A new theory of MHC evolution: beyond selection on the immune genes

Abstract

The major histocompatibility complex (MHC) is a dense region of immune genes with high levels of polymorphism, which are arranged in haplotype blocks. Traditional models of balancing selection (i.e. overdominance and negative frequency dependence) were developed to study the population genetics of single genes. However, the MHC is a multigene family surrounded by linked (non-neutral) polymorphisms, and not all of its features are well explained by these models. For example, (i) the high levels of polymorphism in small populations, (ii) the unexpectedly large genetic differentiation between populations, (iii) the shape of the allelic genealogy associated with trans-species evolution, and (iv) the close associations between particular MHC (human leucocyte antigen, HLA) haplotypes and the approximately 100 pathologies in humans. Here, I propose a new model of MHC evolution named Associative Balancing Complex evolution that can explain these phenomena. The model proposes that recessive deleterious mutations accumulate as a 'sheltered load' nearby MHC genes. These mutations can accumulate because (i) they are rarely expressed as homozygotes given the high MHC gene diversity and (ii) purifying selection is inefficient with low recombination rates (cf. Muller's ratchet). Once fixed, these mutations add to balancing selection and further reinforce linkage through epistatic selection against recombinants.

Figure 1

Schematic of ABC evolution. Positive epistatic selection maintains moderate linkage between combinations of functional immune genes (coloured squares and triangles) that work well together (Gregersen et al. 2006). At (a) t=t₀: the homozygotes (hom.) show a low fitness (overdominant selection), the recombinants (rec.) a low fitness (epistatic selection) and the heterozygotes (het.) a high fitness (heterosis). At (b) t=t₁: recessive deleterious mutations (red circles) accumulate in haploblocks because purifying selection is inefficient when recombination rates are low (Haddrill et al. 2007). These mutations fix in a process similar to Muller's ratchet (Muller 1932). Once fixed, these mutations increase the efficacy of balancing selection and further reinforce linkage through epistatic selection against recombinants. At t=t₁, the homozygotes have a very low fitness (overdominant and purifying selection), the recombinants a very low fitness (epistatic and purifying selection) and heterozygotes a high fitness (heterosis and no purifying selection). At (c) t=t₂: even in the absence of balancing selection on the actual immune genes (open squares and triangles), purifying selection operates against the recessive deleterious mutations when expressed in homozygous condition, thus maintaining the polymorphism in the population. Homozygotes and recombinants have a low fitness (purifying selection), and heterozygotes have a high fitness (no purifying selection).

Figure 2

Epistatic selection (E) against the recombinant haplotypes can prevent the breakdown of LD by recombination between haploblocks. In this example, there are two haploblocks separated by a recombination hot spot with a recombination rate (c=0.01). Each haplotype block contains a genetic load unique to the block (red circles), consisting of a completely recessive deleterious mutation (s=0.4, h=0). The immune genes (squares) have no fitness effect. The fitness effects of mutations are multiplicative across loci. The fitness of individuals homozygous for both blocks equals w=(1−0.4)²=0.36. Completely heterozygous individuals have a fitness of w=1. Recombinant haplotypes have a fitness equal to w=(1−0.4)=0.6, because they always carry one mutant in homozygous condition. This assumes that recombinants are rare and combine with ancestral haplotypes only. The strength of epistatic selection is given by the fitness difference between the (a) ancestral and (b) recombinant haplotypes (E=1−0.6−0.6+0.36=0.16) (see Crow & Kimura 1970).

Figure 3

Genealogies, haplotype frequencies and genetic loads of simulated populations over 3×10⁵ generations. Each step in the genealogies (a–c) represents a mutation in the MHC gene. Total number of accumulated MHC mutations and time are shown on the x- and y-axes, respectively. Dotted vertical lines represent the ancestral MHC allele that is replaced by its derived mutant (solid vertical line). Only ancestral alleles with extant descendants are shown. (a) ABC evolution results in long terminal branches and large differentiation between extant alleles. (b) Overdominant selection results in a rapid turnover rate of alleles and little allelic differentiation. (c) Neutral evolution results in low level of polymorphism in the population (see table S1 and text S1 in the electronic supplementary material). (d) Marked unevenness in haplotype frequencies in the population under ABC evolution is consistent with the empirical data on the MHC (Richman 2000). (e) Deleterious mutations continue to accumulate in each haplotype, which might drive the birth and death process of multigene evolution (Nei & Rooney 2005). Brown circles, H1; red circles, H2; blue triangles, H3; green triangles, H4; pink squares, H5.

Figure 4

Genetic diversity with ABC evolution (filled circles) and overdominant selection (open circles) in simulated fox and guppy populations across a range of selection coefficients. Selection coefficients necessary to explain the observed MHC diversity are considerably lower under continual selection with ABC evolution than under temporary overdominant selection. (a) Mean (5–95% CL) expected heterozygosity (He) at the MHC in simulated populations of the fox (U. l. dickeyi) after a two-generation single-pair bottleneck. The heterozygosity after the bottleneck (He=0.36, Aguilar et al. 2004) is indicated by the dotted line. Genetic polymorphism in simulated fox populations can be maintained with selection coefficients (s≥0.2) with ABC evolution (black arrow). However, considerably stronger selection (S≥0.8) is necessary to explain the observed gene diversity (open arrow), assuming that overdominant selection operates during the bottleneck generations only (Aguilar et al. 2004). (b) The mean (5–95% CL) number of simulated MHC alleles in samples of 21 guppies (P. reticulata) in populations under ABC evolution (purifying selection every generation) and overdominant selection (operating in alternating generations) (van Oosterhout et al. 2007a). The dotted line at A=5 shows the number of observed alleles at each locus (van Oosterhout et al. 2006). Selection coefficients s≥0.2 (ABC evolution, black arrow) and S≥0.4 (overdominance, open arrow) are required to explain the observed MHC polymorphism.