QTL Hotspot on Mouse Distal Chromosome 1 Figure 5. QTL for aminoacyl-tRNA synthetases in distal Qrr1. Transcripts of Gars, Cars, Nars, Mars, and Yars map as trans-QTLs to Qrr1 at LOD.4 (genome-wide p-value,0.01) in the BXD hippocampus dataset. The trans-QTLs have peak LOD precisely on markers in distal part of Qrr1, ,175–177.5 Mb (shaded regions). Yellow seismograph on Chr 1 (x-axis) tracks SNP density between B and D alleles. Affymetrix probe set ID for each transcript is shown. doi:10.1371/journal.pgen.1000260.g005 comparison indicates that the strongest trans-effect is from Qrr1d. A possible reason why the trans-effect is not detected in the CXB RI strains, despite being SNP rich in Qrr1, is that the crucial SNPs underlying the trans-QTLs may not be segregating in this cross or that undetected copy number variants make important contribu- tions to the Qrr1 effects. A final explanation may be that the small CXB dataset (13 strains) is simply underpowered. High-Ranking Candidates Based on Cross Specificity of cis-QTLs We used the specificity of cis-QTLs in the multiple crosses to identify higher priority candidates in Qrr1. The assumption is that candidate genes whose transcripts have cis-QTLs (LOD score above 3) in the B66D2 and B66C3H crosses but not in the LXS and CXB RI strains are stronger candidates for trans-QTLs that are detected in the former two crosses but not in the latter two crosses. In contrast, cis-QTLs with the inverse cross specificity are less likely to underlie these trans-QTLs. Based on this criterion, there are four high-ranking candidates in Qrr1p—Purkinje cell protein 4-like 1 (Pcp4l1), prefoldin (Pfdn2), WD repeat domain 42 a (Wdr42a), and Kcnj10 (table 3). There are only two high-ranking candidates in Qrr1d—formin 2 (Fmn2), an actin binding protein involved in cytoskeletal organization, and regulator of G-protein signaling 7 (Rgs7) (table 3). Table 5. Transcripts of aminoacyl tRNA synthetases that have trans-QTLs in Qrr1 (LOD$3) in one or multiple CNS datasets. Gene Nars Gars Rars Cars Yars Iars Sars Mars Hars Iars2 Tars Aars Lars Ears2 Aarsd1 Dars Name asparaginyl-tRS glycyl-tRS arginyl-tRS cysteinyl-tRS tyrosyl-tRS isoleucine-tRS seryl-tRS methionine-tRS histidyl-tRS isoleucine-tRS threonyl-tRS alanyl-tRS leucyl-tRS glutmyl-tRS alanyl-tRS domain 1 aspartyl-tRS ProbeIDa 1452866_at_A 1423784_at 1416312_at_A 10024406001 10024399842 1426705_s_at 1426257_a_at 1455951_at 1438510_a_at 1426735_at 10024395655 1451083_s_at 1448403_at_A ILM5290446 1424006_at 1423800_at_A Chrb Chr 18 Chr 6 Chr 11 Chr 7 Chr 4 Chr 13 Chr 3 Chr 10 Chr 18 Chr 1 Chr 15 Chr 8 Chr 18 Chr 7 Chr 11 Chr 1 Datasetc BXD cerebellum BXD hippocampus BXD forebrain B6C3HF2 brain B6C3HF2 brain BXD cerebellum BXD cerebellum BXD hippocampus BXD hippocampus BXD hippocampus B6C3HF2 brain BXD eye BXD cerebellum BXD ILM striatum B6D2F2 brain BXD cerebellum LODd 12.0 10.6 8.9 8.9 8.0 7.8 6.9 6.5 5.2 4.3 4.0 3.9 3.7 3.7 3.5 3.2 B/De B B B B B B B B B B B B B B B D aProbe/Probe set ID. bPhysical location of gene; Iars2 is located on Chr 1 at 186.9 Mb, and Dars on Chr 1 at 130 Mb. cDataset in which transcript has highest trans-QTL in Qrr1. dHighest LOD score in Qrr1. eAllele that increases expression. doi:10.1371/journal.pgen.1000260.t005 PLoS Genetics | www.plosgenetics.org 9 November 2008 | Volume 4 | Issue 11 | e1000260