EIF2S1-PELO co-expression architecture in human brain: pairing-family decomposition reveals constitutive...

EIF2S1 (eIF2α, translation initiation surveillance) and PELO (Pelota, ribosome rescue) operate within established ribosome-associated quality control and translation-initiation surveillance pathways. Direct cross-talk between these systems is mediated through ZAK/GCN-mediated eIF2α phosphorylation under ribosome-stall stress. At the transcriptional layer, however, EIF2S1-PELO co-regulation has not been quantitatively characterized. Using pairing-family architectural decomposition on multi-region GTEx co-expression and BA9 prefrontal cortex RNA-seq from Parkinson's disease and control donors (GSE68719, n = 44 controls, n = 29 PD), we find: (1) EIF2S1 and PELO share near-identical genome-wide co-expression architecture (continuous Weighted Jaccard = 0.914) with substantial top-partner overlap (binary Jaccard at top 5% = 0.490), producing a Type 1 dissociation gap of 0.424, significantly smaller than 200 random gene-pair gaps (mean 0.644, z = -2.57, permutation p = 0.015), and the lowest gap in a 21-pair quality-control gene panel; (2) the relationship is approximately linear-monotonic (Type 6 Pearson-Spearman gap ≈ 0.004); (3) cellular functional co-dependency in DepMap CRISPR screens is essentially zero (Jaccard = 0.006, gene-effect Pearson r = -0.07), consistent with layer separation between regulatory architecture and cellular phenotype; (4) in an exploratory single-cohort comparison of PD versus control prefrontal cortex, the dissociation gap was larger in PD (0.536 versus 0.424 in control), but this between-group difference did not reach statistical significance under a group-label permutation test (p = 0.40; bootstrap 95% CI on the difference [-0.14, 0.29]), so we present it as a hypothesis for replication rather than an established effect. These findings characterize EIF2S1-PELO transcriptional co-regulation as a constitutive architectural feature distinct from the ZAK/GCN-mediated direct mechanism. The constitutive coupling replicated in independent Alzheimer's disease and ALS frontal-cortex cohorts and across microarray and RNA-seq platforms; a disease-associated weakening of the coupling was directionally consistent across all three diseases but did not reach statistical significance. We note that co-expression patterns are consistent with shared upstream regulatory programs but do not by themselves establish direct co-regulation; the architectural findings reported here are correlational at the transcriptional layer.