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

Abstract

Although the statistical complexity of heredity has long been evident, its molecular origins remain elusive. To investigate, we charted a complete genotype-to-phenotype map for 90 complex traits in a large population of wild diploid yeast. Networks defined by these 18,007 loci differed substantially from those determined by gene deletions or protein interactions. Missense, synonymous, and regulatory variants contributed to phenotype. Synonymous variants altered codon adaptation index early in open reading frames. Regulatory variants occurred in open chromatin; their disruption drove hybrid vigor. Pleiotropic variants often altered disordered sequences within signaling hubs. Their effects correlated across environments – even when antagonistic – suggesting that large fitness gains bring concomitant costs. Finally, we estimated distributions of fitness effects for natural variants, revealing that traits appearing ‘omnigenic’ in less powered studies have finite genetic determinants. Integrating these principles into genome reading and writing will be crucial as it becomes routine in research, industry, and medicine.