Beyond Mendel: a call to revisit the genotype-phenotype map through new experimental paradigms

The long-standing notion that genotypes map to phenotypes through simple one gene-one trait relationships continues to shape both research in the life sciences and public understanding, with implications for policy and funding priorities. Yet this paradigm is increasingly recognized as inadequate for explaining continuous phenotypic variation and the complex genetic architectures of the genotype-phenotype map. Modern genetics emerged from the early 20th-century synthesis of Mendelian and biometric schools of heredity, with R.A. Fisher demonstrating early on how multiple discrete loci could collectively produce continuous variation. Despite this fundamental insight, Mendelism-with its focus on single genes and standardized genetic backgrounds-became the dominant framework, shaping current genetics research and molecular biology as well as science education. The advent of large-scale genomic data has revealed yet again the limitations of this reductionist approach. Evidence from quantitative genetics now shows that most phenotypes arise from complex networks of many interdependent genes and their dynamic responses to environmental perturbations. Here we trace the historical roots of how Mendelian classical genetics departed from the biometric school to create the current predominant paradigm in genetics, despite fundamentally unresolved issues. Moving on from this one-sided paradigm will require systematic development of integrative, evolutionarily grounded experimental approaches that better capture the multigenic and context-dependent nature of inheritance. Achieving such an extended perspective will require methodological innovation, including advances in large-scale (e.g. automated) phenotyping. Dedicated research programs will be necessary to advance a new era of genetic research into the complex mechanisms underlying phenotypic variation.