Major Histocompatibility Complex Heterozygosity Reduces Fitness in Experimentally Infected Mice

Petteri Ilmonen^*^,^,1, Dustin J. Penn^*^,, Kristy Damjanovich^*, Linda Morrison^*, Laleh Ghotbi^* and Wayne K. Potts^*

^* Department of Biology, University of Utah, Salt Lake City, Utah 84112 and Konrad Lorenz Institute for Ethology, Austrian Academy of Sciences, A-1160 Vienna, Austria

^¹ Corresponding author: Konrad Lorenz Institute for Ethology, Austrian Academy of Sciences, Savoyenstraße 1a, A-1160 Vienna, Austria.
E-mail: p.ilmonen{at}klivv.oeaw.ac.at

It is often suggested that heterozygosity at major histocompatibilitycomplex (MHC) loci confers enhanced resistance to infectiousdiseases (heterozygote advantage, HA, hypothesis), and overdominantselection should contribute to the evolution of these highlypolymorphic genes. The evidence for the HA hypothesis is mixedand mainly from laboratory studies on inbred congenic mice,leaving the importance of MHC heterozygosity for natural populationsunclear. We tested the HA hypothesis by infecting mice, producedby crossbreeding congenic C57BL/10 with wild ones, with differentstrains of Salmonella, both in laboratory and in large populationenclosures. In the laboratory, we found that MHC influencedresistance, despite interacting wild-derived background loci.Surprisingly, resistance was mostly recessive rather than dominant,unlike in most inbred mouse strains, and it was never overdominant.In the enclosures, heterozygotes did not show better resistance,survival, or reproductive success compared to homozygotes. Onthe contrary, infected heterozygous females produced significantlyfewer pups than homozygotes. Our results show that MHC effectsare not masked on an outbred genetic background, and that MHCheterozygosity provides no immunological benefits when resistanceis recessive, and can actually reduce fitness. These findingschallenge the HA hypothesis and emphasize the need for studieson wild, genetically diverse species.