Theoretical model for gene-gene, gene-environment, and gene-sex interactions based on congenic-strain analysis of blood pressure in Dahl salt-sensitive rats

Abstract

There is a significant literature describing quantitative trait loci (QTL) controlling blood pressure (BP) in the Dahl salt-sensitive (S) rat. In studies to identify the genes underlying BP QTL it has been common practice to place chromosomal segments from low BP strains on the genetic background of the S rat and then reduce the congenic segments by substitution mapping. The present work suggests a model to simulate genetic interactions found using such congenic strains. The QTL are considered to be switches that can be either in series or in parallel represented by the logic operators AND or OR, respectively. The QTL switches can be on/off switches but are also allowed specific leak properties. The QTL switches are represented by a “universal” switch consisting of two molecules binding to form a complex. Genetic inputs enter the model as allelic products of one of the binding molecules and environmental variation (including dietary salt- and sex-related differences) enters as an influence on the concentration of the other binding molecule. The pairwise interactions of QTL are very well simulated and fall into recognizable patterns. There is, however, often more than one assumed model to predict a given pattern so that all patterns do not necessarily have a unique solution. Nevertheless, the models obtained provide a framework for placing the QTL in pathways relative to one another. Moreover, based on their leak properties pairs of QTL could be identified in which one QTL may alter the properties of the other QTL.