Actre1^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Actre1^DBA/2J
• Name: activity response to ethanol 1; DBA/2J
• MGI ID: MGI:2153873
• QTL: Actre1 Location: unknown Genetic Position: Chr1, cM position of peak correlated region/allele: 81.08 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: DBA/2J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers decreased ethanol-induced activation of locomotor activity compared to C57BL/6J. (J:84713)
• Inheritance: Dominant

Notes

Candidate Genes

J:98587

Microarray analysis was used to identify genes showing alcohol-induced differential expression between inbred strains C57BL/6J and DBA/2J. These genes were then correlated to 6 previously identified alcohol-related QTLs to identify potential candidate genes. Two different Affymetrix microarrays were used in the analysis. Brain expression data from parental strains and 56 (DBA/2J x C57BL/6J)F2 intercross animals were used for analysis.

On mouse Chromosome 1, several candidate genes were identified for Alcw1 at 95.8 cM, Alcdp1 (95.8 cM), and Actre1 (85 cM). The highest priority candidate genes identified for chromosome 1 ethanol-related QTLs are Myoc (83.6 cM), Pou2f1 (87.2 cM), Mgst3, Aldh9a1, Sdhc, Kcnj9 (94.2 cM), Darc (94 cM), and Srp9. Other candidate genes with a ranking of modest priority were identified but are not listed here.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:84713

Multiple cross mapping (MCM) was used to identify QTLs associated with ethanol induced activation of locomotor activity. The following F2 crosses were generated and screened for polymorphic markers: (C57BL/6J x DBA/2J)F2, (DBA/2J x LP/J)F2, (BALB/cJ x LP/J)F2, (BALB/cJ x DBA/2J)F2, (C57BL/6J x BALB/cJ)F2, and (C57BL/6J x LP/J)F2.

The data and analysis from the (C57BL/6J x DBA/2J)F2 cross had been previously done and reported in J:71081 and was presented in the article as reference. The QTL identified in that map study was Actre1.

Data from the other 5 crosses was collected in two cohorts, an initial cohort of 400 mice, followed by a second cohort of 200 mice. 250 animals were genotyped from each cross. The threshold for putative QTL was set at p<0.05. Only the (C57BL/6J x BALB/cJ)F2 cross met the threshold. Linkage to ethanol induced locomotor activation was detected on distal mouse Chromosome 1. The QTL information was used to develop an algorithm for sorting and editing the Chr 1 Mit markers. The process yeilded a cluster of markers bewteen 82 and 85 cM. Markers included in this cluster are D1Mit105, 107, 227, 266, 399, 503 and 504.

11.23.2015 Curator Note - When previoulsy identified QTL are cited as confirmed or verified using a different cross than that initially used, we have created a new QTL. We consider each distinct cross to be a separate mapping experiment.

We have named the QTL identified here using the (C57BL/6J x BALB/cJ)F2 population as Actre11. Activity scores were averaged for the two testing trials. The QTL detected in the (C57BL/6J x BALB/cJ)F2 population, Actre11, had a similar profile to that identified in the (C57BL/6J x DBA/2J)F2 cross, Actre1. The BALB/cJ allele appeared to be dominant and was associated with decreased locomotor response.

The authors go on to map the chromosome 1 QTL in an HS sample set previously described in J:71081. (11.23.2015 Curator Note: Since the HS panel is comprised of differing strains than those used to map either Actre1 or Actre11 we also consider the QTL identified in the HS experiment as unique and labeled it Actre12.)

Actre12 mapped to Chromosome 1 peaking between markers D1Mit289 (74.3cM), D1Mit425 (81.6 cM, and D1Mit268 (83.4cM) with a LOD score ranging between 13.5 (D1Mit289-D1Mit425)and 12.7 (D1Mit425-D1Mit268). [Table 1.]

Kcnj9 is a proposed candidate gene.

J:116204

Multiple cross mapping (MCM) was used to identify QTLs associated with ethanol induced activation of locomotor activity. The following F2 crosses were generated and screened for polymorphic markers: (C57BL/6J x DBA/2J)F2, (DBA/2J x LP/J)F2, (BALB/cJ x LP/J)F2, (BALB/cJ x DBA/2J)F2, (C57BL/6J x BALB/cJ)F2, and (C57BL/6J x LP/J)F2. Animals were administered 1.5 g/kg ethanol and monitored for activity for 20 minutes. Parental strains DBA/2J and BALB/cJ exhibit increased locomotor activity after ethanol challenge whereas parental strains C57BL/6J and LP/J exhibit decreased locomotor activity.

Previously identified QTL Actre1 (chr1) was duplicated in this study. This locus is associated with the 2.5-5 minute interval in the (DBA/2J x C57BL/6J)F2 cross with LOD=7.3.

Actre1 was also detected in the (LP/J x C57BL/6)F2 cross with LOD=4.6.

12.09.2015 Curator Note: Because Actre1 was originally mapped in J:70181 in 2001 using both a BXD RI population and an (C57BL/6J x DBA/2J) F2 intercross population, which differs from the (LP/J x C57BL/6J)F2 population, we consider the (LP/J x C57BL/6J)F2 cross a separate mapping experiment and have named the QTL Actre13.

QTL Actre13 maps to mouse Chromosome 1 with a LOD score of 4.3

Another suggestive QTL on Chr 1 was detected in the (BALB/c x C57BL/6J)F2 intercross with LOD=3.4. Homozygosity for C57BL/6J-derived alleles at Actre1, Actre13 and at the suggestive QTL confered increased locomotor activation in all 3 crosses. Analysis of all 3 F2 crosses showed significantgenotype x phenotype interaction at 100 cM near D1Mit150.

Significant linkage to ethanol-induced locomotor activation during the 2.5-5 minute interval mapped to 78.5 cM on mouse Chromosome 3 in the (DBA/2J x BALB/cJ)F2 cross near D3Mit44 (LOD=4.3). Thislocus is named Actre5 (activity response to ethanol 5). BALB/cJ-derived alleles at Actre5 confer increased locomotor activity.

Suggestive linkage ethanol-induced locomotor activity was detected at 58.8 cM in the (LP/J x BALB/cJ)F2 cross near D3Mit216 (LOD=3.3).

Suggestive linkage ethanol-induced locomotor activity was detected at 58.8 cM in the (LP/J x BALB/cJ)F2 cross near D3Mit216 (LOD=3.3).

Actre6 (activity response to ethanol 6) mapped to 27 cM on mouse Chromosome 9 in the (LP/J x C57BL/6J)F2 cross near D9Mit130 (LOD=5.4).This locus is associated with ethanol-induced locomotor activation during the 5-20 minute interval with homozygosity for LP/J-derived alleles conferring decreased locomotor activation.

Suggestive linkage mapped to4 9cM near D9Mit273 (LOD=3) in the (LP/JxBALB/c)F2 cross.

Analysis of heterogeneous stock animals (derived from C57BL/6J, DBA/2J, LP/J, and BALB/cJ) at the G5 generation suggest that 2 QTLs may be present in the Actre1 region at D1Mit355 (97 cM) and at D1Mit218 (67 cM).In both cases the C57BL/6J-derived allele is associated with increased locomotor activity.

Previously identified QTL Actre2 (chr2) was analyzed in this study using heterogenous stock animals (derived from C57BL/6J, DBA/2J, LP/J, and BALB/cJ) at the G5 generation. A maximum LOD score of 5 was attained near D2Mit102-D2Mit62 (52cM - 65 cM) with C57BL/6J-derived alleles conferring increased locomotor activity. SNP analysis of G19 heterogeneous stock animals narrowed the Actre2 interval to a B6-LP:C-D2 biallelic haplotype block between 112.5 Mb and 117.5 Mb.

12.09.2015 Curator Note: Because Actre2 was originally identified in J:71081 in 2001 using a much larger HS sample derived from 8 strains we consider the 4 strain HS stock used here to be a separate mapping experiment mapping a unique QTL labled Actre14.

J:71081

Twenty-five BXD RI strains, 1800 (C57BL/6J x DBA/2J)F2 intercross mice and 550 HS mice were used to identify acute ethnol locomotor response QTL. DBA/2J mice express stimulated locomotor activiity from moderate doses of ethanol while C57BL/6J are only mildly affected. The phenotypic data being measured were adaptation or habituation, thigmotaxis and time.

Candidate QTL were generated from the BXD RI data. A dataset of 400 unique markers, with an average spacing of 4cM, were used to analyze the RI data.QTLs meeting the threshold of a candidate QTL (p^{.01) from the analysis of the RI strains for time dependent distance traveled were found on Chr 2 for time intervals 5-10, 10-15 and 15-20 min. Candidiate QTLs were also found on Chr 6 for time intervals 10-15 and 15-20 minutes and on Chr 1 for time interval 0-5 minutes. No significant RI strain effect was found for thigmotaxis.}

To confirm the candidate QTL reciprocal F1 crosses between C57BL/6J and DBA/2J were used to generate a total of 1800 F2 mice. Onaverage 500 mice were genotyped at each of 82 markers which spanned the entire genome. An F value of 11.3 exceeded the LOD threshold of 4.3. Significant QTLs were detected in the F2 analysis on Chr 1 and 2.

On Chr 1, QTL Actre1 (activity response to ethanol 1) exceeded the highly significant threshold, F=15, for the 0-5 minute interval; and a suggestive QTL,(F=7), was identified for the 5 to 10 minute interval. Using both interval and composite interval mapping Actre1 mapped, between 80-90 cM on Chr 1.[Fig5]

On Chr 2 QTLs exceeding the highly significant threshold were detected at all time intervals, Actre7 at 0-5 minutes; Actre8 at 5-10 minutes; Actre9 at 10-15 minutes, and Actre10 at 15-20 minutes. Using both interval and composite mapping these four QTL peaked in a range between 40-90 cM on Chr 2. [Fig6]

Suggestive QTL were found on Chr 5 at the 5-10 and the 10-15 minute intervals.

No new QTL were detected in the F2 analysis that were not detected in the RI analysis; RI candidate QTL on Chr4and 6 were not confirmed. QTL analysis of the RI strain means for the adaptation phenotype detected a candidate QTL only on Chr X. The parallel F2 analysis did not confirm this candidate QTL.

HS mice from a cross of 8 inbred strains, C57BL/6J, DBA/2J,CBA/2J,C3H/HeJ, A/J, AKR/J, BALB/cJ and LP/J from G32 to G35 were analyzed. A total of 550 mice were phenotyped for the ethanol locomoter response (distance traveled). Authors state that using a diallele cross (B6 alleles vs non-B6 alleles) that they were unable to confirm the Chr 1 QTL detected in the F2 intercross; but that they did confirm the Chr 2 QTL.

12.07.2015 Curator Note: Because the strains comprising the HS mice differ from those of the RI strains and the F2 cross used here we consider the HS analysis a separate mapping experiment and have created unique QTL for the QTL detected in the differing experiments.

Using the HS mice the region of interest on Chr 2 decomposed into three separate linkage groups:

In the first linkage group characterizedby D2Mit94 and D2Mit436 a highly significant QTL, Actre2 (activity response to ethanol 2), was detected at the 10-15 minute time interval, F=16.0. The B6 allele was dominant with a trend towards overdominance at D2Mit94. Suggestive QTLs (F<11.3) were detected at time interval 0-5 min, F=2.2; 5-10 min, F=10.1 and 15-20 min, F=9.4.

No significant QTLs were detected in the second linkage group at D2Mit43.

The third linkage group, ranging from D2Mit207 (62.6cM) to D2Mit304 (70.1cM) detected two additive QTLs, Actre3 at D2Mit207 and Actre4 at D2Mit420, within the 10-15 minute interval. These were both characterized by dominant B6 alleles which increased the ethanol response accounting for 11% of the phenotypic variance. These QTL were not detected in the F2 intercross.

References

• Original: J:71081 Demarest K, et al., Further characterization and high-resolution mapping of quantitative trait loci for ethanol-induced locomotor activity. Behav Genet. 2001 Jan;31(1):79-91
• All: 2 reference(s)