Correlated evolution of nucleotide substitution rates and allelic variation in Mhc-DRB lineages of primates.
BACKGROUND
The major histocompatibility complex (MHC) is a key model of genetic polymorphism. Selection pressure by pathogens or other microevolutionary forces may result in a high rate of non-synonymous substitutions at the codons specifying the contact residues of the antigen binding sites (ABS), and the maintenance of extreme MHC allelic variation at the population/species level. Therefore, selection forces favouring MHC variability for any reason should cause a correlated evolution between substitution rates and allelic polymorphism. To investigate this prediction, we characterised nucleotide substitution rates and allelic polymorphism (i.e. the number of alleles detected in relation to the number of animals screened) of several Mhc class II DRB lineages in 46 primate species, and tested for a correlation between them.


RESULTS
First, we demonstrate that species-specific and lineage-specific evolutionary constraints favour species- and lineage-dependent substitution rate at the codons specifying the ABS contact residues (i.e. certain species and lineages can be characterised by high substitution rate, while others have low rate). Second, we show that although the degree of the non-synonymous substitution rate at the ABS contact residues was systematically higher than the degree of the synonymous substitution rate, these estimates were strongly correlated when we controlled for species-specific and lineage-specific effects, and also for the fact that different studies relied on different sample size. Such relationships between substitution rates of different types could even be extended to the non-contact residues of the molecule. Third, we provide statistical evidence that increased substitution rate along a MHC gene may lead to allelic variation, as a high substitution rate can be observed in those lineages in which many alleles are maintained. Fourth, we show that the detected patterns were independent of phylogenetic constraints. When we used phylogenetic models that control for similarity between species, due to common descent, and focused on variations within a single lineage (DRB1*03), the positive relationship between different substitution rates and allelic polymorphisms was still robust. Finally, we found the same effects to emerge in the analyses that eliminated within-species variation in MHC traits by using strictly single population-level studies. However, in a set of contrasting analyses, in which we focused on the non-functional DRB6 locus, the correlation between substitution rates and allelic variation was not prevalent.


CONCLUSIONS
Our results indicate that positive selection for the generation of allelic polymorphism acting on the functional part of the protein has consequences for the nucleotide substitution rate along the whole exon 2 sequence of the Mhc-DRB gene. Additionally, we proved that an increased substitution rate can promote allelic variation within lineages. Consequently, the evolution of different characteristics of genetic polymorphism is not independent.
Department of Biology, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, Wilrijk, Belgium. laszlo.garamszegi@ebd.csic.es
László Z
LZ
Garamszegi
Natasja G
NG
de Groot
Ronald E
RE
Bontrop
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D003062:Codon / Q000235:genetics; D019143:Evolution, Molecular; D005091:Exons; D005787:Gene Frequency; D005802:Genes, MHC Class II; D006684:HLA-DR Antigens / Q000235:genetics; D059806:HLA-DR beta-Chains; D006801:Humans; D008957:Models, Genetic; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011323:Primates / Q000235:genetics* / Q000276:immunology; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D013045:Species Specificity
D003062:Codon; D006684:HLA-DR Antigens; D059806:HLA-DR beta-Chains; C069699:HLA-DRB6 antigen