Alcp1^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Alcp1^DBA/2J
• Name: alcohol preference locus 1, male specific; DBA/2J
• MGI ID: MGI:2155190
• QTL: Alcp1 Location: Chr2:45228128-67838868 bp Genetic Position: Chr2, cM position of peak correlated region/allele: 27.37 cM
• QTL Note: genome coordinates based on the boundaries of the QTL region

Variant origin

• Strain of Specimen: DBA/2J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers decreased alcohol preference compared to C57BL/6J. (J:94343)
• Inheritance: Dominant

Notes

Alcp1 exhibits male-specific inheritance.

Candidate Genes

J:98595

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 alcohol-related QTLs to identify potential candidate genes. The experiment involved identifying genes expressed differentially in alcohol-induced and non-induced animals but the following list of candidate genes are only for alcohol-induced states.

On mouse Chromosome 2, several candidate genes were identified for Actre2 at 48 cM,Actre3 at 63 cM, Actre4 at 65 cM, and Alcp1 at 37 cM. Candidate genes for Actre2 are Dlx1 (44 cM), Frzb (49.75 cM), D2Ertd391e, and Kai1 (49.6 cM). Candidate genes for Actre3 and Actre4 are Bdnf (62 cM) and Actc1 (64 cM), respectively. Candidate genes forAlcp1 are Pbx3 (22 cM), Hspa5 (22.5 cM), Rprm, Pkp4, and March7 (formerly Axot).

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:33277

Backcross progeny from crosses between (C57BL/6J x DBA/2J)F1 females x C57BL/6J males (N = 262) and C57BL/6J females x (C57BL/6J x DBA/2J)F1 males (N = 73) were analyzed for alcohol consumption. The difference in alcohol consumption between male and female backcross progeny is significant at a P value of 0.00004, therefore sexes were analyzed separately using chi-square analysis to find quantitative trait loci (QTL). A region of mouse Chromsome 2 bounded proximally by D2Mit241 and distally by D2Mit125 was associated with alcohol consumption in male mice and given the symbol Alcp1. The genetic distances between the informative microsatellite loci were as follows: D2Mit293 - 16 cM - D2Mit241 - 15 cM - D2Mit125 - 6 cM - D2Mit436.

Male animals homozygous for C57BL/6J-derived alleles at Alcp1 exhibit increased alcohol consumption compared to heterozygous animals.

J:52086

Backcross progeny from two sets of crosses between (C57BL/6J x DBA/2J)F1 females x C57BL/6J males (N2 = 82) and C57BL/6J females x (C57BL/6J x DBA/2J)F1 males (N2 = 78) were analyzed for alcohol consumption. The difference in alcohol consumption between male and female backcross progeny is significant. Therefore sexes were analyzed separately using chi-square analysis to find quantitative trait loci (QTL). P<0.006 was obtained for linkage with D2Mit241 in males. This provides further support for the existence of the Alcp1 locus and its sex specific effect on alcohol consumption previously described in J:33277.

References

• Original: J:52086 Peirce JL, et al., A major influence of sex-specific loci on alcohol preference in C57Bl/6 and DBA/2 inbred mice. Mamm Genome. 1998 Dec;9(12):942-8
• All: 3 reference(s)