Genome-wide study identifies epistatic interactions between immune genes in Arabidopsis

In Arabidopsis thaliana, the quantitative resistance gene ACCELERATED CELL DEATH 6 (ACD6) has been implicated in the trade-off between growth and defense in natural strains. ACD6-Est-1-type alleles can lead to spontaneous activation of immune responses, including leaf necrosis. The extent of visible hyperimmunity varies, however, substantially between ACD6-Est-1 carriers1. To identify genes that modulate ACD6 activity, we performed a genome-wide association study (GWAS) of 84 strains that carry the ACD6-Est-1 allele. GWA together with linkage analysis identified both MODULATORS OF HYPERACTIVE ACD6 1 (MHA1, an unknown gene) and MHA2 (an uncharacterized subtilase) as ACD6 modifiers for cell death regulation. MHA1, coding for a small protein of ~7kDa, and its paralog MHA1-LIKE (MHAL) differentially interact with different ACD6 protein variants, and MHA1/MHAL interactions with ACD6 are important for expression of autoimmunity as well as disease resistance. The identification of ACD6 modifiers further led to resolving the biochemical activity of ACD6 affected by gain-of-function mutations. Finally, Haplotype analysis suggested that the epistatic interactions between the ACD6-Est-1 allele and its modifiers have been favoured by natural selection in the field. We propose that allelic diversity at MHA1 and MHA2 contributes to the maintenance of ACD6-Est-1 in A. thaliana populations, and that epistatic interactions are an important component of quantitative disease resistance