MGI ID Symbol Name 2680094 Rrodp1 Rotarod performance 1 Bone mineral density 5 Bone mineral density 1 Spontaneous crescentic glomerulonephritis QTL 1 2661242 Cd8mts1 CD8 T memory cell subset 1 Trypansomiasis infection response 3c Escape latencies during navigation task Emotionality 1 Alcohol dependency 1 Alcohol withdrawal 1 Caffeine metabolism QTL 1 Seizure susceptibility 1 Circulating hormone level QTL 1 Pentobarbital withdrawal QTL 1 Triglycerides Graft-versus-host disease 1 Radiation pulmonary fibrosis 2 Pentobarbital withdrawal modifier Atherosclerosis 9 Basal locomotor activity 4 Cerebellum weight 1 Cholesterol QTL 2 Ethanol induced locomotor activity Fasting glucose 2 Haloperidol induced catalepsy 2 Susceptibility to Salmonella typhimurium antigens 2 immune 2389129 Bmd5 1349434 Bmd1 3624655 Scgq1 1891474 Tir3c 2387316 Elnt 1350920 Emo1 3050452 Alcdp1 1309452 Alcw1 2150827 Cafq1 1098770 Szs1 3613641 Chlq1 1345638 Pbw1 2661145 Ssta2 3522039 Trglyd 1346066 Gvhd1 2155287 Radpf2 2151854 Pbwm 1890350 Ath9 2682357 Bslm4 1891174 Cbm1 2137602 Cq2 2680927 Eila1 2660561 Fglu2 2137474 Hpic2 2149094 Sle9 3579342 Sphsr1 2148991 Yaa4 3613551 Bglu3 1890554 Melm2 Melanoma modifier 2 2684308 Mnotch Modifier of Notch Systematic lupus erythematosus susceptibility 9 Spermatocyte heat stress resistance 1 Y-linked autoimmune acceleration Blood glucose level 3 doi:10.1371/journal.pgen.1000260.t001 both datasets (for the common trans-QTLs, the average distance between peak markers in the two datasets is 2.7 Mb). Strikingly, out of the 54 trans-QTLs common to both crosses, 52 are in Qrr1 (figure 1). Among the transcripts with the most consistent trans-QTLs are glycyl-tRNA synthetase (Gars), cysteinyl-tRNA synthetase (Cars), asparaginyl-tRNA synthetase (Nars), isoleucyl tRNA synthetase (Iars), asparagine synthetase (Asns), and activating transcription factor 4 (Atf4). These transcripts map to Qrr1 in almost all datasets in which the strong trans-effect is detected. Gars, Cars, and Nars are aminoacyl-tRNA synthetases (ARS) that charge tRNAs with amino acids during translation. Asns and Atf4 are also involved in amino acid metabolism—Asns is required for asparagine synthesis and is under the regulation of Atf4, which in turn is sensitive to cellular amino acid levels [53]. Other transcripts that consistently map as trans-QTLs to Qrr1 include brain expressed X- linked 2 (Bex2), splicing factor Sfrs3, ribonucleoproteins Snrpc and QTL Hotspot on Mouse Distal Chromosome 1 Table 1. Classical QTLs on Chr 1 from 172–178 Mb; listed by approximate position from proximal to distal end (adapted from Mouse Genome Informatics). PLoS Genetics | www.plosgenetics.org 3 November 2008 | Volume 4 | Issue 11 | e1000260 Cross C3H/HeJ6C57BL/6J C57BL/6J6CAST/Ei C57BL/6J6SCG/Kj C57BL/6J6DBA/2J BALB/cJ6C57BL/6J C57BL/6J6DBA/2J C57BL/6J6DBA/2J 129S6/SvEvTac6C57BL/6J A/JOlaHsd; BALB/cJOlaHsd; C57BL/6JOlaHsd C57BL/66DBA/2 BALB/c6C3H6C57BL/66DBA/2 BALB/cJ6C3H/HeJ6C57BL/6J6DBA/2J C57BL/6J6DBA/2J HIII6LIII B10.D2-H2d6C57BL/10J C3H/Kam6C57BL/6J C57BL/6J6DBA/2J BALB/cJ6C57BL/6J; C57BL/6J6DBA/2J; C57BL/6J6LP/J C57BL/6J6DBA/2J Snrpd1, ring finger protein 6 (Rnf6), and RAS oncogene family member Rab2. Candidates in Qrr1 Qrr1 contains 164 known genes. The proximal part of Qrr1 is gene-rich and has several genes with high expression in the CNS (e.g. Pea15, Kcnj9, Kcnj10, Atp1a2). The middle to distal part of Qrr1 is relatively gene sparse and consists mostly of clusters of olfactory receptors and members of the interferon activated Ifi200 gene family. Though comparatively gene sparse, the middle to distal part of Qrr1 contains a small number of genes that have high expression in the CNS—Igsf4b, Dfy, Fmn2, and Rgs7. A subset of 35 genes were initially selected as high priority candidates based on the number of known and inferred sequence differences between the B6 allele (B) and D2 allele (D) and based on expression levels in multiple CNS datasets (table 3). Eleven of these candidates contain missense SNPs segregating in B66D2 Type bone bone kidney behavior immune behavior behavior behavior behavior CNS immune endocrine behavior Immune Immune behavior behavior CNS behavior tumor immune other immune metabolism C3H/HeJ6APN metabolism C57BL/6J6RR metabolism C57BL/6J6FVB/NCr metabolism C57BL/6J6KK-Ay behavior C3H/HeJ6C57BL/6J metabolism C57BL/6J6KK-Ay C57BL/6J6DBA/2J BALB/cJ6C57BL/6J 129X1/SvJ6C57BL/6J BXSB/J6C57BL/10Ola C57BL/6CrSlc6MRL/MpJSlc BXSB/J6C57BL/10Ola metabolism C3H/HeJ6C57BL/6J Reference [10] [11] [12] [13] [14] [15] [5] [16] [6] [7] [17] [18] [19] [8] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [9] [31] [32] [33] [34] [35] [36]