Ap3q^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Ap3q^C57BL/6J
• Name: alcohol preference 3 QTL; C57BL/6J
• MGI ID: MGI:2155848
• QTL: Ap3q Location: Chr4:151654451-151654550 bp Genetic Position: Chr4, cM position of peak correlated region/allele: 82.64 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

Ap3q is consistent with a dominant or additive mode of inheritance.

Candidate Genes

J:92934

Six genes showing differential expression in the brains of ethanol-preferring strain C57BL/6J and ethanol-avoiding strain DBA/2J were identified using mRNA differential display. Two of the six mRNA sequences matched functionally known genes, Stx12 (60 cM) on mouse Chromosome 4 and Rlpb1 (39 cM) on mouse Chromosome 7. These genes were typed in 480 (C57BL/6 x DBA/2J)F2 mice and found to segregate with the ethanol preference phenotype.

Rlbp1 shows significantly higher expression in the brains of alcohol-preferring F2 mice compared to alcohol-avoiding F2 mice. This effect is stronger in (C57BL/6J x DBA/2J)F2 animals compared to the reciprocal cross (DBA/2J x C57BL/6J)F2. Rlpb1 maps near a suggestive QTL for alcohol preference (D7Mit7, 54 cM) and hypnotic dose sensitivity (Mmpv1, 28 cM) mapped by Rodriguez et al, 1995.

Stx12 shows significantly lower expression in the brains of alcohol-preferring F2 mice compared to alcohol-avoiding F2 mice. This effect is stronger in (C57BL/6J x DBA/2J)F2 animals compared to the reciprocal cross (DBA/2J x C57BL/6J)F2. Stx12 maps near a previously identified alcohol preference QTLs Ap3q (81 cM) and a previously identified suggestive QTL for alcohol consumption mapped by Phillips et al, 1994.

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 4, several candidate genes were identified for Ap3q at 81 cM and Alcw2 at 40 cM. Candidate genes for Ap3q are Clic4, 2610510H01Rik, Park7, and Tnfrsf9 (75.5 cM). Candidate genes for Alcw2 are Mpdz (38.6 cM) and Nfib (38.6 cM).

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, Aldh4a1 (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.

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: 1 reference(s)