Sexual Dimorphism through the Lens of Genome Manipulation, Forward Genetics, and Spatiotemporal Sequencing

Sexual reproduction often leads to selection that favors the evolution of sex-limited traits or sex-specific variation for shared traits. These sexual dimorphisms manifest due to sex-specific genetic architectures and sex-biased gene expression across development, yet the molecular mechanisms underlying these patterns are largely unknown. The first step is to understand how sexual dimorphisms arise across the genotype–phenotype–fitness map. The emergence of “4D genome technologies” allows for efficient, high-throughput, and cost-effective manipulation and observations of this process. Studies of sexual dimorphism will benefit from combining these technological advances (e.g., precision genome editing, inducible transgenic systems, and single-cell RNA sequencing) with clever experiments inspired by classic designs (e.g., bulked segregant analysis, experimental evolution, and pedigree tracing). This perspective poses a synthetic view of how manipulative approaches coupled with cutting-edge observational methods and evolutionary theory are poised to uncover the molecular genetic basis of sexual dimorphism with unprecedented resolution. We outline hypothesis-driven experimental paradigms for identifying genetic mechanisms of sexual dimorphism among tissues, across development, and over evolutionary time.