Causal drift, robust signaling, and complex disease
Abstract
The phenotype of many regulatory circuits in which mutations can cause complex, polygenic diseases is to some extent robust to DNA mutations that affect circuit components. Here I demonstrate how such mutational robustness can prevent the discovery of genetic disease determinants. To make my case, I use a mathematical model of the insulin signaling pathway implicated in type 2 diabetes, whose signaling output is governed by 15 genetically determined parameters. Using multiple complementary measures of a parameter's importance for this phenotype, I show that any one disease determinant that is crucial in one genetic background will be virtually irrelevant in other backgrounds. In an evolving population that drifts through the parameter space of this or other robust circuits through DNA mutations, the genetic changes that can cause disease will vary randomly over time. I call this phenomenon causal drift. It means that mutations causing disease in one (human or non-human) population may have no effect in another population, and vice versa. Causal drift casts doubt on our ability to infer the molecular mechanisms of complex diseases from non-human model organisms.
References
Single gene disorders or complex traits: lessons from the thalassaemias and other monogenic diseases
Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation.
Citations
Life is a simulation of life - or is it?: What we observe is just one run of a probabilistic process
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