The road less traveled: from genotype to phenotype in flies and humans

Robert R. H. Anholt, Trudy F. C. Mackay

Understanding how genomic variation gives rise to phenotypic variation is essential for elucidating mechanisms of adaptive evolution, plant and animal breeding, and precision medicine. However, identifying causal links between DNA sequence variants and variation in phenotypes is challenging in human populations, due to large blocks of linkage disequilibrium in the genome and heterogeneous developmental histories, lifestyles, and social and physical environments. Drosophila melanogaster presents a powerful genetic model, since linkage disequilibrium decays rapidly, facilitating assignment of causality to polymorphisms associated with phenotypic variation, and large numbers of individuals can be reared under defined environmental conditions, economically, and without regulatory restrictions. The D. melanogaster Genetic Reference Panel (DGRP), a population of 205 sequenced, inbred wild-derived flies, has enabled genome-wide association studies of morphological, physiological, behavioral, and life history traits, and demonstrated that genetic architectures of complex traits are highly polygenic, sexually dimorphic, and context dependent with extensive sex-, environment-, and genetic background (epistatic) effects. These features together with a modular organization of the transcriptome illustrate a dynamic integrative genetic architecture for complex traits. The complexity of the genetic architectures for complex traits in Drosophila provides important caveats for the interpretation of genetic studies in human populations. Aspects of the genetic underpinnings of complex traits can be represented as simplified gene networks on which human orthologues can be superimposed to provide blueprints for subsequent studies on analogous traits in human populations. Fundamental principles of the genetic architectures of Drosophila complex traits are likely applicable across phyla, from the DGRP to human populations.