Heterozygote advantage cannot explain MHC diversity, but MHC diversity can explain heterozygote advantage

Area of Science:

• Immunogenetics
• Evolutionary Biology
• Population Genetics

Background:

• Major Histocompatibility Complex (MHC) genes exhibit remarkable diversity.
• Previous theoretical models suggested heterozygote advantage could alone explain this high MHC diversity.
• Recent models by Siljestam and Rueffler (2024) proposed heterozygote advantage as a sole driver of realistic MHC diversity.

Purpose of the Study:

• To critically evaluate the hypothesis that heterozygote advantage alone can explain MHC diversity.
• To demonstrate the limitations of heterozygote advantage as the sole mechanism for maintaining MHC genetic variation.
• To propose an alternative perspective on the relationship between heterozygote advantage and MHC diversity.

Main Methods:

• Analysis of theoretical models concerning heterozygote advantage and MHC diversity.
• Examination of the sensitivity of model outcomes to parameter variations.
• Conceptual analysis of selective pressures acting on MHC haplotypes under heterozygote advantage.

Main Results:

• The high MHC diversity generated in Siljestam and Rueffler's models is highly sensitive to specific parameter values, questioning its general applicability.
• Selective forces favoring heterozygotes can paradoxically lead to increased homozygous fitness, thereby reducing or eliminating the heterozygote advantage.
• The contribution of heterozygote advantage to overall MHC diversity is likely minor in most species.

Conclusions:

• Heterozygote advantage alone is insufficient to explain the widespread and high diversity observed in MHC genes.
• Other evolutionary forces are likely the primary drivers of MHC diversity.
• Substantial heterozygote advantage may emerge as a consequence of pre-existing MHC diversity, rather than being its sole cause.