The Problem of Passenger Genes in Transgenic Mice

Lusis, Aldons J.; Yu, Jiujiu; Wang, Susanna S.

doi:10.1161/atvbaha.107.147918

Cited by 61 publications

(71 citation statements)

References 25 publications

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“…In addition to encoding proteins performing a wide diversity of functions (see below), the regulated genes in both Cx43 KO and SI astrocytes were located on all chromosomes as presented in Figure 2A. This lack of association of altered genes with a particular chromosome indicates that effects of both knockdown and knockout are not due to bystander effects related to chromosome location (see Cajiao et al, 2004) or "passenger effects" of the transgene construct (see Lusis et al 2007). …”

Section: Gene Expression Regulationmentioning

confidence: 98%

Similar Transcriptomic Alterations in Cx43 Knockdown and Knockout Astrocytes

Iacobaş

Urban-Maldonado

et al. 2008

Cell Communication & Adhesion

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Previous findings of widespread transcriptomic alteration in tissues from connexin null mice raise the issue of whether the transcriptomic changes are directly due to connexin downregulation or to "compensatory" developmental alterations for the missing gene. To start addressing this question, the authors compared with wild-type control the gene expression profiles of connexin43 (Cx43) knockout and Cx43siRNA knockdown wild-type cortical astrocytes. Array analysis revealed remarkable parallelism of transcriptomic changes in knockout and knockdown astrocytes, with similarly altered genes being located on all chromosomes and encoding proteins involved in a wide diversity of cell functions. Moreover, gene expression variability was analogously higher in Cx43 null and siRNA-treated astrocytes, and expression interlinkages were similarly altered among a selected subset of genes. This highly significant overlap between transcriptomic alterations in Cx43 knockout and knockdown astrocytes suggests that the widespread changes more likely reflect connexin-dependent Gene Regulatory Networks rather than developmental compensation for the missing gene.

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Section: Gene Expression Regulationmentioning

confidence: 98%

Similar Transcriptomic Alterations in Cx43 Knockdown and Knockout Astrocytes

Iacobaş

Urban-Maldonado

et al. 2008

Cell Communication & Adhesion

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“…The fi rst study showed a signifi cant association between cholesterol effl ux from human skin fi broblasts and increased carotid intima media thickness (cIMT; a surrogate endpoint for cardiovascular endpoints) in nine individuals (49). The second study, of 142 subjects undergoing coronary angiography, showed correct interpretation diffi cult (79). The wide-spread use of cholate-containing atherogenic diets, especially in that period, causing liver toxicity and gall stone formation, further complicates matters (80).…”

Section: Other Potentially Atheroprotective Propertiesmentioning

confidence: 99%

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

Vergeer

Holleboom

Kastelein

et al. 2010

Journal of Lipid Research

200

122

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This article is available online at http://www.jlr.org the imagination. Because of a general consensus that HDL protects against atherosclerosis, what we shall term the HDL hypothesis, strategies have been developed to raise plasma HDL levels or to improve HDL function. However, it is increasingly questioned whether such interventions will indeed reduce the risk of atherosclerosis. This review summarizes the reported evidence that supports the HDL hypothesis. EPIDEMIOLOGYA low plasma HDL-C concentration is among the strongest, statistically independent risk factors for cardiovascular disease (CVD) (2). In a widely cited meta-analysis of four large studies (total number of individuals studied: 15,252), a 1 mg/dl increase of HDL-C levels was reported to be associated with a 2-3% decreased CVD risk (3). This result provides an epidemiological argument in favor of therapeutically raising HDL-C levels. One may draw parallels with the detrimental consequences of elevated lowdensity lipoprotein cholesterol (LDL-C) levels and blood pressure, which have been successfully controlled through therapy, resulting in signifi cant reductions of cardiovascular mortality and morbidity (4, 5) . It should be noted, however, that the associations between elevated LDL-C and blood pressure and increased CVD risk refl ect causal relationships, whereas such a relation between low HDL-C levels and increased CVD is not undisputed (6, 7). This is related to the fact that HDL-C levels are infl uenced by many different variables that also affect CVD risk: 1 ) Men have on average lower HDL-C levels than women (8). (1) reported that plasma levels of high-density lipoprotein cholesterol (HDL-C) were reduced in patients with coronary artery disease. In 1977, Gordon et al. (2) subsequently showed that low HDL-C is a risk factor for coronary heart disease in the Framingham study. These important fi ndings have given rise to a large number of diverse HDL studies over the last few decades. The numerous different and apparently unrelated beneficial effects that have since been ascribed to HDL appeal to

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“…Genetargeted mice are usually initially created on one of the many substrains of 129 mice, and the null mutation subsequently transferred into C57BL/6 (B6). Thus, unless separated by recombinations, the region flanking the targeted gene from 129 will be carried with the targeted gene (2). This can lead to incorrect conclusions if allelic differences between 129 and B6 affect HDL.…”

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confidence: 99%

Genetic basis of HDL variation in 129/SvImJ and C57BL/6J mice: importance of testing candidate genes in targeted mutant mice

Wang²,

Tsaih

et al. 2009

Journal of Lipid Research

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To evaluate the effect of genetic background on high-density lipoprotein cholesterol (HDL) levels in Soat1 2/2 mice, we backcrossed sterol O-acyltransferase 1 (Soat1) 2/2 mice, originally reported to have elevated HDL levels, to C57BL/6 mice and constructed a congenic strain with only a small region (3.3Mb) of 129 alleles, specifically excluding the nearby apolipoprotein A-II (Apoa2) gene from 129. HDL levels in these Soat1 2/2 mice were no different from C57BL/6, indicating that the passenger gene Apoa2 caused the previously reported elevation of HDL in these Soat1 2/2 mice. Because many knockouts are made in strain 129 and then subsequently backcrossed into C57BL/6, it is important to identify quantitative trait loci (QTL) that differ between 129 and C57BL/6 so that one can guard against effects ascribed to a knockout but really caused by a passenger gene from 129. To provide such data, we generated 528 F 2 progeny from an intercross of 129S1/SvImJ and C57BL/6 and measured HDL concentrations in F 2 animals first fed chow and then atherogenic diet. A genome wide scan using 508 single-nucleotide polymorphisms (SNPs) identified 19 QTL, 2 of which were male specific and 2 were female specific. Using comparative genomics and haplotype analysis, we narrowed QTL on chromosomes 3, 5, 8, 17, and 18 to 0.5, 6.3, 2.6, 1.1, and 0.6 Mb, respectively. These data will serve as a reference for any effort to test the impact of candidate genes on HDL using a knockout strategy.-Su, Z., X. Wang, S-W. Tsaih, A. Zhang, A. Cox, S. Sheehan, and B. Paigen. Plasma high-density lipoprotein cholesterol (HDL) is a quantitative trait determined by the interactions of multiple genes and environmental factors. Because elevated plasma HDL is protective for cardiovascular disease (1), there has been considerable interest in understanding genetic factors contributing to variations in HDL levels. One method to determine whether a candidate quantitative trait loci (QTL) gene truly affects the phenotype is to construct a mouse line with a deficiency of the gene. Genetargeted mice are usually initially created on one of the many substrains of 129 mice, and the null mutation subsequently transferred into C57BL/6 (B6). Thus, unless separated by recombinations, the region flanking the targeted gene from 129 will be carried with the targeted gene (2). This can lead to incorrect conclusions if allelic differences between 129 and B6 affect HDL. The HDL levels of the targeted mice might be attributable to the effects of the targeted gene when the difference is really caused by flanking linked loci. This is exemplified by the observations described in this paper that elevated HDL levels in Soat1 knockout (KO) mice were due to a passenger allele of Apoa2 from strain 129 rather than the null mutation. Soat1 encodes sterol O-acyltransferase (acyl-CoA: cholesterol acyltransferase, ACAT) 1, which is an intracellular enzyme that catalyzes the formation of cholesteryl esters from cholesterol and fatty acyl-CoA (3).The problem of misinterpreting the cause...

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The Problem of Passenger Genes in Transgenic Mice

Cited by 61 publications

References 25 publications

Similar Transcriptomic Alterations in Cx43 Knockdown and Knockout Astrocytes

Similar Transcriptomic Alterations in Cx43 Knockdown and Knockout Astrocytes

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

Genetic basis of HDL variation in 129/SvImJ and C57BL/6J mice: importance of testing candidate genes in targeted mutant mice

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