Epistatic interaction between Arabidopsis FRI and FLC flowering time genes generates a latitudinal cline in a life history trait

Epistatic gene interactions are believed to be a major factor in the genetic architecture of evolutionary diversification. In Arabidopsis thaliana, the FRI and FLC genes mechanistically interact to control flowering time, and here we show that this epistatic interaction also contributes to a latitudinal cline in this life history trait within the species. Two major FLC haplogroups (FLC ^A and FLC ^B) are associated with flowering time variation in A. thaliana in field conditions, but only in the presence of putatively functional FRI alleles. Significant differences in latitudinal distribution of FLC haplogroups in Eurasia and North Africa also depend on the FRI genotype. There is significant linkage disequilibrium between FRI and FLC despite their location on separate chromosomes. Although no nonsynonymous polymorphisms differentiate FLC ^A and FLC ^B, vernalization induces the expression of an alternatively spliced FLC transcript that encodes a variant protein with a radical amino acid replacement associated with the two FLC haplogroups. Numerous polymorphisms differentiating the FLC haplogroups also occur in intronic regions implicated in the regulation of FLC expression. The features of the regulatory gene interaction between FRI and FLC in contributing to the latitudinal cline in A. thaliana flowering time are consistent with the maintenance of this interaction by epistatic selection. These results suggest that developmental genetic pathways and networks provide the molecular basis for epistasis, contributing to ecologically important phenotypic variation in natural populations and to the process of evolutionary diversification.