Global Mouse mRNA and Protein Levels Comparison Figure 6. Global analyses of proteome and transcriptome genetic regulation. A) Global eQTL profile for the 14463 eQTLs and 1368 pQTLs superimposed on each other. In this plot, larger dots represent protein association and smaller dots represent transcript association. The diagonal line with strong association depicts the local eQTLs and pQTLs and each off-diagonal dot depicts the location of distant eQTLs and pQTLs. B) eQTL landscape for protein and transcript data. For each dataset, the genome was divided into 2 Mb bins and the number of eQTLs (grey) and pQTLs (red) were counted separately in each bin as the windows were slid every 50 kb. The frequency of eQTLs and pQTLs in each window are plotted as the fraction of total significant associations (14463 for transcripts and 1368 for proteins). doi:10.1371/journal.pgen.1001393.g006 from which 339 mapped to more than one locus (Table 2). In general, the mapping data for molecular phenotypes can be subdivided into ‘‘local eQTLs/pQTLs’’ to highlight the presence of genetic variation near/within the gene controlling the transcript or protein levels and ‘‘distant eQTLs/pQTLs’’ to discover trans- acting gene-locus interactions at the genetic level [29]. An empirical calculation of haplotype blocks in the HMDP panel (based on continuous stretch of SNPs with the R-squared value above 0.5) showed an average size of 0.73 Mb and a range from less than a kb to 11 Mb (median = 0.25 Mb). Given this fine mosaic structure in the HMDP genotypes, we defined a local eQTL/pQTL as an eQTL/pQTL with the peak SNP located in the 4 Mb window flanking 2 MB on either side of the transcription start site and transcription termination site of the gene. Based on this, from the total of 14463 significant associations in the transcript data, 2066 were local and 12397 were distant eQTLs. In the protein data the numbers of local and distant eQTLs were 144 and 1224, respectively. The proportion of variance explained by the peak SNP in local pQTLs was 44%, local eQTL was 42%, distant pQTL was 27%, and distant eQTL was 23%. The difference in proportion of variance explained between the distant pQTLs and distant eQTLs was highly significant (Student t-test p- value,1e-16), however, a similar comparison showed no signif- icant difference between the mean effect sizes of local pQTL and local eQTLs (Figure S5). For each dataset, the proportion of variance explained by the local SNPs was significantly larger, as expected, as compared to the distant SNPs. Absence of hotspot loci regulating numerous transcripts/ proteins A previous study in plants found that a small number of loci regulated the levels of many proteins [11]. Accordingly, we examined our data for the existence of similar ‘‘hotspots’’. In the transcript data, we found that the 14463 eQTLs mapped to 9108 distinct peak SNPs. Over 85% of these SNPs (8034 out of 9108) were associated with either one or two transcripts and only a small fraction (334 SNPs) were associated with five or more transcripts. In the protein data, 1368 significant pQTLs mapped to 1088 Table 2. Genome-wide association profiles for the proteome and the transcriptome data. Number of Probesets/ Peptides With at least Number of Probesets/ Total Number One Significant Peptides with Local Number of Number of Probesets/ of Significant Association (% Total Associations (% Total Distant Peptides Associations Phenotypes) Phenotypes) Associations Number of Genes With at least One Number of Genes Number of Genes Total Number of Significant with Local (Number of Probesets/ Significant Association (% Total Associations (% of Peptides) Associations Genes) Total Genes) Number of Probesets/ Peptides With More Than One Significant Association (% Total Phenotypes) 3651 (37%) 339 (21%) Number of Genes With More Than One Significant Association (% Total Phenotypes) 205 (51%) 171 (43%) Global Analysis Transcriptome Proteome Transcript- Protein Pairs Transcriptome Proteome 9896 1543 396 (607) 396 (1343) doi:10.1371/journal.pgen.1001393.t002 PLoS Genetics | www.plosgenetics.org 10 June 2011 | Volume 7 | Issue 6 | e1001393 14463 1368 878 920 6299 (63%) 672 (43%) 297 (75%) 242 (61%) 2066 (21%) 144 (9%) 79 (20%) 46 (9%) 12397 1224 Number of Distant Associations 799 874