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The causes of autoimmune disease remain poorly defined. However, it is known that genetic factors contribute to disease susceptibility. Hitherto, studies have focused upon single nucleotide polymorphisms as both tools for mapping and as probable causal variants. Recent studies, using genome-wide analytical techniques, have revealed that, in the genome, segments of DNA ranging in size from kilobases to megabases can vary in copy number. These changes of DNA copy number represent an important element of genomic polymorphism in humans and in other species and may therefore make a substantial contribution to phenotypic variation and population differentiation. Furthermore, copy number variation (CNV) in genomic regions harbouring dosage-sensitive genes may cause or predispose to a variety of human genetic diseases. Several recent studies have reported an association between CNV and autoimmunity in humans such as systemic lupus, psoriasis, Crohn's disease, rheumatoid arthritis and type 1 diabetes. The use of novel analytical techniques facilitates the study of complex human genomic structures such as CNV, and allows new susceptibility loci for autoimmunity to be found that are not readily mappable by single nucleotide polymorphism-based association analyses alone. [ABSTRACT FROM AUTHOR]

Genes of the major histocompatibility complex (MHC) are indispensable for pathogen defence in vertebrates. With wild-caught three-spined sticklebacks ( Gasterosteus aculeatus) we conducted the first study to relate individual reproductive parameters to both MHC class I and II diversities. An optimal MHC class II B diversity was found for male nest quality. However, male breeding colouration was most intense at a maximal MHC class I diversity. One MHC class I allele was associated with male redness. Similarly, one MHC class II B allele was associated with continuous rather than early female reproduction, possibly extending the reproductive period. Both alleles occurred more frequently with increasing individual allele diversity. We suggest that if an allele is currently not part of the optimum, it had not been propagated by choosy females. The parasite against which this allele provides resistance is therefore unlikely to have been predominant the previous year – a step to negative frequency-dependent selection. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex (MHC) antigen-presenting genes are the most variable loci in vertebrate genomes. Host–parasite co-evolution is assumed to maintain the excessive polymorphism in the MHC loci. However, the molecular mechanisms underlying the striking diversity in the MHC remain contentious. The extent to which recombination contributes to the diversity at MHC loci in natural populations is still controversial, and there have been only few comparative studies that make quantitative estimates of recombination rates. In this study, we performed a comparative analysis for 15 different ungulates species to estimate the population recombination rate, and to quantify levels of selection. As expected for all species, we observed signatures of strong positive selection, and identified individual residues experiencing selection that were congruent with those constituting the peptide-binding region of the human DRB gene. However, in addition for each species, we also observed recombination rates that were significantly different from zero on the basis of likelihood-permutation tests, and in other non-quantitative analyses. Patterns of synonymous and non-synonymous sequence diversity were consistent with differing demographic histories between species, but recent simulation studies by other authors suggest inference of selection and recombination is likely to be robust to such deviations from standard models. If high rates of recombination are common in MHC genes of other taxa, re-evaluation of many inference-based phylogenetic analyses of MHC loci, such as estimates of the divergence time of alleles and trans-specific polymorphism, may be required.Heredity (2006) 97, 427–437. doi:10.1038/sj.hdy.6800892; published online 30 August 2006 [ABSTRACT FROM AUTHOR]

Genes of the major histocompatibility complex (MHC) have been studied for several decades because of their pronounced allelic polymorphism. Structural allelic polymorphism is, however, not the only source of variability subjected to natural selection. Genetic variation may also exist in gene expression patterns. Here, we show that in a natural population of three-spined sticklebacks ( Gasterosteus aculeatus) the expression of MHC class IIB genes was positively correlated with parasite load, which indicates increased immune activation of the MHC when infections are frequent. To experimentally study MHC expression, we used laboratory-bred sticklebacks that were exposed to three naturally occurring species of parasite. We found strong differences in MHC class IIB expression patterns among fish families, which were consistent over two generations, thus demonstrating a genetic component. The average number of MHC class IIB sequence variants within families was negatively correlated to the MHC expression level suggesting compensatory up-regulation in fish with a low (i.e. suboptimal) MHC sequence variability. The observed differences among families and the negative correlation with individual sequence diversity imply that MHC expression is evolutionary relevant for the onset and control of the immune response in natural populations. [ABSTRACT FROM AUTHOR]

We have assessed the variability of maternally (mtDNA) and biparentally (allozymes) inherited genes of 443 chamois (Rupicapra r. rupicapra) from 19 regional samples in the Eastern Alps, to estimate the degree and patterns of spatial gene pool differentiation, and their possible causes. Based on a total mtDNA-RFLP approach with 16 hexanucleotide-recognizing restriction endonucleases, we found marked substructuring of the maternal gene pool into four phylogeographic groups. A hierarchical AMOVA revealed that 67.09% of the variance was partitioned among these four mtDNA-phylogroups, whereas only 8.04% were because of partitioning among regional samples within the populations, and 24.86% due to partitioning among individuals within regional samples. We interpreted this spatial pattern of mtDNA variability as a result of immigration of chamois from different Pleistocene refugia surrounding the Alps after the withdrawal of glaciers, rather than from topographic barriers to gene flow, such as Alpine valleys, extended glaciers or woodlands. However, this striking geographical structuring of the maternal genome was not paralleled by allelic variation at 33 allozyme loci, which were used as nuclear DNA markers. Wright's hierarchical F-statistics revealed that only ⩽ 0.45% of the explained allozymic diversity was because of partitioning among the four mtDNA-phylogroups. We conclude that this discordance of spatial patterns of nuclear and mtDNA gene pools results from a phylogeographic background and sex-specific dispersal, with higher levels of philopatry in females. [ABSTRACT FROM AUTHOR]