Experiment
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.
Analysis Tools