BACs to individual ESTs.
Aim 4 is to develop bioinformatic tools to integrate genetic markers, ESTs, and tiled clones into conserved synteny maps for comparative genomics of humans and teleosts.
Aim 5 is to test predictions of the hypotheses of subfunctionalization and neofunctionalization as mechanisms for the functional evolution of gene duplicates by using gar sequences to detect non-coding elements that function in transgenic zebrafish. Significance: Achieving these aims will provide resources that facilitate the connectivity of teleost and human genomes, thereby translating teleost biology to human biomedicine. Comparative maps of gar, teleost and human genomes focus attention on regions of the gar genome that contain singletons corresponding to duplicated biomedical genes in teleosts and to discover the functions of these unduplicated genes. Teleost researchers can exploit this knowledge to distinguish ancestral from derived gene structure and function, a critical question for teleost-to-human translational research.

Public Health Relevance

Fish biomedical models allow rapid and efficient analysis of human disease mechanisms. Most model fish species, however, possess a duplicated genome that often disrupts the one-to-one relationship between human and fish genes. Proposed work will provide genomic resources for an unduplicated fish genome that will better link model fish and human genomes and thus will more effectively translate research on fish biomedical models to human health and disease.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Project (R01)
Project #
8R01OD011116-07
Application #
8299075
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Chang, Michael
Project Start
2005-07-18
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$658,038
Indirect Cost
$184,278
Name
University of Oregon
Department
Other Basic Sciences
Type
Organized Research Units
DUNS #
948117312
City
Eugene
State
OR
Country
United States
Zip Code
97403
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Braasch, Ingo; Guiguen, Yann; Loker, Ryan et al. (2014) Connectivity of vertebrate genomes: Paired-related homeobox (Prrx) genes in spotted gar, basal teleosts, and tetrapods. Comp Biochem Physiol C Toxicol Pharmacol 163:24-36
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Schartl, Manfred; Walter, Ronald B; Shen, Yingjia et al. (2013) The genome of the platyfish, Xiphophorus maculatus, provides insights into evolutionary adaptation and several complex traits. Nat Genet 45:567-72
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Amemiya, Chris T; Alfoldi, Jessica; Lee, Alison P et al. (2013) The African coelacanth genome provides insights into tetrapod evolution. Nature 496:311-6

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