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Resources for Teleost Gene Duplicates and Human Disease

Award Number: R01OD011116
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/18/2005
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Resources for Teleost Gene Duplicates and Human Disease - PROJECT SUMMARY/ABSTRACT: Genome-wide association studies (GWAS) have detected thousands of single nucleotide polymorphisms (SNPs) at hundreds of loci associated with numerous human diseases. Understanding GWAS loci can help decipher mechanisms of complex diseases and personalize therapies across many NIH institutes. The problem is that GWAS disease loci occupy blocks of linkage disequilibrium containing several or no genes, are merely linked to the as yet unknown causative agents, and usually reside in difficult-to- study noncoding regions that are likely regulatory and often act at long range. The usual hypothesis is that the gene nearest the lead SNP is causative, but this idea must be tested. A barrier to progress is that, because cis-regulatory modules can act at a distance, their targets and modes of action are usually unclear. Comparative medicine can help provide a way forward. Teleost fish, including zebrafish, share physiology, behavior, development, and orthologous genetic pathways with humans, but possess evolved genomic differences we can exploit to understand GWAS locus functions. Prior support uncovered the Teleost Genome Duplication (TGD) and showed that spotted gar represents the most recently diverging lineage before the TGD with a genome that bridges teleost medical models to human biology. These features help associate GWAS loci with target genes because the two teleost duplicates often retained different ancestral tissue-specific regulatory elements or protein domains (subfunctionalization); duplicated genes resolved to single copy differently in different teleosts; and teleosts have many chromosome rearrangements compared to human. We exploit these features to distinguish targets from bystander genes at GWAS loci. Our broad goal is to develop resources to help annotate functions of non-coding genetic elements, including GWAS loci, for human disease. Aim1 is to develop a resource that connects teleost genomes to human biology by mapping human conserved non-coding elements (CNEs) to teleost genomes; by analyzing conserved syntenies to address hypotheses for GWAS disease locus targets; and by providing results in an interactive genome browser. Aim2 is to identify regulatory loci by mapping actively transcribing genes, regions of open chromatin, and chromatin conformation domains in key developmental stages and tissues standardized across four ray-fin fish; and by making results public in a UCSC browser and ZFIN. Aim3 is to find functions of GWAS loci for bone mineral density (BMD) diseases by making and characterizing phenotypes of loss-of-function alleles of zebrafish orthologs of human GWAS BMD loci and by testing these loci for enhancer activity. Expected outcomes include a resource for ruling out potential targets of GWAS loci; a genome-wide correlation of expression and epigenetic landmarks for teleost orthologs of human GWAS loci, and a better understanding of the mechanisms by which GWAS loci alter human bone mineral density. Significance: these studies provide resources to improve teleost models for understanding the roles of human non-coding functional elements, including GWAS loci, in health and disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$2,208 )
2023	2020	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	000	14	1/23/2023	NON-COMPETING CONTINUATION	-$1,462
2023	2020	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	001	14	1/23/2023	SUPPLEMENT FOR EXPANSION	-$746
														Subtotal = -$2,208

Issue Date FY: 2020 ( Subtotal = $952,673 )
2020	2020	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	000	14	6/30/2020	NON-COMPETING CONTINUATION	$630,812
2020	2020	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	001	14	7/29/2020	SUPPLEMENT FOR EXPANSION	$321,861
														Subtotal = $952,673

Issue Date FY: 2019 ( Subtotal = $630,812 )
2019	2019	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	000	13	6/27/2019	NON-COMPETING CONTINUATION	$630,812
														Subtotal = $630,812

Issue Date FY: 2018 ( Subtotal = $630,812 )
2018	2018	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	000	12	6/1/2018	NON-COMPETING CONTINUATION	$630,812
														Subtotal = $630,812

Issue Date FY: 2017 ( Subtotal = $599,272 )
2017	2017	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	003	11	9/6/2017	NON-COMPETING CONTINUATION	$31,541
2017	2017	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	002	11	5/30/2017	NON-COMPETING CONTINUATION	$567,731
2017	2016	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	001	10	4/17/2017	COMPETING CONTINUATION	$2,208
2017	2014	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	000	9	4/17/2017	SUPPLEMENT FOR EXPANSION	-$2,208
														Subtotal = $599,272

Issue Date FY: 2016 ( Subtotal = $473,109 )
2016	2016	UNIVERSITY OF OREGON	POST OFFICE BOX 3237	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	002	10	9/12/2016	COMPETING CONTINUATION	$473,109
2016	2014	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	000	9	8/31/2016	NON-COMPETING CONTINUATION	$0
2016	2014	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	001	9	9/11/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $473,109

Issue Date FY: 2014 ( Subtotal = $849,792 )
2014	2014	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	000	9	6/26/2014	NON-COMPETING CONTINUATION	$618,443
2014	2014	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	001	9	8/27/2014	SUPPLEMENT FOR EXPANSION	$231,349
														Subtotal = $849,792

Issue Date FY: 2013 ( Subtotal = $604,594 )
2013	2013	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	000	8	7/15/2013	NON-COMPETING CONTINUATION	$604,594
														Subtotal = $604,594

Issue Date FY: 2012 ( Subtotal = $658,038 )
2012	2012	UNIVERSITY OF OREGON	5219 UNIVERSITY OF OREGON	EUGENE	OR	97403	LANE	USA	Research Infrastructure Programs	000	7	6/18/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$658,038
														Subtotal = $658,038

Grand Total All Awards = $5,396,894

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Resources for Teleost Gene Duplicates and Human Disease

Award Number: R01OD011116

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/18/2005

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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