0 D I Schlipalius W Chen P J Collins T Nguyen P E B Reilly P R Ebert 2008 Gene interactions constrain the course of evolution of phosphine resistance in the lesser grain borer, Rhyzopertha dominica Heredity 100 506-516 <p>Phosphine, a widely used fumigant for the protection of stored grain from insect pests, kills organisms indirectly by inducing oxidative stress. High levels of heritable resistance to phosphine in the insect pest of stored grain, <em>Rhyzopertha dominica</em> have been detected in Asia, Australia and South America. In order to understand the evolution of phosphine resistance and to isolate the responsible genes, we have undertaken genetic linkage analysis of fully sensitive (QRD14), moderately resistant (QRD369) and highly resistant (QRD569) strains of<em> R. dominica </em>collected in Australia. We previously determined that two loci, <em>rph1</em> and <em>rph2</em>, confer high-level resistance on strain QRD569, which was collected in 1997. We have now confirmed that <em>rph1</em> is responsible for the moderate resistance of strain QRD369, which was collected in 1990, and is shared with a highly resistant strain from the same geographical region, QRD569. In contrast, <em>rph2 </em>by itself confers only very weak resistance, either as a heterozygote or as a homozygote and was not discovered in the field until weak resistance (probably due to <em>rph1</em>) had become ubiquitous. Thus, high-level resistance against phosphine has evolved via stepwise acquisition of resistance alleles, first at<em> rph1 </em>and thereafter at <em>rph2</em>. The semi-dominance of rph2 together with the synergistic interaction between<em> rph1 </em>and <em>rph2</em> would have led to rapid selection for homozygosity. A lack of visible fitness cost associated with alleles at either locus suggests that the resistance phenotype will persist in the field.</p>