Biomedical subjects

John Spence

Publications and source records attributed to John Spence.

5 recordsLinked to original sources

PubMed2005

Expression profiling and QTL analysis: a powerful complementary strategy in drug abuse research.

Alcoholism is a complex disease exhibiting a multifactorial mode of transmission. To simplify the genetic and phenotypic complexity of the alcoholic phenotype, alcohol-preferring (P) and -non-preferring (NP) rats were developed on the basis of alcohol preference and consumption as an animal model of alcoholism. Total gene expression analysis (TOGA) and quantitative trait loci (QTL) analysis were applied to selectively bred, inbred P and NP rats as complementary studies to identify genetic factors that contribute to alcohol preference and consumption. TOGA analysis was utilized to screen for differential expression in several brain regions involved in the mesocorticolimbic dopamine (DA) system. Genes exhibiting differences in expression were then screened for an association to the alcohol preference phenotype, the quantitative trait of a previously identified QTL. By evaluating differences in gene expression for linkage to a quantitative trait, this combined approach was implemented to identify alpha-synuclein, a candidate gene for alcohol preference.

Animals↗

PubMed2004

Extinction-free electron diffraction refinement of bonding in SrTiO3.

Accurate low-order Fourier coefficients of the crystal potential of SrTiO(3) are measured by quantitative convergent-beam electron diffraction. The accuracy in the corresponding derived X-ray structure factors is about 0.1% for the strong low-order reflections (sin theta/lambda < 0.3 A(-1)). This accuracy is better than for conventional X-ray diffraction and equivalent to the accuracy of the X-ray Pendellosung method. Combination of these structure factors with high-order X-ray diffraction measurements allows accurate bonding information to be obtained from a multipole model fitted to the experimental data. It is shown that Ti-O has a covalent component and that the Sr-O bond is mainly ionic. The role of Ti 3d electrons in Ti-O bonding is also discussed.

Journal Article↗

PubMed2003

alpha-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats.

Total gene expression analysis (TOGA) was used to identify genes that are differentially expressed in brain regions between the alcohol-naive, inbred alcohol-preferring (iP), and -nonpreferring (iNP) rats. alpha-Synuclein, expressed at >2-fold higher levels in the hippocampus of the iP than the iNP rat, was prioritized for further study. In situ hybridization was used to determine specific brain regions and cells expressing alpha-synuclein in the iP and iNP rats. Similar to alpha-synuclein mRNA levels, protein levels in the hippocampus were higher in iP rats than iNP rats. Higher protein levels were also observed in the caudate putamen of iP rats compared with iNP rats. Sequence analysis identified two single nucleotide polymorphisms in the 3' UTR of the cDNA. The polymorphism was used to map the gene, by using recombination-based methods, to chromosome 4, within a quantitative trait locus for alcohol consumption that was identified in the iP and iNP rats. A nucleotide exchange in the iNP 3' UTR reduced expression of the luciferase reporter gene in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the alpha-synuclein gene may contribute to alcohol preference in the iP rats.

3' Untranslated Regions↗

PubMed2003

Confirmation of alcohol preference quantitative trait loci in the replicate high alcohol drinking and low alcohol drinking rat lines.

OBJECTIVE: Selective breeding has been employed to develop replicate high-alcohol-drinking (HAD1 and HAD2) and low-alcohol-drinking (LAD1 and LAD2) rat lines from the heterogeneous N/Nih rat. Within-family selection and a rotational breeding design were used to discourage inbreeding (Li et al., 1993). A genome screen was previously performed using 459 HAD1xLAD1 F2 progeny to identify quantitative trait loci (QTLs) on rat chromosomes 5, 10, 12 and 16 that contribute to alcohol preference and consumption in these non-inbred rat models of alcoholism. METHODS: To confirm these QTLs in the replicate lines, 16 HAD2 and 16 LAD2 rats were genotyped for microsatellite markers within each of these QTL intervals. RESULTS: Review of the genotypic data support confirmation of the QTLs on chromosomes 5 and 10; several markers in the QTL region display different alleles in the HAD2 and LAD2 rats, suggesting linkage disequilibrium between the microsatellite markers and the QTL. Although the QTL on chromosome 12 had the highest LOD score in the HAD1 and LAD1 studies, little evidence supported confirmation of this QTL based on the genotyped markers. CONCLUSIONS: Further evaluation of each of these QTL regions is ongoing in a sample of HAD2xLAD2 F2 progeny currently being generated that will be used to assess the evidence of linkage in each of these QTL regions.

Alcohol Drinking↗

PubMed2003

Analyses of quantitative trait loci contributing to alcohol preference in HAD1/LAD1 and HAD2/LAD2 rats.

BACKGROUND: The high-alcohol-drinking (HAD1/HAD2) and low-alcohol-drinking (LAD1/LAD2) rat lines, derived from the N/NIH rat, were developed by using a within-family selection and rotational breeding design for alcohol preference and alcohol consumption. Previously, a 20-cM genome screen identified quantitative trait loci (QTLs) on chromosomes 5, 10, 12, and 16 by using F2 progeny from HAD1 and LAD1 animals. METHODS: A total of 459 F2 HAD1 x LAD1 animals had been previously genotyped, and 428 HAD2 x LAD2 F2 animals were genotyped for microsatellite markers within the identified QTL regions. Linkage analyses were performed with the program QTL Express, a recently developed Web-based interface that implements a least-squares method. RESULTS: The linkage peaks previously identified in the HAD1 x LAD1 genome scan relied on one or two markers. Placement of additional markers in and around the QTL regions provided further support for each of the QTLs. Two of the QTLs on chromosomes 10 and 16 were confirmed in the replicate line; these QTLs exhibited linkage in both the HAD1/LAD1 and HAD2/LAD2 studies. CONCLUSIONS: This study demonstrated the importance of confirmation of QTLs in a replicate line, as well as the complexity of the genetic contribution to alcohol preference. Assessing these QTL regions in the inbred HAD/LAD animals will further facilitate characterization of these regions.

Alcohol Drinking↗