With consistent significant enrichment of DEGs and coexpression modules for the immune response, we hypothesized that these DEGs, with uniquely adaptable cellular biology, would be more likely tolerant of phenotypic consequences of gene disruption and thus be evolutionarily less constrained. To test this, we examined the gene and transcript constraint scores28 of the global ancestry-associated DEGs. We found a significant depletion of DEGs for highly constrained genes (Fisher’s exact test, FDR < 0.0001; Fig. 3a). At the transcript level, we found a similar trend (Fig. 3b) with differentially expressed transcripts (DETs) associated with less constrained genes. Furthermore, we observed a significant negative correlation with the DEG signal (LFSR), and gene and transcript constraint scores (Pearson correlation, P < 0.0001; Fig. 3c). These results suggest that ancestry-associated differentially expressed features are associated with more rapidly evolving genes as previously seen in immunity-related genes29,30.
