Barcoded Bulk QTL mapping reveals highly polygenic and epistatic architecture of complex traits in yeast
Bibliographic record
Abstract
Mapping the genetic basis of complex traits is critical to uncovering the biological mechanisms that underlie disease and other phenotypes. Genome-wide association studies (GWAS) in humans and quantitative trait locus (QTL) mapping in model organisms can now explain much of the observed heritability in many traits, allowing us to predict phenotype from genotype. However, constraints on power due to statistical confounders in large GWAS and smaller sample sizes in QTL studies still limit our ability to resolve numerous small-effect variants, map them to causal genes, identify pleiotropic effects across multiple traits, and infer non-additive interactions between loci (epistasis). Here, we introduce barcoded bulk quantitative trait locus (BB-QTL) mapping, which allows us to construct, genotype, and phenotype 100,000 offspring of a budding yeast cross, two orders of magnitude larger than the previous state of the art. We use this panel to map the genetic basis of eighteen complex traits, finding that the genetic architecture of these traits involves hundreds of small-effect loci densely spaced throughout the genome, many with widespread pleiotropic effects across multiple traits. Epistasis plays a central role, with thousands of interactions that provide insight into genetic networks. By dramatically increasing sample size, BB-QTL mapping demonstrates the potential of natural variants in high-powered QTL studies to reveal the highly polygenic, pleiotropic, and epistatic architecture of complex traits. Significance statement Understanding the genetic basis of important phenotypes is a central goal of genetics. However, the highly polygenic architectures of complex traits inferred by large-scale genome-wide association studies (GWAS) in humans stand in contrast to the results of quantitative trait locus (QTL) mapping studies in model organisms. Here, we use a barcoding approach to conduct QTL mapping in budding yeast at a scale two orders of magnitude larger than the previous state of the art. The resulting increase in power reveals the polygenic nature of complex traits in yeast, and offers insight into widespread patterns of pleiotropy and epistasis. Our data and analysis methods offer opportunities for future work in systems biology, and have implications for large-scale GWAS in human populations.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".