Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

Park, Christopher C.; Ahn, Sangtae; Bloom, Joshua S.; Lin, Andy; Wang, Richard T.; Wu, Tongning; Sekar, Aswin; Ah, Khan; Farr, Carol L.; Lusis, Aldons J.; Leahy, Richard M.; Lange, Kenneth; Smith, Desmond J.

doi:10.1038/ng.113

Cited by 28 publications

(39 citation statements)

References 43 publications

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“…55]). These data are consistent with published eQTL studies that have indicated that trans-eQTL intervals encode many different gene classes, such as transcription factors, microRNAs, ligands, receptors, enzymes, substrates, or subunits of protein complexes that can affect their target transcript via a context-dependent mechanism (26,56,57). These studies have also shown that functional variants underlying cis-eQTLs often involve multiple linked polymorphisms resulting in haplotype effects (58)(59)(60).…”

Section: Figuresupporting

confidence: 90%

Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression

Papeta¹,

Chan²,

Prakash³

et al. 2009

J. Clin. Invest.

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Multiple studies have linked podocyte gene variants to diverse sporadic nephropathies, including HIV-1-associated nephropathy (HIVAN). We previously used linkage analysis to identify a major HIVAN susceptibility locus in mouse, HIVAN1. We performed expression quantitative trait locus (eQTL) analysis of podocyte genes in HIV-1 transgenic mice to gain further insight into genetic susceptibility to HIVAN. In 2 independent crosses, we found that transcript levels of the podocyte gene nephrosis 2 homolog (Nphs2), were heritable and controlled by an ancestral cis-eQTL that conferred a 3-fold variation in expression and produced reactive changes in other podocyte genes. In addition, Nphs2 expression was controlled by 2 trans-eQTLs that localized to the nephropathy susceptibility intervals HIVAN1 and HIVAN2. Transregulation of podocyte genes was observed in the absence of HIV-1 or glomerulosclerosis, indicating that nephropathy susceptibility alleles induce latent perturbations in the podocyte expression network. Presence of the HIV-1 transgene interfered with transregulation, demonstrating effects of gene-environment interactions on disease. These data demonstrate that transcript levels of Nphs2 and related podocyte-expressed genes are networked and suggest that the genetic lesions introduced by HIVAN susceptibility alleles perturb this regulatory pathway and transcriptional responses to HIV-1, increasing susceptibility to nephropathy.

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Section: Figuresupporting

confidence: 90%

Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression

Papeta¹,

Chan²,

Prakash³

et al. 2009

J. Clin. Invest.

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“…This fi nding is consistent with published eQTL studies, which have indicated that trans -eQTL intervals encode many different gene classes, including receptors and their ligands, which can affect their target transcript via a context-dependent mechanism (51)(52)(53). Together, the central components of the trans -networks typically represented hierarchically high positions in signaling cascades, whereas downstream components of signaling pathways were represented in the cis -networks.…”

Section: Whole-genome Association Analyses For Abundance Of Transcripsupporting

confidence: 90%

Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model

Ponsuksili

Muráni

Brand

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org lated to body composition, leanness, and obesity. Traits related to fatness are important not only as economic factors in pork production but also because of their association with serious diseases in humans ( 1, 2 ). Pigs share many similarities with humans in physiology and genomes and, therefore, provide a good model to study the genetic determination of complex traits ( 3 ). The study of a porcine model is benefi cial because a number of fatness traits (e.g., "fat area") can be determined quantitatively with great accuracy and reproducibility post mortem, and RNA samples are available for transcriptomic approaches. In humans, indices for obesity are obtained intra vitam (i.e., body mass index or body fat percentage are estimated based on statistical models of measures of near-infrared interactance, body average density measurement, bioelectrical impedance analysis, or anthropometric methods) ( 4 ).Functional genomics provides an insight into the molecular processes underlying phenotypic differences. The analysis of trait-correlated expression levels reveals genes belonging to pathways or networks relevant for the control of quantitative traits. However, holistic expression profi ling does not often discriminate differential expression of the genes as either an effect or a cause of variation.Genome-wide association studies (GWAS) in large natural populations of unrelated individuals have resulted in the association of many genes with complex traits (http:// www. genome.gov/gwastudies). Unfortunately, for a conAbstract Traits related to fatness, important as economic factors in pork production, are associated with serious diseases in humans. Genetical genomics is a useful approach for studying the effects of genetic variation at the molecular level in biological systems. Here we applied a whole-genome association analysis to hepatic gene expression traits, focusing on transcripts with expression levels that correlated with fatness traits in a porcine model. A total of 150 crossbred pigs [Pietrain×(German Large White × German Landrace)] were studied for transcript levels in the liver. The 24K Affymetrix expression microarrays and 60K Illumina single nucleotide polymorphism (SNP) chips were used for genotyping. A total of 663 genes, whose expression signifi cantly correlated with the trait "fat area," were analyzed for enrichment of functional annotation groups as defi ned in the Ingenuity Pathways Knowledge Base (IPKB). Genes involved in metabolism of various macromolecules and nutrients as well as functions related to dynamic cellular processes correlated with fatness traits. Regions affecting the transcription levels of these genes were mapped and revealed 4,727 expression quantitative trait loci (eQTL) at P < 10 The metabolic activities of the liver are essential for providing fuel to the peripheral organs. Most components absorbed by the intestine pass through the liver, which enables it to regulate the levels of many metabolites in the blood. Storage, ...

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“…By accounting for the length of gene regulatory domains, GREAT is able to highlight biologically meaningful terms and their associated cis -regulatory regions and genes, in a manner that remains robust if there are false associations between input regions and genes. Moreover, these regulatory-domain definitions can naturally incorporate future results from three-dimensional conformation capture studies 17–19 , radiation hybrid maps 42 and other emerging approaches for measuring the regulatory genome in action. By coupling this methodology with many ontologies that span a wealth of biological information types, GREAT produces specific, accurate enrichments that provide insight into the biological roles of cis -regulatory data sets of interest.…”

Section: Discussionmentioning

confidence: 99%

“…50). Future releases of the tool will continue to refine regulatory domains as technological advances, including three-dimensional conformation capture studies 17–19 and radiation hybrid maps 42 , further elucidate interactions between regulatory DNA and its target genes.…”

Section: Methodsmentioning

confidence: 99%

GREAT improves functional interpretation of cis-regulatory regions

et al. 2010

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We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions. GREAT incorporates annotations from 20 ontologies and is available as a web application. Applying GREAT to data sets from chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3 and p300 in different developmental contexts, we recover many functions of these factors that are missed by existing gene-based tools, and we generate testable hypotheses. The utility of GREAT is not limited to ChIP-seq, as it could also be applied to open chromatin, localized epigenomic markers and similar functional data sets, as well as comparative genomics sets.

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Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

Cited by 28 publications

References 43 publications

Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression

Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression

Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model

GREAT improves functional interpretation of cis-regulatory regions

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