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.

Public Health Relevance

Genome-wide association studies (GWAS) have detected thousands of genetic variations associated with numerous human diseases near hundreds of genes. The problem is that we usually don't know which gene near a GWAS disease locus causes pathologies. Proposed work capitalizes on the advantages of comparative medicine, using evolutionarily rearranged genomes of fish medical models to test hypotheses for potential targets of GWAS disease loci. Expected outcomes will be resources to improve fish as disease models for understanding the roles of human non-coding functional elements, including GWAS loci, in health and disease.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
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Genetic Variation and Evolution Study Section (GVE)
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Contreras, Miguel A
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University of Oregon
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