Genotype–Phenotype Map Characteristics of an In silico Heart Cell

Understanding the causal chain from genotypic to phenotypic variation is a tremendous challenge with huge implications for personalized medicine. Here we argue that linking computational physiology to genetic concepts, methodology, and data provides a new framework for this endeavor. We exemplify this causally cohesive genotype–phenotype (cGP) modeling approach using a detailed mathematical model of a heart cell. In silico genetic variation is mapped to parametric variation, which propagates through the physiological model to generate multivariate phenotypes for the action potential and calcium transient under regular pacing, and ion currents under voltage clamping. The resulting genotype-to-phenotype map is characterized using standard quantitative genetic methods and novel applications of high-dimensional data analysis. These analyses reveal many well-known genetic phenomena like intralocus dominance, interlocus epistasis, and varying degrees of phenotypic correlation. In particular, we observe penetrance features such as the masking/release of genetic variation, so that without any change in the regulatory anatomy of the model, traits may appear monogenic, oligogenic, or polygenic depending on which genotypic variation is actually present in the data. The results suggest that a cGP modeling approach may pave the way for a computational physiological genomics capable of generating biological insight about the genotype–phenotype relation in ways that statistical-genetic approaches cannot

Simulating Human Cardiac Electrophysiology on Clinical Time-Scales

In this study, the feasibility of conducting in silico experiments in near-realtime with anatomically realistic, biophysically detailed models of human cardiac electrophysiology is demonstrated using a current national high-performance computing facility. The required performance is achieved by integrating and optimizing load balancing and parallel I/O, which lead to strongly scalable simulations up to 16,384 compute cores. This degree of parallelization enables computer simulations of human cardiac electrophysiology at 240 times slower than real time and activation times can be simulated in approximately 1 min. This unprecedented speed suffices requirements for introducing in silico experimentation into a clinical workflow