Susceptibility to Seizure-Induced Excitotoxic Cell Death Is Regulated by an Epistatic Interaction between Chr 18 (Sicd1) and Chr 15 (Sicd2) Loci in Mice

Seizure-induced cell death is believed to be regulated by multiple genetic components in addition to numerous external factors. We previously defined quantitative trait loci that control susceptibility to seizure-induced cell death in FVB/NJ (susceptible) and C57BL/6J (resistant) mice. Two of these quantitative trait loci assigned to chromosomes 18 (Sicd1) and 15 (Sicd2), control seizure-induced cell death resistance. In this study, through the use of a series of novel congenic strains containing the Sicd1 and Sicd2 congenic strains and different combinations of the Sicd1 or Sicd2 sub region(s), respectively, we defined these genetic interactions. We generated a double congenic strain, which contains the two C57BL/6J differential segments from chromosome 18 and 15, to determine how these two segments interact with one another. Phenotypic comparison between FVB-like littermates and the double congenic FVB.B6-Sicd1/Sicd2 strain identified an additive effect with respect to resistance to seizure-induced excitotoxic cell death. It thus appears that C57BL/6J alleles located on chromosomes 18 and 15 interact epistatically in an additive manner to control the extent of seizure-induced excitotoxic cell death. Three interval-specific congenic lines were developed, in which either segments of C57BL/6J Chr 18 or C57BL/6J Chr 15 were introduced in the FVB/NJ genetic background, and progeny were treated with kainate and examined for the extent of seizure-induced cell death. All of the interval-specific congenic lines exhibited reduced cell death in both area CA3 and the dentate hilus, associated with the C57BL/6J phenotype. These experiments demonstrate functional interactions between Sicd1 and Sicd2 that improve resistance to seizure-induced excitotoxic cell death, validating the critical role played by gene-gene interactions in excitotoxic cell death.     

Congenic strains provide evidence that a mapped locus on chromosome 15 influences excitotoxic cell death

Inbred strains of mice differ in their susceptibility to excitotoxin‐induced cell death, but the genetic basis of individual variation is unknown. Prior studies with crosses of the FVB/NJ (seizure‐induced cell death susceptible) mouse and the seizure‐induced cell death resistant mouse, C57BL/6J, showed the presence of three quantitative trait loci (QTLs), named seizure‐induced cell death 1 (Sicd1) to Sicd3. To better localize and characterize the Sicd2 locus, two reciprocal congenic mouse strains were created. While the B6.FVB‐Sicd2 congenic mouse was without effect on modifying susceptibility to seizure‐induced excitotoxic cell death, the FVB.B6‐Sicd2 congenic mouse, in which the chromosome (Chr) 15 region of C57BL/6J was introgressed into FVB/NJ, showed reduced seizure‐induced excitotoxic cell death following kainate administration. Phenotypic comparison between FVB and the congenic FVB.B6‐Sicd2 strain confirmed that the Sicd2 interval harbors gene(s) conferring strong protection against seizure‐induced excitotoxic cell death. Interval‐specific congenic lines (ISCLs) that encompass Sicd2 on Chr 15 were generated and were used to fine‐map this QTL. Resultant progeny were treated with kainate and examined for the extent of seizure‐induced cell death in order to deduce the Sicd2 genotypes of the recombinants through linkage analysis. All of the ISCLs exhibited reduced cell death associated with the C57BL/6J phenotype; however, ISCL‐2 showed the most dramatic reduction in seizure‐induced cell death in both area CA3 and in the dentate hilus. These findings confirm the existence of polymorphic loci within the reduced critical region of Sicd2 that regulate the severity of seizure‐induced cell death.     

Acute locomotor responses to cocaine in adolescents vs. adults from four divergent inbred mouse strains

Growing evidence suggests that adolescent mice display differential sensitivity to the acute locomotor activating effects of cocaine as compared to adults, but the direction of the difference varies across studies and the reasons are not clear. Few studies have directly examined genetic contributions to age differences in locomotor stimulation from cocaine. The goal of this study was to determine the extent to which reduced stimulation in C57BL/6J adolescents as compared to adults generalizes to other strains. Therefore, we examined male and female mice from four genetically divergent inbred stains (BALB/cByJ, C57BL/6J, DBA/2J and FVB/NJ) at two ages, postnatal day 30 and postnatal day 65. Mice received either saline or cocaine (15 or 30 mg/kg), and then immediately were placed back into their home cages. Locomotor activity was recorded continuously in the home cage by video tracking. Adolescents displayed reduced stimulation as compared to adults for C57BL/6J, BALB/cByJ and female FVB/NJ mice. No age differences were observed for DBA/2J or male FVB/NJ. No main effects of sex were observed. Strain differences in pharmacokinetics, neural development or physiology could contribute to the observed differences between ages across strains. Future comparative studies could discover biological differences between strains that explain age differences in cocaine sensitivity.     

Distributions of single nucleotide polymorphisms in differential chromosome segments of congenic resistant strains that define minor histocompatibility antigens

Minor histocompatibility antigens (MiHAs) stimulate the rejection of allografts when donors and recipients are matched at the major histocompatibility complex (MHC). The majority of identified autosomal MiHAs were generated by non-synonymous (NS) substitutions that alter MHC class I-binding peptides. The mosaic distribution of single nucleotide polymorphisms (SNPs) that distinguish inbred mouse strains led us to hypothesize that MiHA genes defined by congenic strains on C57BL/6 and C57BL/10 backgrounds map to chromosomal regions with relatively high numbers of NS SNPs that distinguish C57 strains from other common inbred strains. To test this hypothesis, we mapped the ends of differential chromosome segments of congenic strains, which define 12 MiHAs, relative to microsatellites and SNPs. The lengths of differential segments ranged from 9.7 to 105.9 Mbp in congenic strains where no attempts were made to select recombinants within these segments. There was no apparent correlation between differential segment length and number of backcrosses, suggesting that factors other than the number of opportunities for recombination affected the differential segment lengths in these congenics. These differential segments included higher numbers of NS SNPs that distinguish C57BL/6J from A/J, DBA/2J, and 129S1/J than would be predicted if these SNPs were uniformly distributed along the chromosomes. The most extreme case was the H8 congenic that included 74% of the SNPs on chromosome 14 within its 9.7-11.1 Mbp differential segment. These results point toward a direct relationship between the level of genomic divergence, as indicated by numbers of NS SNPs, and numbers of MiHAs that collectively determine the magnitude of allograft rejection.     

Mapping hyper-susceptibility to colitis-associated colorectal cancer in FVB/NJ mice

Inbred strains of mice differ in susceptibility to colitis-associated colorectal cancer (CA-CRC). We tested 10 inbred strains of mice for their response to azoxymethane/dextran sulfate sodium-induced CA-CRC and identified a bimodal inter-strain distribution pattern when tumor multiplicity was used as a phenotypic marker of susceptibility. The FVB/NJ strain was particularly susceptible showing a higher tumor burden than any other susceptible strains (12.5-week post-treatment initiation). FVB/NJ hyper-susceptibility was detected as early as 8-week post-treatment initiation with FVB/NJ mice developing 5.5-fold more tumors than susceptible A/J or resistant B6 control mice. Linkage analysis by whole genome scan in informative (FVB/NJ×C3H/HeJ)F2 mice identified a novel susceptibility locus designated as C olon c ancer s usceptibility 6 (Ccs6) on proximal mouse chromosome 6. When gender was used as a covariate, a LOD score of 5.4 was computed with the peak marker being positioned at rs13478727, 43.8 Mbp. Mice homozygous for FVB/NJ alleles at this locus had increased tumor multiplicity compared to homozygous C3H/HeJ mice. Positional candidates in this region of chromosome 6 were analyzed with respect to a possible role in carcinogenesis and a role in inflammatory response using a new epigenetic gene scoring tool (Myeloid Inflammation Score).     

Mapping of a Chromosome 12 Region Associated with Airway Hyperresponsiveness in a Recombinant Congenic Mouse Strain and Selection of Potential Candidate Genes by Expression and Sequence Variation Analyses

In a previous study we determined that BcA86 mice, a strain belonging to a panel of AcB/BcA recombinant congenic strains, have an airway responsiveness phenotype resembling mice from the airway hyperresponsive A/J strain. The majority of the BcA86 genome is however from the hyporesponsive C57BL/6J strain. The aim of this study was to identify candidate regions and genes associated with airway hyperresponsiveness (AHR) by quantitative trait locus (QTL) analysis using the BcA86 strain. Airway responsiveness of 205 F2 mice generated from backcrossing BcA86 strain to C57BL/6J strain was measured and used for QTL analysis to identify genomic regions in linkage with AHR. Consomic mice for the QTL containing chromosomes were phenotyped to study the contribution of each chromosome to lung responsiveness. Candidate genes within the QTL were selected based on expression differences in mRNA from whole lungs, and the presence of coding non-synonymous mutations that were predicted to have a functional effect by amino acid substitution prediction tools. One QTL for AHR was identified on Chromosome 12 with its 95% confidence interval ranging from 54.6 to 82.6 Mbp and a maximum LOD score of 5.11 (p = 3.68×10⁻³). We confirmed that the genotype of mouse Chromosome 12 is an important determinant of lung responsiveness using a Chromosome 12 substitution strain. Mice with an A/J Chromosome 12 on a C57BL/6J background have an AHR phenotype similar to hyperresponsive strains A/J and BcA86. Within the QTL, genes with deleterious coding variants, such as Foxa1, and genes with expression differences, such as Mettl21d and Snapc1, were selected as possible candidates for the AHR phenotype. Overall, through QTL analysis of a recombinant congenic strain, microarray analysis and coding variant analysis we identified Chromosome 12 and three potential candidate genes to be in linkage with airway responsiveness.     

Integrating QTL and high-density SNP analyses in mice to identify Insig2 as a susceptibility gene for plasma cholesterol levels

The use of inbred strains of mice to dissect the genetic complexity of common diseases offers a viable alternative to human studies, given the control over experimental parameters that can be exercised. Central to efforts to map susceptibility loci for common diseases in mice is a comprehensive map of DNA variation among the common inbred strains of mice. Here we present one of the most comprehensive high-density, single nucleotide polymorphism (SNP) maps of mice constructed to date. This map consists of 10,350 SNPs genotyped in 62 strains of inbred mice. We demonstrate the utility of these data via a novel integrative genomics approach to mapping susceptibility loci for complex traits. By integrating in silico quantitative trait locus (QTL) mapping with progressive QTL mapping strategies in segregating mouse populations that leverage large-scale mapping of the genetic determinants of gene expression traits, we not only facilitate identification of candidate quantitative trait genes, but also protect against spurious associations that can arise in genetic association studies due to allelic association among unlinked markers. Application of this approach to our high-density SNP map and two previously described F2 crosses between strains C57BL/6J (B6) and DBA/2J and between B6 ApoE(-/-) and C3H/HeJ ApoE(-/-) results in the identification of Insig2 as a strong candidate susceptibility gene for total plasma cholesterol levels.     

Genetic Dissection of Quantitative Trait Loci for Hemostasis and Thrombosis on Mouse Chromosomes 11 and 5 Using Congenic and Subcongenic Strains

Susceptibility to thrombosis varies in human populations as well as many inbred mouse strains. Only a small portion of this variation has been identified, suggesting that there are unknown modifier genes. The objective of this study was to narrow the quantitative trait locus (QTL) intervals previously identified for hemostasis and thrombosis on mouse distal chromosome 11 (Hmtb6) and on chromosome 5 (Hmtb4 and Hmtb5). In a tail bleeding/rebleeding assay, a reporter assay for hemostasis and thrombosis, subcongenic strain (6A-2) had longer clot stability time than did C57BL/6J (B6) mice but a similar time to the B6-Chr11^A/J consomic mice, confirming the Hmtb6 phenotype. Six congenic and subcongenic strains were constructed for chromosome 5, and the congenic strain, 2A-1, containing the shortest A/J interval (16.6 cM, 26.6 Mbp) in the Hmtb4 region, had prolonged clot stability time compared to B6 mice. In the 3A-2 and CSS-5 mice bleeding time was shorter than for B6, mice confirming the Hmtb5 QTL. An increase in bleeding time was identified in another congenic strain (3A-1) with A/J interval (24.8 cM, 32.9 Mbp) in the proximal region of chromosome 5, confirming a QTL for bleeding previously mapped to that region and designated as Hmtb10. The subcongenic strain 4A-2 with the A/J fragment in the proximal region had a long occlusion time of the carotid artery after ferric chloride injury and reduced dilation after injury to the abdominal aorta compared to B6 mice, suggesting an additional locus in the proximal region, which was designated Hmtb11 (5 cM, 21.4 Mbp). CSS-17 mice crossed with congenic strains, 3A-1 and 3A-2, modified tail bleeding. Using congenic and subcongenic analysis, candidate genes previously identified and novel genes were identified as modifiers of hemostasis and thrombosis in each of the loci Hmtb6, Hmtb4, Hmtb10, and Hmtb11.     

Strain-dependent differences in responses to exercise training in inbred and hybrid mice

The aim of this study was to characterize the response to exercise training in several mouse strains and estimate the genetic contribution to phenotypic variation in the responses to exercise training. Male mice from three inbred strains [C57Bl/6J (BL6), FVB/NJ (FVB), and Balb/cJ (Balb/c)] and three hybrid F(1) strains [CB6F1/J (CB6 = female Balb/c x male BL6), B6F F(1) (female BL6 x male FVB), and FB6 F(1) (female FVB x male BL6)] completed an exercise performance test before and after a 4-wk treadmill running program. Distance was used as the primary estimate of endurance exercise performance. FVB mice showed the greatest response to training, with five- to sevenfold greater increases in distance run compared with BL6 and Balb/c strains. Specifically, BL6, FVB, and Balb/c strains increased distance by 33, 172, and 23%, respectively. A similar pattern of changes across strains was observed for run time (17, 87, and 11%) and work (99, 287, and 57%). As a group, F(1) hybrid mice derived from BL6 and FVB strains showed an intermediate response to training (61%). However, further analysis indicated that training responses in FB6 F(1) mice (80%) were approximately 2.5-fold greater than responses in B6F F(1) mice (33%, P = 0.08). A similar pattern of changes between FB6 and B6F F(1) mice was observed for run time (44.5 and 17%) and work (141 and 59%). These data demonstrate that there are large strain-dependent differences in training responses among inbred mouse strains, suggesting that genetic background contributes significantly to adaptation to exercise. Furthermore, the contrasting responses in B6F and FB6 F(1) strains show that a maternal component strongly influences strain-dependent differences in training responses.     

Gene expression between a congenic strain that contains a quantitative trait locus of high bone density from CAST/EiJ and its wild-type strain C57BL/6J

Peak bone density is an important determining factor of future osteoporosis risk. We previously identified a quantitative trait locus (QTL) that contributes significantly to high bone density on mouse chromosome 1 from a cross between C57BL/6J (B6) and CAST/EiJ (CAST) mouse strains. We then generated a congenic strain, B6.CAST-1T, in which the chromosomal fragment containing this QTL had been transferred from CAST to the B6 background. The congenic mice have a significantly higher bone density than the B6 mice. In this study we performed cDNA microarray analysis to evaluate the gene expression profile that might yield insights into the mechanisms controlling the high bone density by this QTL. This study led to several interesting observations. First, approximately 60% of 8,734 gene accessions on GEM I chips were expressed in the femur of B6 mice. The expression and function of two-thirds of these expressed genes and ESTs have not been documented previously. Second, expression levels of genes related to bone formation were lower in congenic than in B6 mice. These data are consistent with a low bone formation in the congenic mice, a possibility that is confirmed by reduced skeletal alkaline phosphatase activity in serum compared with B6 mice. Third, expression levels of genes that might have negative regulatory action on bone resorption were higher in congenic than in B6 mice. Together these findings suggest that the congenic mice might have a lower bone turnover rate than B6 mice and raise the possibility that the high bone density in the congenic mice could be due to reduced bone resorption rather than increased bone formation. Electronic Publication     

Genetic differences in leverpress escape/avoidance conditioning in seven mouse strains

Studies of inbred mouse strains can provide us with important information about the genetic basis of learning and memory. The present experiment studies the acquisition of a leverpress escape/avoidance task in six commonly studied inbred mouse strains (C57BL/6NCrlBR, DBA/2NCrlBR, C3H/HeJ, FVB/NJ, BALB/cByJ and 129S6/SvEvTac), and one outbred strain, the CD1. Results indicated that the strains formed three discrete performance clusters. The C57BL/6NCrlBR, C3HeB/FeJ, BALB/cByJ, and CD1 strains acquired the avoidance response comparably to Sprague-Dawley rats, avoiding approximately 40% of shocks by the fourth and final training session. The 129S6/SvEvTac and FVB/NJ were extremely poor at the avoidance task throughout training. The FVB/NJ strain remained in an escape mode, while the 129S6/SvEvTac animals performed few responses of any type. Finally, the DBA/2NCrlBR strain performed exceptionally well, avoiding over 90% of the shocks by the final session. Results are discussed in terms of genetic differences in learning and how the nigrostriatal dopamine system may mediate the observed differences.     

Genetic analysis of cholesterol accumulation in inbred mice.

Genetic linkage analysis in the laboratory mouse identified chromosomal regions containing genes that contribute to cholesterol accumulation in the liver and plasma. Comparisons between five inbred strains of mice obtained from the Jackson Laboratory (DBA/2, AKR, C57BL/6, SJL, and 129P3) revealed a direct correlation between intestinal cholesterol absorption and susceptibility to diet-induced hypercholesterolemia. This correlation was lost in the F1 generation arising from crosses between high- and low-absorbing strains. Linkage analyses in AKxD recombinant inbred strains and 129xSJL129F1 N2 backcross mice identified four quantitative trait loci (QTL) that influenced Liver cholesterol accumulation (Lcho1-4) and one locus that affected Plasma cholesterol accumulation (Pcho1). These loci map to five chromosomes and, with one exception, are different from the seven QTL identified previously that influence intestinal cholesterol absorption. We conclude that a large number of genes affects the amount of cholesterol absorbed in the small intestine and its accumulation in the liver and plasma of inbred mice.     

Synchronizing allelic effects of opposing quantitative trait loci confirmed a major epistatic interaction affecting acute lung injury survival in mice

Increased oxygen (O(2)) levels help manage severely injured patients, but too much for too long can cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and even death. In fact, continuous hyperoxia has become a prototype in rodents to mimic salient clinical and pathological characteristics of ALI/ARDS. To identify genes affecting hyperoxia-induced ALI (HALI), we previously established a mouse model of differential susceptibility. Genetic analysis of backcross and F(2) populations derived from sensitive (C57BL/6J; B) and resistant (129X1/SvJ; X1) inbred strains identified five quantitative trait loci (QTLs; Shali1-5) linked to HALI survival time. Interestingly, analysis of these recombinant populations supported opposite within-strain effects on survival for the two major-effect QTLs. Whereas Shali1 alleles imparted the expected survival time effects (i.e., X1 alleles increased HALI resistance and B alleles increased sensitivity), the allelic effects of Shali2 were reversed (i.e., X1 alleles increased HALI sensitivity and B alleles increased resistance). For in vivo validation of these inverse allelic effects, we constructed reciprocal congenic lines to synchronize the sensitivity or resistance alleles of Shali1 and Shali2 within the same strain. Specifically, B-derived Shali1 or Shali2 QTL regions were transferred to X1 mice and X1-derived QTL segments were transferred to B mice. Our previous QTL results predicted that substituting Shali1 B alleles onto the resistant X1 background would add sensitivity. Surprisingly, not only were these mice more sensitive than the resistant X1 strain, they were more sensitive than the sensitive B strain. In stark contrast, substituting the Shali2 interval from the sensitive B strain onto the X1 background markedly increased the survival time. Reciprocal congenic lines confirmed the opposing allelic effects of Shali1 and Shali2 on HALI survival time and provide unique models to identify their respective quantitative trait genes and to critically assess the apparent bidirectional epistatic interactions between these major-effect loci.     

Genetic regulation of endotoxin-induced airway disease

To identify novel genes regulating the biologic response to lipopolysaccharide (LPS), we used a combination of quantitative trait locus (QTL) analysis and microarray-based gene expression studies of C57BL/6J x DBA/2J(BXD) F2 and recombinant inbred (RI) mice. A QTL affecting pulmonary TNF-alpha production was identified on chromosome 2, and a region affecting both polymorphonuclear leukocyte recruitment and TNF-alpha levels was identified on chromosome 11. Microarray analyses of unchallenged and LPS-challenged BXD RI strains identified approximately 500 genes whose expression was significantly changed by inhalation of LPS. Of these genes, 28 reside within the chromosomal regions identified by the QTL analyses, implicating these genes as high priority candidates for functional studies. Additional high priority candidate genes were identified based on their differential expression in mice having high and low responses to LPS. Functional studies of these genes are expected to reveal important molecular mechanisms regulating the magnitude of biologic responses to LPS.     

Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68

Seasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza that reproduces the hallmark high viral load and overexpression of cytokines associated with susceptibility to severe influenza in humans. We mapped genetic determinants of the host response using a panel of 29 closely related mouse strains (AcB/BcA panel of recombinant congenic strains) created from influenza-susceptible A/J and influenza-resistant C57BL/6J (B6) mice. Combined clinical quantitative trait loci (QTL) and lung expression QTL mapping identified candidate genes for two sex-specific QTL on chromosomes 2 and 17. The former includes the previously described Hc gene, a deficit of which is associated with the susceptibility phenotype in females. The latter includes the phospholipase gene Pla2g7 and Tnfrsf21, a member of the TNFR superfamily. Confirmation of the gene underlying the chromosome 17 QTL may reveal new strategies for influenza treatment.     

Quantitative trait loci in a bacterially induced model of inflammatory bowel disease

Inflammatory bowel diseases (IBDs) are complex disorders caused by a combination of environmental, microbial, and genetic factors. Genome-wide association studies in humans have successfully identified multiple genes and loci associated with disease susceptibility, but the mechanisms by which these loci interact with each other and/or with environmental factors (i.e., intestinal microbiota) to cause disease are poorly understood. Helicobacter hepaticus-induced intestinal inflammation in mice is an ideal model system for elucidating the genetic basis of IBD susceptibility in a bacterially induced system, as there are significant differences in H. hepaticus-induced disease susceptibility among inbred mouse strains. Infected A/J mice develop acute overexpression of proinflammatory cytokines followed 2?C3?months later by chronic cecal inflammation, whereas infected C57BL/6 mice fail to develop cecal inflammation or increased cytokine expression. The goal of this project was to use quantitative trait locus (QTL) mapping to evaluate genetic factors that contribute to the differential disease susceptibility between these two mouse strains. Using acute cecal IL-12/23p40 expression as a biomarker for disease susceptibility, QTL analysis of H. hepaticus-infected F₂ mice revealed involvement of multiple loci. The loci with the strongest association were located on Chromosome 3 and Chromosome 17, with logarithm of odds (LOD) scores of 6.89 and 3.09, respectively. Cecal expression of IL-12/23p40 in H. hepaticus-infected C57BL/6J-Chr3^A/J/NaJ chromosome substitution mice had an intermediate phenotype, significantly higher than in resistant C57BL/6 but lower than in susceptible A/J mice, confirming the importance of this locus to the immune response to H. hepaticus infection.     

Sensitivity to the locomotor-stimulant effects of ethanol and allopregnanolone: a quantitative trait locus study of common genetic influence

Previous studies have suggested that common genetic mechanisms influence sensitivity to the locomotor-stimulant effects of ethanol and allopregnanolone. We conducted two quantitative trait locus (QTL) studies to identify chromosomal regions that harbor genes that influence locomotor response to ethanol (2 g/kg) and allopregnanolone (17 mg/kg) using F2 crosses between C57BL/6J and DBA/2J mice. Because our previous data from the BXD recombinant inbred strains had indicated that chromosome 2 contained QTL for sensitivity to the locomotor-stimulant effects of both ethanol and allopregnanolone, we also tested reciprocal chromosome 2 congenic strains for sensitivity to the locomotor-stimulant effects of both drugs. The F2 analysis for ethanol sensitivity identified significant QTL on chromosomes 1 and 2 and suggestive QTL on chromosomes 5 and 9. The analysis of the allopregnanolone F2 study identified suggestive QTL on chromosomes 3, 5 and 12. Suggestive evidence for a female-specific QTL on chromosome 2 was also found. The studies of congenic mouse strains indicated that both the congenic strains captured one or more QTL for sensitivity to the locomotor-stimulant effects of both ethanol (2 g/kg) and allopregnanolone (17 mg/kg). When Fisher's method was used to combine the P values for the RI, F2 and congenic studies of the chromosome 2 QTL, cumulative probability scores of 9.6 x 10(-15) for ethanol and 7.7 x 10(-7) for allopregnanolone were obtained. These results confirm the presence of QTL for ethanol and allopregnanolone sensitivity in a common region of chromosome 2 and suggest possible pleiotropic genetic influence on sensitivity to these drugs.     

Identification of quantitative trait loci for susceptibility to mouse adenovirus type 1

Adult SJL/J mice are highly susceptible to mouse adenovirus type 1 (MAV-1) infections, whereas other inbred strains, including BALB/cJ, are resistant (K. R. Spindler, L. Fang, M. L. Moore, C. C. Brown, G. N. Hirsch, and A. K. Kajon, J. Virol. 75:12039-12046, 2001). Using congenic mouse strains, we showed that the H-2(s) haplotype of SJL/J mice is not associated with susceptibility to MAV-1. Susceptibility of MAV-1-infected (BALB/cJ x SJL/J)F(1) mice was intermediate between that of SJL/J mice and that of BALB/cJ mice, indicating that susceptibility is a genetically controlled quantitative trait. We mapped genetic loci involved in mouse susceptibility to MAV-1 by analysis of 192 backcross progeny in a genome scan with 65 simple sequence length polymorphic markers. A major quantitative trait locus (QTL) was detected on chromosome 15 (Chr 15) with a highly significant logarithm of odds score of 21. The locus on Chr 15 alone accounts for 40% of the total trait variance between susceptible and resistant strains. QTL modeling of the data indicated that there are a number of other QTLs with small effects that together with the major QTL on Chr 15 account for 54% of the trait variance. Identification of the major QTL is the first step in characterizing host genes involved in susceptibility to MAV-1.