Dynamic variation in allele-specific gene expression of Paraoxonase-1 in murine and human tissues

Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada.
Human Molecular Genetics (Impact Factor: 6.39). 09/2008; 17(21):3263-70. DOI: 10.1093/hmg/ddn222
Source: PubMed


Differential allelic expression has been shown to be common in mice, humans and maize, and variability in the expression of polymorphic alleles has been associated with human disease. Here, we describe the differential expression pattern of Paraoxonase-1, a gene involved in lipid metabolism and implicated in the formation of atherosclerotic lesions. We measured the expression of the murine Paraoxonase-1 gene (Pon1) in livers at different stages of embryonic development using F1 hybrid crosses and quantified the transcriptional level of both parental alleles. Using human foetal tissues, we analysed the expression of the human orthologue (PON1) and found monoallelic or preferential allelic expression in 6/7 and 4/4 samples from liver and pancreas, respectively. We observed that Pon1 does not show a parent-of-origin preference in its allelic expression, but has dramatic variations in allele-specific expression occurring throughout development. This study has important repercussions in the analysis of haplotypes at disease loci, since it implies that the expression of polymorphic alleles can be unequal and dynamic.

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    • "Allelic imbalance (AI) in gene expression, which refers to the differential expression of alternative alleles of the same gene, was initially characterized for epigenetic events such as gene imprinting or X chromosome inactivation. However, recent studies have found convincing evidence that AI exists in autosomal non-imprinted genes and demonstrated that AI is a common phenomenon in humans as well as in other species (Yan et al., 2002b; Lo et al., 2003; Guo et al., 2004; Pant et al., 2006; Parker-Katiraee et al., 2008). Genome-wide analysis of AI has suggested that about 4.6% of heterozygous SNP-sample pairs show evidence of AI (Heap et al., 2009). "
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    ABSTRACT: Human dendritic cells (DCs) play an important role in induction and progression of Crohn's disease (CD). Accumulating evidence suggests that viral infection is required to trigger CD pathogenesis in genetically predisposed individuals. NOD2 and ATG16L1 are among the major CD susceptibility genes implicated in impaired immune response to bacterial infection. In this study, we investigated gene expression and allelic imbalance (AI) of NOD2 and ATG16L1 using common variants in human monocyte-derived DCs. Significant AI was observed in ~40% and ~70% of NOD2 and ATG16L1 heterozygotes, respectively (p<0.05). AI of NOD2 was inversely associated with its expression level (p=0.015). No correlation was detected between gene expression and AI for ATG16L1. When infected with Newcastle disease virus (NDV), NOD2 expression in DCs was induced about four-fold (p<0.001), whereas ATG16L1 expression was not affected (p=0.88). In addition, NDV infection tended to lower the variance in AI among DC populations for the NOD2 gene (p=0.05), but not the ATG16L1 gene (p=0.32). Findings of a simulation study, aimed to verify whether the observed variation in gene expression and AI is a result of sample-to-sample variability or experimental measurement error, suggested that NOD2 AI is likely to result from a deterministic event at a single cell level. Overall, our results present initial evidence that AI of the NOD2 and ATG16L1 genes exists in populations of human DCs. In addition, our findings suggest that viral infection may regulate NOD2 expression.
    Gene 07/2013; 527(2). DOI:10.1016/j.gene.2013.06.066 · 2.14 Impact Factor
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    • "Allele-specific expression is independent of which parent the specific allele originated from, but it is inherited and disease susceptibility genes in humans display allele-specific expression . Heterozygous carriers of several disease susceptibility genes express the wild-type allele but have undetectable levels of the disease susceptibility allele (Okamoto et al., 1994; Yan et al., 2002b; Parker-Katiraee et al., 2008; Voutsinas et al., 2010). It is estimated that most individuals are carriers of a few deleterious genes yet do not display disease symptoms (Morton et al., 1956), and relatively small changes in gene expression can have a dramatic impact on susceptibility to disease (Yan et al., 2002a). "
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    ABSTRACT: Hybrids between genetically diverse varieties display enhanced growth, and increased total biomass, stress resistance and grain yield. Gene expression and metabolic studies in maize, rice and other species suggest that protein metabolism plays a role in the growth differences between hybrids and inbreds. Single trait heterosis can be explained by the existing theories of dominance, overdominance and epistasis. General multigenic heterosis is observed in a wide variety of different species and is likely to share a common underlying biological mechanism. This review presents a model to explain differences in growth and yield caused by general multigenic heterosis. The model describes multigenic heterosis in terms of energy-use efficiency and faster cell cycle progression where hybrids have more efficient growth than inbreds because of differences in protein metabolism. The proposed model is consistent with the observed variation of gene expression in different pairs of inbred lines and hybrid offspring as well as growth differences in polyploids and aneuploids. It also suggests an approach to enhance yield gains in both hybrid and inbred crops via the creation of an appropriate computational analysis pipeline coupled to an efficient molecular breeding program.
    New Phytologist 03/2011; 189(4):923-37. DOI:10.1111/j.1469-8137.2010.03574.x · 7.67 Impact Factor
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    ABSTRACT: Exposure to organophosphate (OP's) insecticides and nerve gases during the Persian Gulf War has been implicated in the development of Gulf War Syndrome. Paraoxonase (PON1) present in human serum detoxifies OP's. We determined the levels of PON1 in the serum of Gulf War Veterans and compared these to those found in a control population. One hundred fifty-two Gulf War Veterans from the UK who self-reported the presence of Gulf War Syndrome via a questionnaire and 152 age and gender matched controls were studied. PON1 activity, concentration, and genotype were determined. In the Gulf War Veterans, paraoxon hydrolysis was less than 50% of that found in the controls (100.3 (14.8-233.8) vs 214.6 (50.3-516.2) nmol/min/ml, P < 0.001). This low activity was independent of the effect of PON1 genotype. The serum PON1 concentration was also lower in the Gulf War Veterans (75.7 (18.1-351.3) vs 88.2 (34.5-527.4) microg/ml, P < 0.00025), which was again independent of PON1 genotype. There was no difference in the rate of diazoxon hydrolysis between the groups (10. 2 +/- 4.1 micromol/min/ml vs 9.86 +/- 4.4, P = NS). A decreased capacity to detoxify OP insecticides resulting from low serum PON1 activity may have contributed to the development of Gulf War Syndrome.
    Biochemical and Biophysical Research Communications 10/2000; 276(2):729-33. DOI:10.1006/bbrc.2000.3526 · 2.30 Impact Factor
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