Major Histocompatibility Complex Heterozygosity Reduces Fitness in Experimentally Infected Mice

Abstract

It is often suggested that heterozygosity at major histocompatibility complex (MHC) loci confers enhanced resistance to infectious diseases (heterozygote advantage, HA, hypothesis), and overdominant selection should contribute to the evolution of these highly polymorphic genes. The evidence for the HA hypothesis is mixed and mainly from laboratory studies on inbred congenic mice, leaving the importance of MHC heterozygosity for natural populations unclear. We tested the HA hypothesis by infecting mice, produced by crossbreeding congenic C57BL/10 with wild ones, with different strains of Salmonella, both in laboratory and in large population enclosures. In the laboratory, we found that MHC influenced resistance, 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. On the contrary, infected heterozygous females produced significantly fewer pups than homozygotes. Our results show that MHC effects are not masked on an outbred genetic background, and that MHC heterozygosity provides no immunological benefits when resistance is recessive, and can actually reduce fitness. These findings challenge the HA hypothesis and emphasize the need for studies on wild, genetically diverse species.

MHC influences infection with parasites and winter survival in the root vole Microtus oeconomus

“…MHC heterozygosity has been shown to be associated with decreased infection rates in both laboratory and field studies (McClelland et al 2003;Froeschke and Sommer 2005), but several other studies have found no such association (Harf and Sommer 2005;Dionne et al 2009). Ilmonen et al (2007) found that wild-derived mice that were MHC heterozygotes did not show better resistance to Salmonella or better survival in semi-natural enclosures, even though earlier laboratory experiments documented a heterozygote advantage (Penn et al 2002). These results emphasise the importance of studies on wild, outbred species.…”

The hidden benefits of sex: Evidence for MHC‐associated mate choice in primate societies

“…Such findings may explain choice for particular MHC genotypes, although as yet there is no choice documented for genotypes identified as conferring disease resistance. In addition, while disassortative mate choice has been commonly reported, the hypothesised advantage of MHC diversity for disease resistance has received mixed empirical support, although it may be more apparent in the context of multiple infections [88,89]. Finally, particular host/pathogen interactions may not translate into MHCassociated fitness effects over a host's lifetime.…”

Major histocompatibility complex (MHC) heterozygote superiority to natural multi-parasite infections in the water vole ( Arvicola terrestris )

“…In some cases, there is evidence that heterozygotes actually have reduced fitness relative to homozygotes ( Wedekind et al 2005;Ilmonen et al 2007). However, a potential criticism of laboratory tests of MHC and parasite associations is that some relationships may be contextdependent and therefore only emerge under particular environmental conditions, which are hard to reproduce artificially (Bernatchez & Landry 2003;Sommer 2005;.…”