Red Queen Processes Drive Positive Selection on Major Histocompatibility Complex (MHC) Genes.

Area of Science:

• Evolutionary immunology
• Molecular genetics
• Computational biology

Background:

• Major Histocompatibility Complex (MHC) genes are crucial for adaptive immunity in vertebrates, presenting pathogen-derived antigens.
• High MHC gene polymorphism is observed across species, attributed to pathogen-driven balancing selection.
• The precise mechanisms maintaining MHC polymorphism, such as heterozygote advantage and host-pathogen coevolution, remain debated.

Purpose of the Study:

• To investigate the relative contributions of heterozygote advantage and the Red Queen process (host-pathogen arms race) to MHC polymorphism.
• To determine how pathogen mutation rates influence the selection dynamics at MHC antigen-binding sites (ABS).

Main Methods:

• Individual-based computer simulations were employed to model MHC evolution under varying conditions.
• Simulations explored the impact of different pathogen mutation rates on MHC polymorphism.
• The study analyzed selection pressures on novel mutations at MHC antigen-binding sites.

Main Results:

• MHC polymorphism was primarily driven by the Red Queen process at high pathogen mutation rates, and by heterozygote advantage at low rates.
• Novel mutations at ABSs were strongly favored by the Red Queen process, irrespective of pathogen mutation rate.
• Despite increased allele turnover under the Red Queen process, allelic lineages persisted longer at high pathogen mutation rates compared to heterozygote advantage.

Conclusions:

• The Red Queen process offers a compelling explanation for positive selection and long coalescence times at MHC loci when pathogens evolve rapidly.
• A tension exists between the advantage of novel alleles and their persistence, particularly under high pathogen mutation rates, warranting further investigation.
• Understanding these dynamics is key to comprehending vertebrate immune system evolution and host-pathogen interactions.