Ap2q^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Ap2q^C57BL/6J
• Name: alcohol preference 2 QTL; C57BL/6J
• MGI ID: MGI:2155112
• QTL: Ap2q Location: Chr2:60520612-60520756 bp Genetic Position: Chr2, cM position of peak correlated region/allele: 34.9 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased alcohol preference compared to DBA/2J. (J:49707)
• Inheritance: Not Specified

Notes

Ap2q is consistent with an additive or recessive mode of inheritance.

Ap2q and Ap6q participate in epistatic interactions. When Ap6q is homozygous for DBA/2J-derived alleles the genotype at Ap2q exerts little effect. However, homozygosity for C57BL/6J-derived alleles at both Ap2q and Ap6q results in a dramatic increase for alcohol preference.

Candidate Genes

J:99482

Several alcohol preference QTL map to proximal mouse Chromosome 2 including Alcp1 (47.5 cM), Ap2q (34 cM), Etohc1 (28 cM), and Etohc2 (50 cM). This study investigates Stxbp1 as a candidate gene for the chromosome 2 alcohol-associated locus.

Alcohol preferring inbred strain C57BL/6J and alcohol avoiding inbred strain DBA/2J differ at nucleotide 646 of the Stxbp1 sequence. G646A is a non-conservative change in the Stxbp1 coding sequence resulting in the absence of a turn/turn motif in the C57BL/6J allele.

Analysis of 23 BXD RI strains shows correlation of the Stxbp1 polymorphism to alcohol consumption, acute alcohol withdrawal severity, and alcohol-induced conditioned taste aversion. This observation was confirmed in 3 other experiments.

1) Stxbp1 genotype was established for 86 (C57BL/6J x DBA/2J)F2 animals. F2 homozygotes for C57BL/6J-derived Stxbp1 alleles display 2X increased alcohol consumption compared to heterozygotes, and 3.5X increased alcohol consumption compared to F2 DBA/2J homozygotes (P=0.001).The effect of the C57BL/6J-derived Stxbp1 allele appears to be additive.

2) Fourth generation phenotype-selection lines derived from C57BL/6J and DBA/2J progenitors were assessed for allele frequencies at Stxbp1. The low alcohol preferring selection line STDRLO showed significant enrichment for DBA/2J-derived Stxbp1 alleles compared to the high alcohol preferring selection line STDRHI (P<0.0001).

3) Stxbp1 genotype and alcohol consumption was analyzed in 15 inbred strains. Ten inbred strains carrying C57BL/6J-like Stxbp1 allele tend to consume more alcohol compared to the five inbred strains carrying DBA/2J-like Stxbp1 alleles. The difference in alcohol consumption did not reach statistical significant but supports the hypothesis that Stxbp1 is a candidate gene for alcohol preference traits.

J:110030

Candidate genes for alcohol traits were identified using gene expression analysis. Total brain RNA from 70-90 day old male mice were hybridized to DNA microarrays to detect expression differences between high and low alcohol preference selection lines (HAP and LAP, respectively) and high and low tolerance selection lines (HAFT and LAFT, respectively). All selection lines were derived from HS/Ibg and were between 19 to 24 generations of selective breeding. Candidate genes mapping to previously identified expression and behavior QTL intervals are described below. Candidate genes were also confirmed using strain distribution patterns from 30 BXD (C=C57BL/6J; D=DBA/2J) recombinant inbred (RI) strains.

Kif5c (32.5 cM) on mouse Chromosome 2 exhibits differential expression between high and low acute functional tolerance strains in the BXD RI set. This gene maps near previously identified alcohol preference QTLs Alcp1 (47.5 cM), Ap2q (34 cM), Etohc1 (28 cM), Etohc2 (50 cM), and Alpq2 (45 cM).

Gstm1 (108.39 Mb) on mouse Chromosome 3 is more highly expressed in high alcohol preferring lines compared to low alcohol preferring lines. D3Ertd254e (aka LOC241944) at 19 cM exhibits differential expression between high and low acute functional tolerance strains in theBXD RI set. This gene maps near a previously identified locus at D3Pas1 (22.7 cM) associated with basal cAMP signaling.

Gnb1 at 79.4 cM (153.38 Mb) on mouse Chromosome 4 is more highly expressed in low alcohol preference lines compared to high alcohol preference lines (LOD=17.13). This gene maps near previously identified alcohol preference QTL Ap3q at 81 cM.

Evi5 (56 cM ) and Pdap1 on mouse Chromosome 5 exhibits differential expression between high and low acute functional tolerance strains in the BXDRI set. These genes map near a locus at D5Mit201 (44 cM) suggestively linked to alcohol preference.

On mouse Chromosome 9, 4930422I07Rik (88.99 Mb), D930028F11Rik (expressed sequence C130036J11; 48.5 Mb), and Mthfs (130.69 Mb) are more highly expressedin high alcohol preference lines compared to low alcohol preference lines (LOD=7.46, 9.5, and 7.16, respectively). Hyou1 (44.48 Mb) is more highly expressed in low alcohol preference lines compared to high alcohol preference lines (LOD=4.18). Hyou1 and D930028F11Rik map to the Alpq3 (alcohol preference QTL 3) interval (17 cM - 53 cM).

Flnb on mouse Chromosome 14 exhibits differential expression between high and low acute functional tolerance strains in the BXD RI set. This gene maps near a previously identified QTL at D14Byu1 (o.5 cM) associated with basal and forskolin-induced cAMP signaling.

Brd2 at 18.5 cM (31.81 Mb) on mouse Chromosome 17 is more highly expressed in high alcohol preferring lines compared to low alcohol preferring lines (LOD=3.93).

Galnt1 (24.43 Mb) on mouse Chromosome 18 is more highly expressed in high alcohol preference lines compared to low alcohol preference lines (LOD=2.93).

Tbl1x (30.9 cM) on mouse Chromosome X exhibits differential expression between high and low acute functional tolerance strains in the BXD RI set.

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

J:49707

Genome scan was performed on 218 (C57BL/6J x DBA/2J)F2 intercross animals using 101 microsatellite markers to identify QTLs associated with alcohol preference. Parental strain C57BL/6J exhibits higher alcohol preference compared to parental strain DBA/2J. Significant alcohol preference QTLs mapped to mouse Chromosome 1 spanning 45 cM - 95 cM (Ap1q, LOD = 4.5 between D1Mit194 and D1Mit110), mouse Chromosome 4 spanning 65 cM - telomere (Ap3q, LOD = 4.7 at D4Mit42), and mouse Chromosome 9 spanning 10 cM - 35 cM (Apq5, LOD = 4.8 cM at D9Mit330). Suggestive QTLs mapped to mouse Chromosome 2 spanning 30 cM - 50 cM (Ap2q, LOD = 3.1 at D2Mit61), mouse Chromosome 10 (Ap4q) spanning 18 cM - 57 cM, and mouse Chromosome 3 spanning 38 cM - 60 cM (Ap6q, LOD = 3.4 between D3Mit12 and D3Mit86). Ap1q, Ap2q, Ap3q, and Ap4q were provisionally mapped in BXD RI strains and confirmed in the present study, while Ap5q and Ap6q are novel. C57BL/6J-derived alleles increases alcohol preference at all loci mapped. Ap1q is follows adominant mode of inheritance and maps near Chrnd (Acrd), Chrng (Acrg), and Htr5b. Ap2q is consistent with a recessive or additive mode of inheritance and maps near Scn1a, Scn2a, Scn3a, and Scn7a Ap3q is consistent with a dominant or additive mode of inheritance and maps near Htr1da, Htr1db, Ahd1 (Ssdh1), and Tas1r3 (Sac). Ap5q is consistent with a dominant or additive mode of inheritance and maps near Htr1b and Drd2. Ap6q is most consistent with an additive mode of inheritance and maps near the alcohol dehydrogenase gene complex at approximately 71.2 cM on mouse Chromosome 3.

J:71165

Several alcohol preference QTL (Ap1q, Ap2q, Ap3q, Ap4q, Ap5q, Ap6q) were mapped in a previous study by Tarantino et al, 1998 (J:49707). Parental strain C57BL/6J exhibits higher alcohol preference compared to parental strain DBA/2J. In this study, genotype data from the (C57BL/6J x DBA/2J)F2 intercross population was reanalyzed for epistatic interactions. Significant interaction was detected between markers mapping to the Ap2q interval on mouse Chromosome 2 and the Ap6q interval on mouse Chromosome 3. Markers D2Mit61 (34 cM) and D3Mit12 (49.2 cM) and markers D2Mit94 (48.1 cM) and D3Mit12 (49.2 cM) show the greatest evidence for epistatic interaction (P=0.0015 and P=0.0006, respectively). It appears Ap6q is epistatic to Ap2q. When Ap6q is homozygous for DBA/2J-derived alleles the genotype at Ap2q has little effect on the phenotype. But homozygosity for C57BL/6J-derived alleles at both Ap2q and Ap6q confers the greatest increase in alcohol preference.

References

• Original: J:49707 Tarantino LM, et al., Confirmation of quantitative trait loci for alcohol preference in mice. Alcohol Clin Exp Res. 1998 Aug;22(5):1099-105
• All: 2 reference(s)