Effect of Regulatory Architecture on Broad versus Narrow Sense Heritability

Additive genetic variance (VA) and total genetic variance (VG) are core concepts in biomedical, evolutionary and production-biology genetics. What determines the large variation in reported VA/VG ratios from line-cross experiments is not well understood. Here we report how the VA/VG ratio, and thus the ratio between narrow and broad sense heritability (h2/H2), varies as a function of the regulatory architecture underlying genotype-to-phenotype (GP) maps. We studied five dynamic models (of the cAMP pathway, the glycolysis, the circadian rhythms, the cell cycle, and heart cell dynamics). We assumed genetic variation to be reflected in model parameters and extracted phenotypes summarizing the system dynamics. Even when imposing purely linear genotype to parameter maps and no environmental variation, we observed quite low VA/VG ratios. In particular, systems with positive feedback and cyclic dynamics gave more non-monotone genotype-phenotype maps and much lower VA/VG ratios than those without. The results show that some regulatory architectures consistently maintain a transparent genotype-to-phenotype relationship, whereas other architectures generate more subtle patterns. Our approach can be used to elucidate these relationships across a whole range of biological systems in a systematic fashion.Author Summary: The broad-sense heritability of a trait is the proportion of phenotypic variance attributable to genetic causes, while the narrow-sense heritability is the proportion attributable to additive gene effects. A better understanding of what underlies variation in the ratio of the two heritability measures, or the equivalent ratio of additive variance VA to total genetic variance VG, is important for production biology, biomedicine and evolution. We find that reported VA/VG values from line crosses vary greatly and ask if biological mechanisms underlying such differences can be elucidated by linking computational biology models with genetics. To this end, we made use of models of the cAMP pathway, the glycolysis, circadian rhythms, the cell cycle and cardiocyte dynamics. We assumed additive gene action from genotypes to model parameters and studied the resulting GP maps and VA/VG ratios of system-level phenotypes. Our results show that some types of regulatory architectures consistently preserve a transparent genotype-to-phenotype relationship, whereas others generate more subtle patterns. Particularly, systems with positive feedback and cyclic dynamics resulted in more non-monotonicity in the GP map leading to lower VA/VG ratios. Our approach can be used to elucidate the VA/VG relationship across a whole range of biological systems in a systematic fashion.