<i>Cis</i>-acting expression quantitative trait loci in mice

Doss, Sudheer; Schadt, Eric E.; Drake, Thomas A.; Lusis, Aldons J.

doi:10.1101/gr.3216905

Cited by 252 publications

(268 citation statements)

References 26 publications

Supporting

Mentioning

249

Contrasting

Order By: Relevance

“…In each cross, thousands of QTLs for transcript levels (expression QTLs or eQTLs) were identified, and those eQTLs mapping over their corresponding structural genes were considered to be cis-acting (i.e., because of variations of the gene itself). This cis-eQTL approach to identify cis-acting genes has been previously validated using a classic cis-trans test (13). Because both the BxH and BxD intercrosses demonstrated a DCC QTL at the Dyscalc1 locus, we reasoned that the causal gene would exhibit a cis-eQTL in both crosses.…”

Section: Resultsmentioning

confidence: 99%

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

Meng

Vera²,

Che³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

119

130

View full text Add to dashboard Cite

The genetic factors contributing to the complex disorder of myocardial calcification are largely unknown. Using a mouse model, we fine-mapped the major locus (Dyscalc1) contributing to the dystrophic cardiac calcification (DCC) to an 840-kb interval containing 38 genes. We then identified the causal gene by using an approach integrating genetic segregation and expression array analyses to identify, on a global scale, cis-acting DNA variations that perturb gene expression. By studying two intercrosses, in which the DCC trait segregates, a single candidate gene (encoding the ATPbinding cassette transporter ABCC6) was identified. Transgenic complementation confirmed Abcc6 as the underlying causal gene for Dyscalc1. We demonstrate that in the cross, the expression of Abcc6 is highly correlated with the local mineralization regulatory system and the BMP2-Wnt signaling pathway known to be involved in the systemic regulation of calcification, suggesting potential pathways for the action of Abcc6 in DCC. Our results demonstrate the power of the integrative genomics in discovering causal genes and pathways underlying complex traits.expression quantitative trait locus ͉ transgenic ͉ positional cloning ͉ osteopontin C haracterized by hydroxyapatite deposition in necrotic myocytes, myocardial calcification is common in specific forms of cardiomyopathy and in myocardial infarction. It has been estimated that Ϸ8% of patients with severe myocardial infarction develop myocardial calcification within 6 years, suggesting a genetic predisposition for postinjury healing and remodeling processes (1). Historically, dystrophic cardiac calcification (DCC) has been considered a spontaneous form of cardiomyopathy in mice, associated with a variety of predisposing factors, but with normal blood levels of calcium and phosphate. Experimentally, it can be reproducibly initiated using a transdiaphragmal freeze-thaw injury or a high-phosphorous (HP) diet (2, 3). Several inbred mouse strains, including C3H/HeJ (C3H) and DBA/2J (DBA), are highly susceptible, whereas many other inbred mouse strains, including C57BL/6J (B6), C57BL/10J (B10), A/J, MRL/MpJ, and BALB/cJ are resistant (refs. 4 and 5; X.W., T.A.D., and A.J.L., unpublished data). In DCC susceptible strains, calcification has also been observed in skeletal muscle, including in the tongue and diaphragm, and kidney, suggesting a systemic defect (2, 5).Using quantitative trait locus (QTL) analysis of an F 2 intercross between B6 and C3H mice (BxH), we previously mapped four DCC loci (6, 7). The locus on chromosome 7 (Dyscalc1), which exhibits recessive inheritance, explains 31% of the total genetic variance and is the major contributor. Dyscalc1 was confirmed by separate intercrosses of B6 and DBA mice (BxD) (5, 8). The C3H strain was originally derived from an outbreeding experiment of the DBA strain, leading us to hypothesize that the susceptible strains C3H and DBA share a common diseasecausing allele (8). To fine map the Dyscalc1 locus, we screened a panel of recombinant congenic (RC) s...

show abstract

Section: Resultsmentioning

confidence: 99%

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

Meng

Vera²,

Che³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

119

130

View full text Add to dashboard Cite

show abstract

“…However, the high cost of microarrays limits the sample size for global genetic mapping of transcript abundance. Many investigations have reported the (Morley et al, 2004;Doss et al, 2005;Hubner et al, 2005;MacLaren and Sikela, 2005;Stranger et al, 2005). Mapping of eQTL to the specific gene indicates that cis changes are responsible for the different expression levels, whereas mapping positions of eQTL that are different from the positions of the corresponding genes indicate trans regulation.…”

Section: Discussionmentioning

confidence: 99%

Expression quantitative trait loci analysis of genes in porcine muscle by quantitative real-time RT-PCR compared to microarray data

et al. 2010

View full text Add to dashboard Cite

Genetic analysis of transcriptional profiling is a promising approach for identifying biological pathways and dissecting the genetics of complex traits. Here, we report on expression quantitative trait loci (eQTL) that were estimated from the quantitative real-time RT-PCR data of 276 F 2 animals and compared with eQTL identified using 74 microarrays. In total, 13 genes were selected that showed trait-dependent expression in microarray experiments and exhibited 21 eQTL. Real-time RT-PCR and microarray data revealed seven cis eQTL in total, of which one was only detected by real-time RT-PCR, one was only detected by microarray analysis, three were consistently found in overlapping intervals and two were in neighbouring intervals on the same chromosome; whereas no trans eQTL was confirmed. We demonstrate that cis regulation is a stable characteristic of individual transcripts. Consequently, a global microarray eQTL analysis of a limited number of samples can be used for exploring functional and regulatory gene networks and scanning for cis eQTL, whereas the subsequent analysis of a subset of likely cis-regulated genes by realtime RT-PCR in a larger number of samples is relevant to narrow down a QTL region by targeting these positional candidate genes. In fact, when modelling SNPs of six genes as fixed effects in the eQTL analysis, eQTL peaks were shifted downwards, experimentally confirming the impact of the respective polymorphic genes, although these SNPs were not located in the regulatory sequence and these shifts occur as a result of linkage disequilibrium in the F 2 population.

show abstract

“…Like many other quantitative traits, variation in gene expression shows evidence of dominance and nonadditive (epistatic) interactions among loci Storey et al, 2005;Vuylsteke et al, 2005). Both cis-and transacting regulatory variants contribute significantly to regulatory variation within a species (Brem et al, 2002;Schadt et al, 2003;Yvert et al, 2003;Monks et al, 2004;Morley et al, 2004;Wayne et al, 2004;Doss et al, 2005;Kirst et al, 2005;Ronald et al, 2005). Although regulatory variation is clearly abundant within populations, its evolutionary significance is harder to ascertain.…”

Section: Genomic Variation In Gene Expressionmentioning

confidence: 99%

Evaluating the role of natural selection in the evolution of gene regulation

Fay¹,

2007

View full text Add to dashboard Cite

Surveys of gene expression reveal extensive variability both within and between a wide range of species. Compelling cases have been made for adaptive changes in gene regulation, but the proportion of expression divergence attributable to natural selection remains unclear. Distinguishing adaptive changes driven by positive selection from neutral divergence resulting from mutation and genetic drift is critical for understanding the evolution of gene expression. Here, we review the various methods that have been used to test for signs of selection in genomic expression data. We also discuss properties of regulatory systems relevant to neutral models of gene expression. Despite some potential caveats, published studies provide considerable evidence for adaptive changes in gene expression. Future challenges for studies of regulatory evolution will be to quantify the frequency of adaptive changes, identify the genetic basis of expression divergence and associate changes in gene expression with specific organismal phenotypes.

show abstract

Cis-acting expression quantitative trait loci in mice

Cited by 252 publications

References 26 publications

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

Expression quantitative trait loci analysis of genes in porcine muscle by quantitative real-time RT-PCR compared to microarray data

Evaluating the role of natural selection in the evolution of gene regulation

Contact Info

Product

Resources

About