Modeling Diversity: Do Homogeneous Laboratory Strains Limit Discovery?

Abstract

The outcome of chronic infections is highly variable. The heterogeneous disease outcomes in natural populations differ from genetically homogeneous infection models. Here, we use tuberculosis as a 'case study' to contrast the genetic landscape in natural populations with standard infection models, discussing new strategies to bridge this gap.

Keywords: Collaborative Cross; genetic diversity; host genetics; infectious diseases; mouse models; tuberculosis.

Figure 1.. TB susceptibility is a complex trait.

The variability of TB disease is determined by interactions between environment, host genotype and bacterial genotypes. In the lab we simplify these factors by controlling environment, infecting a single inbred mouse strain with a lab adapted Mtb strain and measure a small number of traits that we hypothesize are important for driving overall disease (highlighted in red). While classical inbred lines of mice represent tractable experimental systems, the lack of genetic diversity and homogenous disease states means we are only modeling a small component of the disease that is observed in humans.