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In humans, clearance of hepatitis C virus (HCV) infection is associated with genetic variation near the IL-28B gene and the induction of interferon-stimulated genes, like IP-10. Also in chimpanzees spontaneous clearance of HCV is observed. To study whether similar correlations exist in these animals, a direct comparison of IP-10 and IL-28B polymorphism between chimpanzees and patients was performed. All chimpanzees studied were monomorphic for the human IL-28B SNPs which are associated with spontaneous and treatment induced HCV clearance in humans. As a result, these particular SNPs cannot be used for clinical association studies in chimpanzees. Although these human SNPs were absent in chimpanzees, gene variation in this region was present however, no correlation was observed between different SNP-genotypes and HCV outcome. Strikingly, IP-10 levels in chimpanzees correlated with HCV-RNA load and cGT, while such correlations were not observed in humans. The correlation between IP-10, cGT and virus load in chimpanzees was not found in patients and may be due to the lack of lifestyle-related confounding factors in chimpanzees. Direct comparison of IP-10 and IL-28B polymorphism between chimpanzees and patients in relation to HCV infection, illustrates that the IFN-pathways are important during HCV infection in both species. The Genbank EMBL accession numbers assigned to chimpanzees specific sequences near the IL-28B gene are HE599784 and HE599785. [ABSTRACT FROM AUTHOR]

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. Conclusion: 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. [ABSTRACT FROM AUTHOR]