Interspecific differences in second-site modifiers reshape dominance in a Mendelian trait by altering environmental...

Dominance is an important and evolvable property of the genotype-phenotype map. A longstanding debate in evolutionary genetics concerns whether dominance is determined primarily by intrinsic properties of alleles at the focal locus or by modifiers elsewhere in the genome. Theoretical models show that second-site modifiers of dominance can evolve under some conditions. However, direct empirical tests of these models are rare because they require holding the focal heterozygous genotype constant while changing the rest of the genome. In the Drosophila montium species subgroup, female pigmentation is a Mendelian trait controlled by a single gene, POU domain motif 3 ( pdm3 ), but the dominance relationships between pdm3 alleles differ among species. Using reciprocal introgressions among three closely related species, we compared females carrying the same Light/Dark pdm3 allele combinations in different homozygous or heterozygous genomic backgrounds and across different temperatures. In both species-pair comparisons, changing genomic background significantly altered the phenotype of identical pdm3 heterozygotes, demonstrating the existence of second-site modifiers of dominance. The effects of dominance modifiers depend on the particular pair of pdm3 alleles and on rearing temperature. These results show that dominance in this system is a genotype-by-genotype-by-environment trait, rather than a fixed attribute of individual alleles. The finding that second-site modifiers can alter dominance by reshaping reaction norms provides a developmental mechanism that links the evolution of dominance to phenotypic plasticity.

The causes of allelic dominance, and the mechanisms of its evolution, have been debated since the early work of Fisher, Wright, and Haldane 100 years ago. Recent theoretical models predict that second-site modifiers of dominance can evolve under realistic conditions, but empirical evidence remains scarce and contradictory. This study demonstrates the existence of modifiers that change dominance relationships at a Mendelian locus that controls interspecific differences in Drosophila pigmentation by testing the same pairs of focal alleles in the genomic backgrounds of different species. These modifiers act by altering phenotypic plasticity, providing a previously unappreciated developmental mechanism for the evolution of dominance.