Complex genetic interactions underlying expression differences between Drosophila races: analysis of chromosome substitutions.

Regulation of gene expression is usually separated into cis and trans components. The separation may become artificial if much of the variation in expression is under multigenic and epistatic (e.g., cis-by-trans) control. There is hence a need to quantify the relative contribution of cis, trans, and cis-by-trans effects on expression divergence at different levels of evolution. To do so across the whole genome, we analyzed the full set of chromosome-substitution lines between the two behavioral races of Drosophila melanogaster. Our observations: (i) Only approximately 3% of the genes with an expression difference are purely cis regulated. In fact, relatively few genes are governed by simple genetics because nearly 80% of expression differences are controlled by at least two chromosomes. (ii) For 14% of the genes, cis regulation does play a role but usually in conjunction with trans regulation. This joint action of cis and trans effects, either additive or epistatic, is referred to as inclusive cis effect. (iii) The percentage of genes with inclusive cis effect increases to 32% among genes that are strongly differentiated between the two races. (iv) We observed a nonrandom distribution of trans-acting factors, with a substantial deficit on the second chromosome. Between Drosophila racial groups, trans regulation of expression difference is extensive, and cis regulation often evolves in conjunction with trans effects.