Periodic Reporting for period 5 - PhenomeNal (Inheritance, expressivity and epistasis hidden behindthe phenotypic landscape of natural populations)
Reporting period: 2024-09-01 to 2025-02-28
The Phenome’N’al project addresses one of the most fundamental questions in biology: how does genetic variation translate into phenotypic diversity? Despite extensive work in genetics and genomics, our understanding of the genetic architecture of complex traits remains incomplete. Many traits cannot be fully explained by common variants alone, as rare alleles, structural variants, polyploidy, and gene-gene interactions play major roles. This “missing heritability” limits our ability to accurately predict traits and understand their evolutionary basis.
This challenge has broad significance for society. A deeper grasp of the genotype-phenotype map is essential for progress in human health, where gene regulation and variation underlie disease risk, in agriculture, where trait prediction can aid crop and livestock improvement, and in biotechnology, where understanding genetic diversity can enhance industrial applications such as fermentation.
The overall objectives of the project were therefore to systematically investigate the relationship between genotypes and phenotypes at a population scale, using the budding yeast Saccharomyces cerevisiae as a powerful model. The project aimed to:
- establish comprehensive resources linking genomic and phenotypic diversity;
- dissect the contributions of rare and common variants, structural variation, and genome dynamics to traits;
- analyze fundamental aspects of inheritance, penetrance, and expressivity;
- and develop an integrated framework for connecting genetic variation to phenotypic outcomes.
In its final period, the project concludes that large-scale, population-level approaches are essential to resolve the complexity of the genotype-phenotype relationship and to provide insights of relevance far beyond yeast.
This challenge has broad significance for society. A deeper grasp of the genotype-phenotype map is essential for progress in human health, where gene regulation and variation underlie disease risk, in agriculture, where trait prediction can aid crop and livestock improvement, and in biotechnology, where understanding genetic diversity can enhance industrial applications such as fermentation.
The overall objectives of the project were therefore to systematically investigate the relationship between genotypes and phenotypes at a population scale, using the budding yeast Saccharomyces cerevisiae as a powerful model. The project aimed to:
- establish comprehensive resources linking genomic and phenotypic diversity;
- dissect the contributions of rare and common variants, structural variation, and genome dynamics to traits;
- analyze fundamental aspects of inheritance, penetrance, and expressivity;
- and develop an integrated framework for connecting genetic variation to phenotypic outcomes.
In its final period, the project concludes that large-scale, population-level approaches are essential to resolve the complexity of the genotype-phenotype relationship and to provide insights of relevance far beyond yeast.
From the beginning, the project set out to systematically dissect the relationship between genetic variation and phenotypic diversity using the budding yeast Saccharomyces cerevisiae as a model. This required the coordinated development of comprehensive population genomic resources, high-throughput phenotyping datasets, and new methods for data integration and analysis.
The first phase of the work focused on generating foundational resources. Over 1,000 natural isolates of S. cerevisiae were sequenced and phenotyped, creating one of the most complete population genomic frameworks available for any eukaryote. These resources were complemented with a few telomere-to-telomere genome assemblies, allowing the construction of a detailed pangenome that captures both core and accessory genes as well as large-scale structural variants.
Building on this foundation, the project integrated multi-omics layers - transcriptomes, and proteomes - across hundreds of isolates. This enabled a species-wide analysis of the genetic control of molecular traits and their relationship to organismal phenotypes. Results demonstrated that copy number variants, accessory genes, and rare alleles contribute disproportionately to phenotypic diversity, while transcript and protein abundances are governed by largely distinct genetic architectures. These findings were disseminated through high-profile publications (Nature, Nature Genetics, Nature Communications, PNAS) and made openly available to the scientific community.
The project also extended beyond S. cerevisiae to investigate the role of polyploidization and hybridization in other yeast species, notably Brettanomyces bruxellensis. These studies revealed how genome duplication and hybrid origin shape evolutionary trajectories and adaptive potential.
Exploitation and dissemination were key components of the action.
The genomic, phenotypic, and multi-omics datasets have been deposited in public repositories and linked through dedicated portals, ensuring accessibility for future research. The publications arising from the project have established yeast as a model system to understand genotype-phenotype relationships at population scale, and the methodological advances developed provide a blueprint for similar efforts in other eukaryotic systems.
In summary, the project delivered a comprehensive framework that links natural genomic diversity to molecular and organismal traits. It demonstrated the power of population-scale, multi-layered approaches for resolving complex genotype-phenotype maps and laid the foundation for translating these insights into broader biological and societal contexts.
The first phase of the work focused on generating foundational resources. Over 1,000 natural isolates of S. cerevisiae were sequenced and phenotyped, creating one of the most complete population genomic frameworks available for any eukaryote. These resources were complemented with a few telomere-to-telomere genome assemblies, allowing the construction of a detailed pangenome that captures both core and accessory genes as well as large-scale structural variants.
Building on this foundation, the project integrated multi-omics layers - transcriptomes, and proteomes - across hundreds of isolates. This enabled a species-wide analysis of the genetic control of molecular traits and their relationship to organismal phenotypes. Results demonstrated that copy number variants, accessory genes, and rare alleles contribute disproportionately to phenotypic diversity, while transcript and protein abundances are governed by largely distinct genetic architectures. These findings were disseminated through high-profile publications (Nature, Nature Genetics, Nature Communications, PNAS) and made openly available to the scientific community.
The project also extended beyond S. cerevisiae to investigate the role of polyploidization and hybridization in other yeast species, notably Brettanomyces bruxellensis. These studies revealed how genome duplication and hybrid origin shape evolutionary trajectories and adaptive potential.
Exploitation and dissemination were key components of the action.
The genomic, phenotypic, and multi-omics datasets have been deposited in public repositories and linked through dedicated portals, ensuring accessibility for future research. The publications arising from the project have established yeast as a model system to understand genotype-phenotype relationships at population scale, and the methodological advances developed provide a blueprint for similar efforts in other eukaryotic systems.
In summary, the project delivered a comprehensive framework that links natural genomic diversity to molecular and organismal traits. It demonstrated the power of population-scale, multi-layered approaches for resolving complex genotype-phenotype maps and laid the foundation for translating these insights into broader biological and societal contexts.
The project moved well beyond the state of the art by scaling genotype–phenotype studies to over 1,000 Saccharomyces cerevisiae isolates. Unlike earlier work limited to small sample sizes or single variant types, this project combined sequenced genomes, pangenome construction, and species-wide multi-omics data to analyze rare alleles, genetic variation, and gene content diversity at population scale.
By the end of the project, the expected results are a consolidated public resource of genomic and phenotypic data, a refined understanding of how genetic variants shape diversity, and conceptual frameworks transferable to other species. This establishes yeast as a reference model for population-scale genotype-phenotype mapping.
By the end of the project, the expected results are a consolidated public resource of genomic and phenotypic data, a refined understanding of how genetic variants shape diversity, and conceptual frameworks transferable to other species. This establishes yeast as a reference model for population-scale genotype-phenotype mapping.