# Resources for Teleost Gene Duplicates and Human Disease

> **NIH NIH R01** · UNIVERSITY OF OREGON · 2020 · $630,812

## Abstract

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
den...

## Key facts

- **NIH application ID:** 9967170
- **Project number:** 5R01OD011116-14
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** JOHN H. POSTLETHWAIT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $630,812
- **Award type:** 5
- **Project period:** 2005-07-18 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967170

## Citation

> US National Institutes of Health, RePORTER application 9967170, Resources for Teleost Gene Duplicates and Human Disease (5R01OD011116-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9967170. Licensed CC0.

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