Molecular Origins of Complex Heritability in Natural Genotype-to-Phenotype Relationships

The statistical complexity of heredity has long been evident, but its molecular origins remain elusive. To investigate, we charted 90 comprehensive genotype-to-phenotype maps in a large population of wild diploid yeast. In contrast to long-standing assumptions, all types of genetic variation contributed similarly to phenotype. Causal synonymous and regulatory variants exhibited distinct molecular signatures, as did nonlinearities in heterozygote fitness that likely contribute to hybrid vigor. Highly pleiotropic variants altered disordered sequences within signaling hubs, and their effects correlated across environments-even when antagonistic-suggesting that large fitness gains bring concomitant costs. Natural genetic networks defined by the causal loci differed from those determined by precise gene deletions or protein-protein interactions. Finally, we found that traits that would appear omnigenic in less powered studies do in fact have finite genetic determinants. Integrating these molecular principles will be crucial as genome reading and writing become routine in research, industry, and medicine.