This Month in Genetics

This Is a Story about Controls Unraveling the pathogenesis of a complex disease is daunting. Variation in multiple genes and multiple environmental factors could be at play, as could variation in the interactions of these risk factors with each other. Lest you despair, Cadwell et al. prove that it is possible to reveal features of the disease process through a careful set of experiments with good controls. The researchers previously reported a mouse model of Crohn disease that is hypomorphic for Atg16L1, an autophagy gene that was pulled out of a genome-wide association study for Crohn disease. When these mice were rederived in a different animal facility with higher containment procedures, however, the Crohn-like phenotype was not evident. The group tracked this phenotype difference down to a murine norovirus strain that contributes to the intestinal phenotype through establishment of a persistent infection. Once this infection is established, the mice have increased susceptibility to additional environmental insult in the form of dextran sodium sulfate (DSS), a toxin that injures the intestine. Altogether, Atg16L1 hypomorphic mice that are infected with the norovirus and later given DSS exhibit several pathological features reminiscent of human Crohn disease. However, this is not the full story; the timing of the viral infection and DSS administration must be spaced if one is to see the intestinal damage, which also requires the presence of commensal bacteria in the gut. Treating the Atg16L1 hypomorphic mice with broadspectrum antibiotics to kill these bacteria prevents the damage induced by DSS. Truly, Crohn disease is complex, but this carefully executed set of experiments ties together at least one genetic risk factor with three separate environmental contributions to the disease process. Cadwell et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell, 141:1135–1145.