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Uncovering the hidden origin behind the missing heritability

Project description

Cracking the code of complex traits

Despite sharing much of their genetic makeup, individuals within the same species often display striking differences in their traits. Although modern genomics has uncovered thousands of genetic variants linked to this phenotypic diversity, a substantial portion of this variation still cannot be accounted for. The ERC-funded UnMiss project seeks to uncover the hidden sources of this 'missing heritability'. Using yeast as a model organism, researchers aim to build a massive atlas of genetic variants and traits from over 1 000 natural strains. They will also combine genome sequencing, gene expression and single-cell analyses and explore how rare genetic changes, environmental factors and random variations interact to shape complex traits. The project’s findings could transform how scientists predict genetic outcomes.

Objective

"Understanding the genetic causes of phenotypic diversity in natural populations is a major challenge. While advances have been made in identifying the genetic basis of complex traits, our knowledge remains incomplete. Whole-genome sequencing has enabled genome-wide association studies (GWAS) to link genetic variants to traits, including human diseases. However, even with thousands of causal variants identified, they often account for only a small fraction of phenotypic variation. Uncovering the sources of this ""missing heritability"" is essential for predicting complex traits from genome sequences. The sources of missing heritability are largely unknown but may include: (i) incomplete variant catalogs focusing on single nucleotide variants (SNVs) while neglecting structural variants (SVs), (ii) limited power to detect rare variants in GWAS, (iii) difficulties in accounting for environmental effects and stochastic phenotypic variation, and (iv) complex gene-by-gene and gene-by-environment interactions. The UnMiss project aims to address these gaps using yeast as a model organism, allowing for systematic exploration of missing heritability. By developing a genetic variant atlas and a phenotype panel from 1,011 natural yeast isolates, we will examine how different variants contribute to trait heritability. Comparative GWAS analyses of these isolates and a panel of 1,000 hybrids will help clarify the role of low-frequency and rare variants. Gene expression data across conditions and single-cell analyses will further explore the genetic basis of environmental and stochastic trait variation. By deeply phenotyping the same population, we ensure that all traits are analyzed in the same individuals, allowing for the integration of data across different trait types. This comprehensive approach sets the foundation for large-scale network integration and mediation analyses, aiming to uncover hidden patterns that can facilitate the prediction of complex traits."

Fields of science (EuroSciVoc)

Keywords

Programme(s)

Topic(s)

Funding Scheme

HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

(opens in new window) ERC-2024-ADG

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Host institution

ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS CIC BIOGUNE
Net EU contribution
€ 2 000 275,00
Address
PARQUE TECNOLOGICO EDIFICIO 801 A
48160 DERIO VIZCAYA
Spain
Region
Noreste País Vasco Bizkaia
Activity type
Research Organisations
Links
Total cost
No data

Beneficiaries (2)