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At least 19 recordsLinked to original sources

PubMed2026

Genetic dissection of cardiac iron regulation using transcriptome network analysis and systems genetics in BXD mice.

Cardiac iron homeostasis is essential for myocardial energy metabolism and contractile function, yet the genetic and molecular mechanisms governing iron levels within the heart remain poorly understood. We used a systems genetics approach to dissect the transcriptional regulation of cardiac iron homeostasis. Myocardial iron level varies substantially across BXD strains (40-112 μg/g) and is under heritable genetic control (H2 = 0.38). Elevated cardiac iron is associated with reduced ventricular mass, increased ventricular ectopy, and prolonged atrioventricular conduction in the BXD population. Weighted gene co-expression network analysis of the BXD heart transcriptome identified a co-expression module that was significantly and negatively correlated with cardiac iron levels in both young and old BXD mice and enriched for pathways related to metabolic regulation, cyclic AMP (cAMP) signaling, circadian entrainment, and cardiovascular physiology. The module showed substantial overlap with a curated cardiac iron gene set, and cross-species enrichment analysis confirmed its conservation in human cardiomyopathy differentially expressed genes (enrichment ratio = 1.49; false discovery rate [FDR] = 0.0342). Quantitative trait locus (QTL) mapping of the first principal component of the overlapping module iron genes (n = 38), corroborated by individual gene mapping, identified trans-eQTL hotspots on multiple chromosomes, implicating Fcho2, Gcc2, and Rmdn1 as candidate upstream regulators operating through sequential steps of intracellular iron trafficking. Together, these findings establish a systems-level map of cardiac iron gene regulation, identify candidate genetic regulators, and provide a molecular framework linking disruption of iron-related transcriptional networks to structural and electrical cardiac dysfunction with implications for iron-related heart diseases.

BXD mouse population↗

PubMed2002

Quantitative trait loci regulating relative lymphocyte proportions in mouse peripheral blood.

Relative proportions of peripheral blood (PB) B lymphocytes (B220%) as well as CD4 (CD4%) and CD8 (CD8%) T lymphocytes differ significantly among inbred mouse strains: B220% is high in C57BL/6J (B6) and C57BR/cdJ, intermediate in BALB/cByJ (BALB) and DBA/2J (D2), and low in NOD/LtJ (NOD) and SJL/J (SJL) mice, whereas CD4% and CD8% are high in NOD and SJL mice and low in the other 4 strains. By following segregating genetic markers linked to these traits in (B6 x D2) recombinant inbred (BXD RI) mice, the study defined 2 quantitative trait loci (QTLs) for the B220% phenotype: Pbbcp1 (peripheral blood B cell percentage 1, logarithm of odds [LOD] 4.1, P <.000 01) and Pbbcp2 (LOD 3.7, P <.000 04) on chromosome 1 (Chr 1) at about 63 cM and 48 cM; one suggestive locus for the CD4% phenotype (LOD 2.6, P <.000 57) on Chr 8 at about 73 cM; and one QTL for the CD8% phenotype: Pbctlp1 (peripheral blood cytotoxic T lymphocyte percentage 1, LOD 3.8, P <.000 02) on Chr 19 at about 12 cM. The study further segregated PB lymphocyte proportions in B6SJLF2 mice by using DNA markers adjacent to these mapped QTLs and found that the Pbbcp1 locus (LOD 5.6, P <.000 01) was also important in this mouse population. In both BXD RI and B6SJLF2 mice, QTLs regulating B-cell proportions showed no significant effect on T-cell proportions and vice versa. Thus, PB B- and T-lymphocyte proportions are regulated separately by different genetic elements.

Animals↗

PubMed1998

Developmental loss of effect of a Chromosome 15 QTL on alcohol acceptance.

Human alcohol abuse and alcoholism have clear developmental features, suggesting the possibility of changes over time in heritability and in quantitative genetic architecture, and raising prospects of identifying individual genes or quantitative trait loci (QTLs) that display different influence on alcohol-related phenotypes at different ages. The identification of specific loci showing such age-related changes will open up opportunities of focused association studies and of genotype manipulation by various mating procedures. Most animal model research in alcohol assesses the phenotypes of the animals at an early age; developmental studies are rare. Here we report on a QTL on Chromosome (Chr) 15 of the mouse that has been shown in several populations, including BXD recombinant inbred strains, an F2, and genotypically selected lines, to affect a measure of alcohol consumption. In the present study, we measured alcohol acceptance in the genotypically selected animals and in an F4 sample at about 100 days and again at about 300 days of age. In both groups, and in both sexes, significant differences were observed at 100 days between animals that were homozygous for the "increasing" haplotype defining the QTL region and those homozygous for the "decreasing" haplotype. At 300 days of age, the effect is absent in females and has diminished or disappeared in males. The results provide a further confirmation of the Chr 15 QTL in young mice, offer a new perspective on the development of alcohol-related phenotypes, and have strong implications for research design.

Alcohol Drinking↗

PubMed2000

Cocaine-induced seizure thresholds: quantitative trait loci detection and mapping in two populations derived from the C57BL/6 and DBA/2 mouse strains.

Seizures are a well known consequence of human cocaine abuse, and in rodent models, sensitivity to cocaine seizures has been shown to be strongly influenced by genotype. For example, several studies have reported significant differences between the C57BL/6 (B6) and DBA/2 (D2) inbred mouse strains in their sensitivity to cocaine-induced seizures. This prompted our use of the BXD recombinant inbred (RI) strain set and an F(2) population derived from the B6 and D2 progenitor strains for further genetic analyses and for gene mapping efforts in this study. Cocaine was infused into the lateral tail vein, and the doses needed to induce a running bouncing clonic seizure and a tonic hindlimb extensor seizure were recorded for each mouse. In the BXD RI set, a genome-wide search was carried out for QTLs (quantitative trait loci), which are sites on a chromosome containing genes that influence seizure susceptibility. An F(2) population (B6D2F2, n = 408) was subsequently used as a second, confirmation step. Based on both RI and F(2) results, three QTLs emerged as significant (P <.00005): one for clonic seizures on chromosome 9 (distal), and two for tonic seizures on chromosomes 14 (proximal to mid) and 15 (distal). Two additional QTLs emerged as suggestive (P <.0015), both associated with clonic seizures on chromosomes 9 (proximal) and 15 (distal). Both QTLs on chromosome 9 were sex-specific, with much larger effects on the phenotype seen in females than in males.

Animals↗

PubMed2002

Mapping quantitative trait loci that influence femoral cross-sectional area in mice.

Size and shape are critical determinants of the mechanical properties of skeletal elements and can be anticipated to be highly heritable. Moreover, the genes responsible may be independent of those that regulate bone mineral density (BMD). To begin to identify the heritable determinants of skeletal geometry, we have examined femoral cross-sectional area (FCSA) in male and female mice from two inbred strains of mice with divergent FCSA (C57BL/6 [B6] and DBA/2 [D2]), a large genetically heterogeneous population (n = 964) of B6D2F2 mice and 18 BXD recombinant inbred (RI) strains derived from their F2 cross. Femora were harvested from 16-week-old mice and FCSA (bone and marrow space enclosed within the periosteum) was measured at the midshaft by digital image analysis. In all mouse populations examined, FCSA was positively correlated with body weight and weight-corrected FCSA (WC-FCSA) values were normally distributed in the BXD-RI and F2 populations, suggesting polygenic control of this trait. Genome-wide quantitative trait locus (QTL) analysis of the B6D2F2 population revealed regions on four different chromosomes that were very strongly linked to WC-FCSA (chromosomes 6, 8, 10, and X) in both genders. Evidence of gender-specific genetic influences on femoral geometry was also identified at three other chromosomal sites (chromosomes 2, 7, and 12). Supporting evidence for the WC-FCSA QTLs on chromosomes 2, 7, 8, 10, and 12 also was present in the RI strains. Interestingly, none of these WC-FCSA QTLs were identified in our previous QTL analysis of whole body BMD in the same B6D2F2 population. Thus, the genetic determinants of bone size appear to be largely, if not entirely, distinct from those that regulate BMD attainment. The identification of the genes responsible for geometric differences in bone development should reveal fundamentally important processes in the control of skeletal integrity.

Animals↗

PubMed2004

A new set of BXD recombinant inbred lines from advanced intercross populations in mice.

BACKGROUND: Recombinant inbred (RI) strains are an important resource for mapping complex traits in many species. While large RI panels are available for Arabidopsis, maize, C. elegans, and Drosophila, mouse RI panels typically consist of fewer than 30 lines. This is a severe constraint on the power and precision of mapping efforts and greatly hampers analysis of epistatic interactions. RESULTS: In order to address these limitations and to provide the community with a more effective collaborative RI mapping panel we generated new BXD RI strains from two independent advanced intercrosses (AI) between C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Progeny were intercrossed for 9 to 14 generations before initiating inbreeding, which is still ongoing for some strains. Since this AI base population is highly recombinant, the 46 advanced recombinant inbred (ARI) strains incorporate approximately twice as many recombinations as standard RI strains, a fraction of which are inevitably shared by descent. When combined with the existing BXD RI strains, the merged BXD strain set triples the number of previously available unique recombinations and quadruples the total number of recombinations in the BXD background. CONCLUSION: The combined BXD strain set is the largest mouse RI mapping panel. It is a powerful tool for collaborative analysis of quantitative traits and gene function that will be especially useful to study variation in transcriptome and proteome data sets under multiple environments. Additional strains also extend the value of the extensive phenotypic characterization of the previously available strains. A final advantage of expanding the BXD strain set is that both progenitors have been sequenced, and approximately 1.8 million SNPs have been characterized. This provides unprecedented power in screening candidate genes and can reduce the effective length of QTL intervals. It also makes it possible to reverse standard mapping strategies and to explore downstream effects of known sequence variants.

Animals↗

PubMed1995

Genetic linkage of thymic T-cell proliferative unresponsiveness to mouse chromosome 11 in NOD mice. A possible role for chemokine genes.

Thymic and peripheral T-cells from NOD mice display a proliferative unresponsiveness on stimulation through the T-cell receptor/CD3 complex. Interleukin 4 reverses NOD T-cell unresponsiveness in vitro and prevents the onset of diabetes in vivo, suggesting a causal relationship between the T-cell unresponsiveness and diabetes susceptibility in NOD mice. Both quantitative trait loci analysis of BXD recombinant inbred mice and linkage analysis of NOD outcross populations reveal that the control of NOD thymic T-cell proliferative unresponsiveness genetically maps to a central region on mouse chromosome 11, which includes the beta-chemokine gene family. This finding raises the possibility that a beta-chemokine(s) may regulate T-cell unresponsiveness as well as diabetes susceptibility in NOD mice.

Animals↗

PubMed2002

Genetic regulation of bone mineral density in mice.

Peak bone mass is a major determinant of risk of osteoporotic fracture. Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). However, BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. The number, locations and effects of the individual genes contributing to natural variation in this trait are all unknown. The extreme difficulty of dissecting out environmental factors from genetic ones in humans has motivated the investigation of animal models. Genetically distinct animal strains raised under strict environmental control are critical tools for defining genetic regulation. The availability of inbred strains, combined with its relative fecundity, has established the mouse as the best model system for the study of mammalian genetics and physiology. Importantly, genes identified in murine analyses can usually be readily mapped to particular human chromosomal regions because of the high degree of synteny that exists between the mouse and human genomes. We employed quantitative trait locus (QTL) analysis to examine peak BMD in 24 recombinant inbred (RI) mouse strains, derived from a cross between C57BL/6 (B6) and DBA/2 (D2) progenitors (BXD RI). The distribution of BMD values among these strains clearly indicated the presence of strong genetic influences, with an estimated narrow sense heritability of 35%. The differences in peak whole body BMD in the BXD strains were integrated with a large database of genetic markers previously defined in the RI BXD strains to generate chromosome map sites for QTL locations. This QTL analysis provisionally identified a number of chromosomal sites linked to BMD. In the second phase of our BMD QTL mapping efforts, we used three independent mouse populations (all derived from B6 and D2 progenitor strains) to confirm and narrow the genetic locations of 4 QTLs (on chromosomes 1, 2, 4, and 11) that strongly influence the acquisition of peak BMD in mice. Using a novel, fine-mapping approach (recombinant inbred segregation testing), we have succeeded in narrowing two of the BMD-related chromosomal regions and in the process eliminated a number of candidate genes. The homologous regions in the human genome for each of these murine QTLs have been identified in recent human genetic studies. In light of this, we believe that findings in mice should aid in the identification of specific candidate genes for study in humans.

Journal Article↗

PubMed2003

WebQTL: web-based complex trait analysis.

WebQTL is a website that combines databases of complex traits with fast software for mapping quantitative trait loci (QTLs) and for searching for correlations among traits. WebQTL also includes well-curated genotype data for five sets of mouse recombinant inbred (RI) lines. Thus, to identify QTLs, users need provide only quantitative trait data from one of the supported populations. The WebQTL databases include both biological traits--neuroanatomical, pharmacological, and behavioral traits--and microarray-based gene expression data from BXD RI lines. A search function finds correlations between RNA expression and biological traits, and mapping functions find QTLs for either type of trait. The WebQTL service is available at http://www.webqtl.org/.

Animals↗

PubMed2001

Confirmation and fine mapping of chromosomal regions influencing peak bone mass in mice.

Bone mineral density (BMD) is determined by both environmental influences and polygenic inheritance. The extreme difficulty of dissecting out environmental factors from genetic ones in humans has motivated the investigation of animal models. Previously, we used quantitative trait locus (QTL) analysis to examine peak BMD in 24 recombinant inbred (RI) mouse strains, derived from a cross between C57BL/6 (B6) and DBA/2 (D2) progenitors (RI-BXD). The distribution of BMD values among these strains indicated strong genetic influences and a number of chromosomal sites linked to BMD were identified provisionally. Using three additional independent mapping populations derived from the same progenitors, we have confirmed loci on chromosomes 1, 2, and 4, and 11 that contain genes that influence peak BMD. Using a novel fine-mapping approach (RI segregation testing [RIST]), we have substantially narrowed two of the BMD-related chromosomal regions and in the process eliminated a number of candidate genes. The homologous regions in the human genome for each of these murine QTLs have been identified in recent human genetic studies. In light of this, we believe that findings in mice should aid in the identification of specific candidate genes for study in humans.

Animals↗

PubMed2001

Quantitative trait loci influencing morphine antinociception in four mapping populations.

Analgesia (pain reduction, or antinociception) is a classical and clinically important effect of morphine administration, and in rodent models sensitivity to morphine has been shown to be strongly influenced by genotype. For example, several studies have reported marked differences in morphine antinociception between the insensitive C57BL/6 (B6) and sensitive DBA/2 (D2) inbred mouse strains on the hot-plate assay. This prompted the present genome-wide search for quantitative trait loci (QTLs) that are chromosomal sites influencing the magnitude of antinociception, by using four mapping populations derived from the B6 and D2 progenitor inbred strains. These four were the BXD recombinant inbred (RI) strain set, an F2 (B6D2F2) population, short-term selective breeding for antinociception from a B6D2F2 founding population, and incipient or completed congenic strains. In the BXD RI set and in the B6D2F2, a genome-wide search identified 10-12 provisional QTLs at a nominal p <.05. The other populations were subsequently used as confirmation steps to test each of the provisional QTL regions. Based on all available mapping populations, four QTLs emerged as significant (p <.00005) on proximal Chromosome (Chr) 1 (females only), proximal Chr 9 (females only), mid Chr 9, and proximal Chr 10. The Chr 10 QTL comaps to the same region as the micro-opioid receptor gene (Oprm); this receptor is a known mediator of morphine's antinociceptive effects. The Chr 1 QTL was evident only in females and comapped with the kappa-opioid receptor gene, Oprk.

Analgesia↗

PubMed2006

Prediction of cis-QTLs in a pair of inbred mouse strains with the use of expression and haplotype data from public databases.

Cis-QTLs are important candidates for any other trait that maps to the same locus. In this article we have used publicly available databases and a small microarray data set to "map" cis-QTLs in the ILS and ISS inbred mouse strains without the need to generate microarray data from an ILSXISS segregating population. Expression data were obtained from brains of C57BL/6, DBA/2, ILS, and ISS. Cis-QTLs were mapped for the 760 transcripts found to be differentially expressed between the C57BL/6 and DBA/2 using expression data previously obtained from the BXD RIs. The 469 detected cis-QTLs were then examined for SNP haplotypes and expression patterns that could relate the ILS and ISS to the C57BL/6 and DBA/2. Of the 338 cis-QTL transcripts that had informative haplotypes, 189 were significantly different between the ILS and ISS with 184 showing segregation of haplotype with expression. These were considered to be probable cis-QTLs in the ILS and ISS. There were almost certainly additional ILS/ISS cis-QTLs among the other transcripts with informative haplotypes, but in the absence of an ILS/ISS expression difference, the level of confidence was reduced. Several of the putative ILS/ISS cis-QTLs are considered important candidate genes because they are linked to ILS/ISS behavioral QTLs. A potential ascertainment bias related to strain-dependent target sequences was observed suggesting that as much as 35% of the cis-QTLs were hybridization artifacts. Nonetheless, the results suggest that this approach is an economical and widely applicable method for mapping cis-QTLs in a strain pair of interest.

Animals↗

PubMed2005

Quantitative trait locus analysis using recombinant inbred intercrosses: theoretical and empirical considerations.

We describe a new approach, called recombinant inbred intercross (RIX) mapping, that extends the power of recombinant inbred (RI) lines to provide sensitive detection of quantitative trait loci (QTL) responsible for complex genetic and nongenetic interactions. RIXs are generated by producing F1 hybrids between all or a subset of parental RI lines. By dramatically extending the number of unique, reproducible genomes, RIXs share some of the best properties of both the parental RI and F2 mapping panels. These attributes make the RIX method ideally suited for experiments requiring analysis of multiple parameters, under different environmental conditions and/or temporal sampling. However, since any pair of RIX genomes shares either one or no parental RIs, this cross introduces an unusual population structure requiring special computational approaches for analysis. Herein, we propose an efficient statistical procedure for QTL mapping with RIXs and describe a novel empirical permutation procedure to assess genome-wide significance. This procedure will also be applicable to diallel crosses. Extensive simulations using strain distribution patterns from CXB, AXB/BXA, and BXD mouse RI lines show the theoretical power of the RIX approach and the analysis of CXB RIXs demonstrates the limitations of this procedure when using small RI panels.

Animals↗

PubMed1993

Use of genetically distinct mouse populations to explore ethanol reinforcement.

Alcohol-induced locomotor stimulation in mice may provide an animal model of human euphoric responses to moderate alcohol (ethanol) doses. If a common mechanism mediates sensitivity to both drug reward (reinforcement) and drug stimulation, rodent models of drug stimulation would provide powerful tools for investigating drug reinforcement. In addition, stimulant sensitivity might provide a simple marker for susceptibility to ethanol reward, and perhaps addiction (e.g., Newlin and Thomson, 1991). This short report describes the use of three genetic mouse models, (1) FAST and SLOW selectively bred lines, (2) BXD Recombinant Inbred Strains, and (3) a panel of inbred strains of diverse genetic origin, to explore mechanisms mediating ethanol stimulation and reinforcement.

Animals↗

PubMed1987

A new cross-reactive idiotype-defined family in the phthalate humoral immune response of mice. I. Linkage of VH-Xmp to IgCH allotype locus and mapping with respect to other known VH genes.

A cross-reactive idiotype family was previously identified from a very large library of phthalate-specific hybridoma clones. The prototype of this idiotype family is the hybridoma, 2E9, secreting an IgM antibody with phthalate specificity. A portion of both primary and secondary anti-phthalate antibodies elicited in all BALB/c mice tested expresses the 2E9 cross-reactive idiotype. This idiotype has now been found in the anti-phthalate antibodies of several other inbred strains of mice (A/HeHa, DBA/2, and C3Hf/HeHa) tested but not in C57BL/6 mice. Anti-phthalate antibodies elicited from congenic mice BC.8, which express the same IgCH allotype as BALB/c mice but possess C57BL/6 genetic background, contain the 2E9 cross-reactive idiotype, whereas this idiotype is not expressed on the anti-phthalate antibodies derived from another congenic mouse CB.20, which expresses a C57BL/6 IgCH allotype and a genetic background of the BALB/c strain. These results indicate that the gene controlling the 2E9 idiotype is closely linked to the IgCH allotype locus. The 2E9 cross-reactive idiotype was also found in all of the F1 mice (BALB/c X C57BL/6) tested, and the level of expression of this idiotype in the F1 mice was quantitatively equivalent to the allotype/idiotype homozygous mice. The expression of the 2E9 idiotype in the phthalate repertoire has been followed in 12 different wild mouse populations. As expected, the 2E9 idiotype was observed in a large proportion of the wild mouse strains. Surprisingly, several examples of nonconcordance in the expression of idiotype and allotype were observed in these mice. One likely explanation for the linkage breakdown is a crossing over of the heavy chain constant and variable region gene complexes. In the SM/J inbred strain of mice, where such a crossover has occurred, nonconcordance between allotype and 2E9 idiotype expression was demonstrated. By using the recombinant inbred BXD strains of mice, the VH gene encoding the 2E9 idiotype has been mapped with respect to other known VH gene families. Relative to other VH genes the VH-Xmp is situated very close to the IgCH gene region.

Chromosome Mapping↗

PubMed1998

High genetic susceptibility to ethanol withdrawal predicts low ethanol consumption.

C57BL/6J (B6) inbred mice are well known to drink large amounts of alcohol (ethanol) voluntarily and to have only modest ethanol-induced withdrawal under fixed dose conditions. In contrast, DBA/2J (D2) mice are "teetotallers" and exhibit severe ethanol withdrawal. Speculation that an inverse genetic relationship existed between these two traits was substantiated by meta-analysis of existing data collected in multiple genetic models, including large panels of standard and recombinant inbred strains, their crosses, and selectively bred mouse lines. Despite methodological differences among laboratories in measurement of both preference drinking and withdrawal, a nearly universal finding was that genotypes consuming large amounts of 10% ethanol (calculated as g/kg/day) during two-bottle choice preference drinking were genetically predisposed to low withdrawal scores in independent studies after either acute or chronic ethanol treatment. Conversely, low-drinking genotypes had higher withdrawal severity scores. The genetic relationship appears to be strongest in populations derived from B6 and D2, where data from more genotypes (BXD RIs, B6D2F2s, BXD RI F1s, and B6D2F2-derived selectively bred lines) were available for analysis. Gene mapping studies in these populations identified four chromosome regions [on Chromosomes (Chrs) 1, 2, 4, and 15] where genes might potentially influence both traits. Among genotypes with greater genetic diversity (for example, a panel of standard inbred strains or selectively bred lines), the relationship was less pronounced. Thus, reduced susceptibility to the development of high alcohol use may be supported by increased genetic susceptibility to ethanol withdrawal symptoms.

Alcohol Drinking↗

PubMed1997

Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene.

We evaluated in vivo interactions between extrinsic (growth factor induced) and intrinsic (genetically determined) effectors of mouse primitive hemopoietic stem cell proliferation and numbers. Accordingly, stem cell frequency and cell cycle kinetics were assessed in eight strains of inbred mice using the cobblestone area-forming cell (CAFC) assay. A strong inverse correlation was observed between mouse lifespan and the number of autonomously cycling progenitors (CAFC day 7) in the femur. The population size of primitive stem cells (CAFC day 35) varied widely (up to sevenfold) among strains, unlike total CAFC day 7 numbers (cycling and quiescent), which were similar. Administration of the early acting cytokine flt-3 ligand to these strains resulted in activation of quiescent primitive stem cells exclusively in strains with high endogenous stem cell numbers (DBA and AKR), but was unrelated to strain-specific progenitor cell cycling. To map loci affecting stem cell frequency, we quantified stem cells in BXD recombinant inbred mice (offspring of C57BL/6 and DBA/2). The resulting strain distribution pattern showed high concordance with a marker that mapped to chromosome 18 (19 cM). Linkage with this genomic interval was associated with a likelihood of odds score of 3.3, surpassing the level required for significance. Interestingly, this segment, containing the EGR-1 gene, shows synteny with human chromosome 5q, a region strongly associated with various hematological malignancies. Our findings indicate that a gene mapping to this region is mutated in either C57BL/6 or DBA/2 (and possibly AKR) mice. These studies in apparently healthy mice may facilitate the identification of a gene implicated in human 5q-syndromes.

Animals↗

PubMed1994

Genetic analysis of nucleotide triphosphatase activity in the mouse brain.

A Ca(2+)- or Mg(2+)-stimulated ecto-ATPase is thought to regulate the hydrolysis of extracellular ATP in nervous tissues. The hydrolysis of nucleotide triphosphates (NTPs) was analyzed in brain microsomal fractions from crosses of DBA/2J (D2) and C57BL/6J (B6) mice. The nucleotide triphosphatase (NTPase) activity was significantly reduced in D2 mice as compared to B6 mice, and B6D2F1 hybrids had activities intermediate to the parentals. A significant positive correlation was found between the hydrolysis of four NTPs (ATP, CTP, GTP and UTP) in 24 B6 x D2 (BXD) recombinant inbred (RI) strains of mice and in 80 B6D2F1 x D2 backcross mice. The RI strains and backcross mice fell into two distinct groups with respect to the NTPase activity. Linkage of NTPase activity was suggested with the chromosome 2 markers, D2Mit6 and Ass-1, in the RI strains, and was confirmed by analysis of other markers in the backcross population. These data suggest that the Ca(2+)- or Mg(2+)-stimulated hydrolysis of NTPs, designated Ntp, is regulated by a single gene located on proximal chromosome 2. Although an association was observed previously between Ca(2+)-ATPase activity and susceptibility to audiogenic seizures (AGS), no significant association was observed for the expression of Ntp and AGS susceptibility.

Animals↗