Rapid and adaptive evolution of MHC genes under parasite selection in experimental vertebrate populations

Abstract

The genes of the major histocompatibility complex are the most polymorphic genes in vertebrates, with more than 1,000 alleles described in human populations. How this polymorphism is maintained, however, remains an evolutionary puzzle. Major histocompatibility complex genes have a crucial function in the adaptive immune system by presenting parasite-derived antigens to T lymphocytes. Because of this function, varying parasite-mediated selection has been proposed as a major evolutionary force for maintaining major histocompatibility complex polymorphism. A necessary prerequisite of such a balancing selection process is rapid major histocompatibility complex allele frequency shifts resulting from emerging selection by a specific parasite. Here we show in six experimental populations of sticklebacks, each exposed to one of two different parasites, that only those major histocompatibility complex alleles providing resistance to the respective specific parasite increased in frequency in the next host generation. This result demonstrates experimentally that varying parasite selection causes rapid adaptive evolutionary changes, thus facilitating the maintenance of major histocompatibility complex polymorphism.

Figure 1. Experimental design.

Twelve randomly caught fish (parental generation, P) were crossed to obtain six laboratory-bred families (Generation 1, G1). A total of 6 families contributed equally to 6 experimental populations (7 males & 7 females per family per population, 84 fish per population, 504 fish in total). Three populations were exposed to laboratory-bred copepods infected with the nematode A. crassus (in total over the 2 generations, N=18,000 copepods and N=49,600 parasite larvae) and 3 were exposed to laboratory-bred copepods infected with the nematode C. lacustris (in total, N=20,000 copepods and N=127,000 parasite larvae). After natural reproduction in the artificial ponds, clutches were collected and fry-reared under standard conditions. Each clutch was then split into two equal groups and fish (N=450 per parental treatment, Generation 2, G2) were exposed either to the same parasite as their parents or the alternative parasite. Blue is used for copepods and fish exposed to C. lacustris, and purple is used for copepods and fish exposed to A. crassus.

Figure 2. MHC Allele frequency shift.

Mean (+1 s.e.m.) frequency changes of the resistance haplotypes between the first generation (G1) and the second generation (G2). After fish were allowed to reproduce under contrasting parasite selection regimes, MHC haplotype frequencies vary between treatments in G2 (NA. crassus=450, NC. lacustris=450, ANOSIM, R=0.033, P=0.001). Two MHC haplotypes (No13.No18 and No01.No12) explained 20.3 and 19.6%, respectively, of the variance between parasite treatments. The frequency change between generations was then tracked within each treatment (a) The haplotype No13.No18 increases in frequency (X²=16.58, d.f.=1, P<0.0005) under C. lacustris selection—a parasite to which it confers resistance. (b) No01.No12 increases in frequency (X²=5.53, d.f.=1, P=0.019) under A. crassus selection, a parasite to which it confers resistance. Frequencies are averaged over replicated experimental ponds. Blue bars represent fish exposed to C. lacustris and purple bars represent fish exposed to A. crassus.

Figure 3. Adaptive significance of MHC frequency shifts.

Mean (+1 s.e.m.) parasite load as a function of the presence ('with') or absence ('without') of the respective resistance haplotypes (a) No13.No18 and (b) No01.No12 in G1 and G2 generations. Haplotype No13.No18 confers resistance against C. lacustris (G1, T=−7.4, d.f.=196, P<0.001; G2, d.f.=385, T=−2.61, P=0.009), whereas the haplotype No01.No12 confers resistance against A. crassus (G1, T=−3.875, d.f.=196, P=0.001, G2 T=−2.353, d.f.=392, P=0.021). Parasite data were log+1 transformed to meet normality assumptions. Parasite load is the difference between the average individual infection with and without the resistance haplotype to the average infection within its family. If values are negative, infection is lower than the average family infection whereas, if values are positive, infection is higher than the average family infection. Blue bars represent 13 (out of 15) segregating fish families exposed to C. lacustris and purple bars represent 12 (out of 15) segregating fish families exposed to A. crassus. Parasites were counted during fish dissection. The other families did not contain individuals both with and without the respective haplotypes and were therefore excluded to guarantee comparability. No13.No18 G1 (N=197) and G2 (N=386). No01.No12 G1 (N=197) and G2 (N=393).