Characterization of the quantitative trait locus for haloperidol-induced catalepsy on distal mouse chromosome 1

Department of Veterans Affairs, Richard L. Roudebush Medical Center, Indianapolis, IN 46202, USA.
Genes Brain and Behavior (Impact Factor: 3.66). 04/2008; 7(2):214-23. DOI: 10.1111/j.1601-183X.2007.00340.x
Source: PubMed


We report here the confirmation of the quantitative trait locus for haloperidol-induced catalepsy on distal chromosome (Chr) 1. We determined that this quantitative trait locus was captured in the B6.D2-Mtv7a/Ty congenic mouse strain, whose introgressed genomic interval extends from approximately 169.1 to 191.3 Mb. We then constructed a group of overlapping interval-specific congenic strains to further break up the interval and remapped the locus between 177.5 and 183.4 Mb. We next queried single nucleotide polymorphism (SNP) data sets and identified three genes with nonsynonymous coding SNPs in the quantitative trait locus. We also queried two brain gene expression data sets and found five known genes in this 5.9-Mb interval that are differentially expressed in both whole brain and striatum. Three of the candidate quantitative trait genes were differentially expressed using quantitative real-time polymerase chain reaction analyses. Overall, the current study illustrates how multiple approaches, including congenic fine mapping, SNP analysis and microarray gene expression screens, can be integrated both to reduce the quantitative trait locus interval significantly and to detect promising candidate quantitative trait genes.

Download full-text


Available from: Nicole A R Walter, Apr 01, 2015
  • Source
    • "The GeneNetwork mapping module (; Chesler et al. 2004; Wang et al. 2003) was used to identify eQTLs in striatum and whole-brain mRNA from untreated B6 × D2 F 2 mice [accessed on 15 September 2011; OHSU/VA B6D2F2 Striatum M430v2 (September 2005) RMA; OHSU/VA B6D2F2 Brain mRNA M430 (August 2005) RMA; Hitzemann et al. 2004; Hofstetter et al. 2008], as well as nucleus accumbens and prefrontal cortex from saline-injected BXD RI mice [accessed on 15 September 2011; VCU BXD NA Sal M430 2.0 (October 2007) RMA; VCU BXD PFC Sal M430 2.0 (December 2006) RMA; Wolen, Putnam & Miles unpublished data) that co-mapped with our behavioral QTLs. We focused on these regions because of their well-known role in drug-induced locomotor activity and reward (Di Chiara & Imperato 1988; Swerdlow et al. 1986); however, examining gene expression in additional brain areas would also be informative. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sensitivity to the locomotor stimulant effects of methamphetamine (MA) is a heritable trait that utilizes neurocircuitry also associated with the rewarding effects of drugs. We used the power of a C57BL/6J × DBA/2J F(2) intercross (n = 676) and the precision of a C57BL/6J × DBA/2J F(8) advanced intercross line (Aap: B6, D2-G8; or F(8) AIL; n = 552) to identify and narrow quantitative trait loci (QTLs) associated with sensitivity to the locomotor stimulant effects of MA. We used the program QTLRel to simultaneously map QTL in the F(2) and F(8) AIL mice. We identified six genome-wide significant QTLs associated with locomotor activity at baseline and seven genome-wide significant QTLs associated with MA-induced locomotor activation. The average per cent decrease in QTL width between the F(2) and the integrated analysis was 65%. Additionally, these QTLs showed a distinct temporal specificity within each session that allowed us to further refine their locations, and identify one QTL with a 1.8-LOD support interval of 1.47 Mb. Next, we utilized publicly available bioinformatics resources to exploit strain-specific sequence data and strain- and region-specific expression data to identify candidate genes. These results illustrate the power of AILs in conjunction with sequence and gene expression data to investigate the genetic underpinnings of behavioral and other traits.
    Genes Brain and Behavior 02/2012; 11(1):52-61. DOI:10.1111/j.1601-183X.2011.00747.x · 3.66 Impact Factor
  • Source
    • "An independent group of 20 mouse samples (5 male D2, 5 female D2, 5 male B6, and 5 female B6 were assessed using the Affymetrix MOE 430 2.0 array. These data were analyzed using the Robust Multichip Average methodology [31] on perfect match probes with the proposed background correction, quantile normalization, and summarization procedures as in previous work [13], [32], [33]. Differential expression was determined using the limma Bioconductor [34] package by fitting a linear model also incorporating gender status. "
    [Show abstract] [Hide abstract]
    ABSTRACT: C57BL/6J (B6) and DBA/2J (D2) are two of the most commonly used inbred mouse strains in neuroscience research. However, the only currently available mouse genome is based entirely on the B6 strain sequence. Subsequently, oligonucleotide microarray probes are based solely on this B6 reference sequence, making their application for gene expression profiling comparisons across mouse strains dubious due to their allelic sequence differences, including single nucleotide polymorphisms (SNPs). The emergence of next-generation sequencing (NGS) and the RNA-Seq application provides a clear alternative to oligonucleotide arrays for detecting differential gene expression without the problems inherent to hybridization-based technologies. Using RNA-Seq, an average of 22 million short sequencing reads were generated per sample for 21 samples (10 B6 and 11 D2), and these reads were aligned to the mouse reference genome, allowing 16,183 Ensembl genes to be queried in striatum for both strains. To determine differential expression, 'digital mRNA counting' is applied based on reads that map to exons. The current study compares RNA-Seq (Illumina GA IIx) with two microarray platforms (Illumina MouseRef-8 v2.0 and Affymetrix MOE 430 2.0) to detect differential striatal gene expression between the B6 and D2 inbred mouse strains. We show that by using stringent data processing requirements differential expression as determined by RNA-Seq is concordant with both the Affymetrix and Illumina platforms in more instances than it is concordant with only a single platform, and that instances of discordance with respect to direction of fold change were rare. Finally, we show that additional information is gained from RNA-Seq compared to hybridization-based techniques as RNA-Seq detects more genes than either microarray platform. The majority of genes differentially expressed in RNA-Seq were only detected as present in RNA-Seq, which is important for studies with smaller effect sizes where the sensitivity of hybridization-based techniques could bias interpretation.
    PLoS ONE 03/2011; 6(3):e17820. DOI:10.1371/journal.pone.0017820 · 3.23 Impact Factor
  • Source
    • "Two expression databases were developed in the laboratory of Robert Hitzemann at Oregon Health Sciences University. The development of the databases is described in Hofstetter [24]. Briefly, mice were maintained in LD 12:12 (lights off at 7 pm). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many genes control circadian period in mice. Prior studies suggested a quantitative trait locus (QTL) on proximal mouse chromosome 12 for interstrain differences in circadian period. Since the B6.D2NAhrd/J strain has DBA/2 alleles for a portion of proximal chromosome 12 introgressed onto its C57BL/6J background, we hypothesized that these mice would have a shorter circadian period than C57BL/6J mice. We compared circadian phenotypes of B6.D2NAhrd/J and C57BL/6 mice: period of general locomotor activity in constant dark and rest/activity pattern in alternating light and dark. We genotyped the B6.D2NAhrd/J mice to characterize the size of the genomic insert. To aid in identifying candidate quantitative trait genes we queried databases about the resident SNPs, whole brain gene expression in C57BL/6J versus DBA/2J mice, and circadian patterns of gene expression. The B6.D2NAhrd/J inbred mice have a shorter circadian period of locomotor activity than the C57BL/6J strain. Furthermore, the genomic insert is associated with another phenotype: the mean phase of activity minimum in the dark part of a light-dark lighting cycle. It was one hour later than in the background strain. The B6.D2NAhrd/J mice have a DBA/2J genomic insert spanning 35.4 to 41.0 megabase pairs on Chromosome 12. The insert contains 15 genes and 12 predicted genes. In this region Ahr (arylhydrocarbon receptor) and Zfp277 (zinc finger protein 277) both contain non-synonymous SNPs. Zfp277 also showed differential expression in whole brain and was cis-regulated. Three genes and one predicted gene showed a circadian pattern of expression in liver, including Zfp277. We not only fine-mapped the QTL for circadian period on chromosome 12 but found a new QTL there as well: an association with the timing of the nocturnal activity-minimum. Candidate quantitative trait genes in this QTL are zinc finger protein 277 and arylhydrocarbon receptor. Arylhydrocarbon receptor is structurally related to Bmal1, a canonical clock gene.
    Journal of Circadian Rhythms 02/2007; 5:7. DOI:10.1186/1740-3391-5-7
Show more