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. 2007 Aug;176(4):2501-8.
doi: 10.1534/genetics.107.074815. Epub 2007 Jul 1.

Major histocompatibility complex heterozygosity reduces fitness in experimentally infected mice

Petteri Ilmonen  1 , Dustin J Penn, Kristy Damjanovich, Linda Morrison, Laleh Ghotbi, Wayne K Potts
Affiliations

Major histocompatibility complex heterozygosity reduces fitness in experimentally infected mice

Petteri Ilmonen et al. Genetics. 2007 Aug.

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.

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Figures

F<sc>igure</sc> 1.—
Figure 1.—
Salmonella resistance of congenic/wild mice in laboratory infection experiments. (a) Exp. 1: MHC genotype-specific bacterial loads (mean of log10 CFU/ml + SEM) in males challenged with a primary infection with single LT2 strain. (b) Exp. 2: Bacterial loads separately for females and males infected with a primary, single LT2 strain. (c) Exp. 3: Bacterial loads in females and males challenged with a primary single LT2 and with a secondary multiple-strain infection with LT2, PMAC45, and M525. (d) Exp. 4: Bacterial loads in females and males challenged with a primary single M525 and with a secondary multiple-strain infection with M525, PMAC51, and χ4665. Sample sizes are indicated above the error bars.
F<sc>igure</sc> 2.—
Figure 2.—
Survival rates (percentage of individuals alive) for homozygous and heterozygous congenic/wild mice in enclosures for Salmonella-infected and control populations.
F<sc>igure</sc> 3.—
Figure 3.—
Reproductive success of MHC heterozygous females in enclosures separately in Salmonella-infected and control populations. The solid bars indicate the observed and the open ones the predicted number of pups produced by heterozygous females. The predicted number of pups is based on the relative proportion of heterozygous to homozygous females (0.6 and 0.4, respectively) within the populations.
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