Intragenic epistasis in couch potato shapes life history traits and climatic adaptation in Drosophila melanogaster

Abstract

Populations adapting to heterogeneous environments often harbor many alleles that covary with environmental gradients, yet how so many adaptive variants can be maintained and show signatures of local adaptation remains unclear. Epistatic non-additive interactions among alleles may concentrate fitness effects at specific allelic combinations to shape complex traits and facilitate adaptation. We evaluate compositional epistasis among three intronic SNPs in the couch potato (cpo) gene, each independently clinal along the North American latitudinal gradient, using recombinant outbred populations fixed for distinct three-locus combinations. Flies carrying all three temperate alleles (cpoTTA) or all three tropical alleles (cpoCGT) show non-additive increases in traits associated with fitness in their respective environments: dormancy, starvation resistance, and lipid storage in temperate flies and fecundity in tropical flies. Intermediate genotype combinations generally show weaker and negative deviations from additive predictions. Temperate genotypes show reduced cpo expression and independently create predicted transcription factor binding sites, suggesting a regulatory basis for the observed phenotypic effects. Consistent with selection shaping haplotype frequencies against a backdrop of ongoing recombination, the temperate and tropical genotypes are enriched above random expectation across the latitudinal cline, with directionally consistent but non-significant seasonal patterns. Our findings demonstrate that non-additive interactions among non-coding variants within a single gene can produce large, pleiotropic fitness effects and shape genotype distributions in natural populations, providing a mechanism by which a small number of regulatory variants can underlie complex climatic adaptation.