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Updated: Jul 14, 2026
Stability and Structure of Bat Major Histocompatibility Complex Class I with Heterologous β2-Microglobulin
Published on: March 10, 2021
Major histocompatibility complex heterozygosity reduces fitness in experimentally infected mice
Petteri Ilmonen1, Dustin J Penn, Kristy Damjanovich
1Konrad Lorenz Institute for Ethology, Austrian Academy of Sciences, Savoyenstrasse 1a, A-1160 Vienna, Austria. p.ilmonen@klivv.oeaw.ac.at
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.
Insights
The heterozygote advantage hypothesis suggests MHC heterozygosity improves disease resistance. However, this study found no benefit in diverse mouse populations, challenging this long-held theory.
Area of Science:
- Immunogenetics
- Evolutionary Biology
- Population Genetics
Background:
- The Major Histocompatibility Complex (MHC) is highly polymorphic, with heterozygote advantage (HA) proposed as a key evolutionary driver.
- Evidence for HA is largely from laboratory studies on inbred mice, leaving its relevance in natural populations uncertain.
Purpose of the Study:
- To test the HA hypothesis by assessing the impact of MHC heterozygosity on disease resistance, survival, and reproduction in a genetically diverse mouse model.
- To evaluate MHC's role in disease resistance on both inbred and outbred genetic backgrounds.
Main Methods:
- Crossbreeding congenic C57BL/10 mice with wild mice to create genetically diverse populations.
- Infecting mice with different strains of Salmonella in both controlled laboratory settings and large population enclosures.
- Analyzing resistance, survival rates, and reproductive success (pup production) in relation to MHC genotype.
Main Results:
- In laboratory settings, MHC influenced resistance, but it was predominantly recessive, not overdominant.
- In population enclosures, MHC heterozygotes showed no enhanced resistance, survival, or reproductive success compared to homozygotes.
- Infected heterozygous females produced fewer offspring than homozygous females, indicating reduced fitness.
Conclusions:
- MHC heterozygosity does not confer immunological benefits in genetically diverse populations when resistance is recessive.
- The HA hypothesis may not be universally applicable, particularly in outbred species.
- Further research on wild, genetically diverse populations is crucial to understand MHC evolution and function.
