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

Diethard Tautz; Luisa F Pallares; Leif Andersson; Neda Barghi; Nick Barton; Rachael Bay; Yingguang Frank Chan; Angela Hancock; Tobias S Kaiser; Daniel Koenig; Zacharias Kontarakis; Miriam Liedvogel; Juliette de Meaux; Magnus Nordborg; Abraham A Palmer; Michael Purugganan; Christian Schlötterer; Karl Schmid; Didier Y R Stainier; Detlef Weigel; Jochen B W Wolf; Dieter Ebert; Greg Gibson

doi:10.1093/genetics/iyag024

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

Genetics. 2026 Feb 17:iyag024. doi: 10.1093/genetics/iyag024. Online ahead of print.

Authors

Diethard Tautz^{1

2}, Luisa F Pallares³, Leif Andersson⁴, Neda Barghi¹, Nick Barton⁵, Rachael Bay⁶, Yingguang Frank Chan⁷, Angela Hancock⁸, Tobias S Kaiser¹, Daniel Koenig⁹, Zacharias Kontarakis¹⁰, Miriam Liedvogel¹¹, Juliette de Meaux¹², Magnus Nordborg¹³, Abraham A Palmer¹⁴, Michael Purugganan¹⁵, Christian Schlötterer¹⁶, Karl Schmid¹⁷, Didier Y R Stainier¹⁸, Detlef Weigel¹⁹, Jochen B W Wolf^{20

21}, Dieter Ebert^{2

22}, Greg Gibson²³

Affiliations

¹ Max-Planck Institute for Evolutionary Biology, Plön 24306, Germany.
² Stellenbosch Institute for Advanced Studies (STIAS), 10 Marais Road, Stellenbosch 7600, South Africa.
³ Friedrich Miescher Laboratory of the Max Planck Society, Tübingen 72076, Germany.
⁴ Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala 75123, Sweden.
⁵ Institute of Science and Technology Austria, Evolution & Ecology, Klosterneuburg 3400, Austria.
⁶ Department of Evolution and Ecology, University of California Davis, Davis, CA 95616, United States.
⁷ Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen 9747AG, Netherlands.
⁸ Department of Botany and Plant Pathology, Purdue University, West Lafayette, IN 40797, United States.
⁹ Department of Botany and Plant Sciences and Institute for Integrative Genome Sciences, University of California, Riverside, CA 92507, United States.
¹⁰ Genome Engineering and Measurement Laboratory (GEML), ETH Zürich, Zürich 8093, Switzerland.
¹¹ Institute of Avian Research, An der Vogelwarte 21, Wilhelmshaven 26386, Germany.
¹² University of Cologne, Plant Molecular Ecology, Institute of Plant Sciences, Cologne 50674, Germany.
¹³ Austria Academy of Sciences, Vienna BioCenter, Gregor Mendel Institute, Vienna 1030, Austria.
¹⁴ Department of Psychiatry and Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093 United States.
¹⁵ Center for Genomics and Systems Biology, New York University, New York, NY 10003, United States.
¹⁶ Institut für Populationsgenetik, Vetmeduni Vienna, Vienna 1210, Austria.
¹⁷ Institute of Plant Breeding, Seed Science and Population Genetics, University of Hohenheim, Stuttgart 70599, Germany.
¹⁸ Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
¹⁹ Department of Molecular Biology, Max Planck Institute for Biology Tübingen, Tübingen 72076, Germany.
²⁰ LMU München, Biozentrum Martinsried, Department of Evolutionary Biology, Großhaderner Straße 2, Martinsried 82152, Germany.
²¹ MPI Biologische Intelligenz, Department of Microevolution and Biodiversity, Eberhard-Gwinner-Straße, Seewiesen 82319, Germany.
²² Department of Environmental Sciences, Zoology, University of Basel, Vesalgasse 1, Basel CH-4051, Switzerland.
²³ Center for Integrative Genomics and School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30302, United States.

PMID: 41701356
DOI: 10.1093/genetics/iyag024

Abstract

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.

Keywords: classic genetics; genotype–phenotype map; quantitative genetics.