The abundance of cis-acting loci leading to differential allele expression in F1 mice and their relationship to loci harboring genes affecting complex traits

Abstract

BackgroundGenome-wide surveys have detected cis-acting quantitative trait loci altering levels of RNA transcripts (RNA-eQTLs) by associating SNV alleles to transcript levels. However, the sensitivity and specificity of detection of cis- expression quantitative trait loci (eQTLs) by genetic approaches, reliant as it is on measurements of transcript levels in recombinant inbred strains or offspring from arranged crosses, is unknown, as is their relationship to QTL’s for complex phenotypes.ResultsWe used transcriptome-wide differential allele expression (DAE) to detect cis-eQTLs in forebrain and kidney from reciprocal crosses between three mouse inbred strains, 129S1/SvlmJ, DBA/2J, and CAST/EiJ and C57BL/6 J. Two of these crosses were previously characterized for cis-eQTLs and QTLs for various complex phenotypes by genetic analysis of recombinant inbred (RI) strains. 5.4 %, 1.9 % and 1.5 % of genes assayed in forebrain of B6/129SF1, B6/DBAF1, and B6/CASTF1 mice, respectively, showed differential allelic expression, indicative of cis-acting alleles at these genes. Moreover, the majority of DAE QTLs were observed to be tissue-specific with only a small fraction showing cis-effects in both tissues. Comparing DAE QTLs in F1 mice to cis-eQTLs previously mapped in RI strains we observed that many of the cis-eQTLs were not confirmed by DAE. Additionally several novel DAE-QTLs not identified as cis-eQTLs were identified suggesting that there are differences in sensitivity and specificity for QTL detection between the two methodologies. Strain specific DAE QTLs in B6/DBAF1 mice were located in excess at candidate genes for alcohol use disorders, seizures, and angiogenesis previously implicated by genetic linkage in C57BL/6J × DBA/2JF2 mice or BXD RI strains.ConclusionsVia a survey for differential allele expression in F1 mice, a substantial proportion of genes were found to have alleles altering expression in cis-acting fashion. Comparing forebrain and kidney, many or most of these alleles were tissue-specific in action. The identification of strain specific DAE QTLs, can assist in assessment of candidate genes located within the large intervals associated with trait QTLs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2922-9) contains supplementary material, which is available to authorized users.

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet syndrome

“…These studies demonstrated relatively lower Gabra2 transcript and protein levels in the B6 and F1 seizure susceptible strains compared to the 129 protective background strain. This strain dependence of expression of GABA receptor subunits is consistent with previous reports (Korostynski et al 2006;Mulligan et al 2012;Yeo et al 2016). Moreover, the administration of the 1,5-BDZ clobazam (CLB) is associated with a higher temperature threshold for hyperthermia-induced seizures in F1.Scn1a +/− mice, which indicates that potentiating GABA A receptors has a strong anti-seizure effect in these mice .…”

“…We and others have previously reported that there is marked strain dependence in the expression levels of the α 2 subunit of GABA A receptors (Mulligan et al 2012;Yeo et al 2016). This strain dependent expression difference is correlated with phenotype severity in the DS mouse model, suggesting that it may contribute to the underlying protection from seizures in 129.Scn1a +/− mice .…”

“…; Yeo et al . ). This strain dependent expression difference is correlated with phenotype severity in the DS mouse model, suggesting that it may contribute to the underlying protection from seizures in 129.…”

“…; Yeo et al . ). Moreover, the administration of the 1,5‐BDZ clobazam (CLB) is associated with a higher temperature threshold for hyperthermia‐induced seizures in F1.…”

Acute and long-term effects of Δ9-tetrahydrocannabinol on object recognition and anxiety-like activity are age- and strain-dependent in mice

“…Strategies such as assessing behavior in a panel of recombinant inbred strains, such as the B6 by D2 cross (BXD RI), allow for genetic mapping of quantitative trait loci (QTLs) or chromosomal regions that may contain genes that influence susceptibility or resistance to THC-related behaviors (Plomin et al, 1991; Williams & Williams, 2017). Newer techniques in RNA and chromatin sequencing also make it possible to identify epigenetic alterations following THC treatment (Scott-Boyer & Deschepper, 2013; Goldowitz et al, 2014; Yeo et al, 2016). These preclinical advances are critical in identifying translational biomarkers of risk and consequences of drug use in human populations (Crabbe, 2016).…”