Control of clonal expression of the KIR genes is one of the most interesting aspects of NK cell genetics. Several studies have suggested an epigenetic mechanism to explain the regulation of clonal KIR transcription. It was shown that DNA methylation in the 5 area correlates with silencing of KIR transcription. Such methylation occurs in a stochastic fashion among NK cell clones. A particularly interesting mechanism was identified in mouse to explain stochastic expression of the Ly49 genes based on probabilistic use of bidirectional promoters. It was recently shown by our collaborators that a similar mechanism also occurs at the KIR locus in humans. We have now begun to study genetic variation in the promoter region of the KIR genes that may impact expression levels. These data have important implications for our understanding of the role of NK cells in disease and transplantation. Genome structural variants, such as copy number variants (CNVs), are a significant component of human genetic variation and important genetic determinants of phenotypic variation. A CNV has been defined as a segment of DNA >1 kb and present at variable copy number. To date, >20,000 such CNVs have been identified in the human genome. CNVs frequently involve genes that influence our response to environmental stimuli, including immune response. Consequently, there is considerable potential for CNVs to play a significant role in susceptibility to infection and they could to some extent explain the variable penetrance of inherited complex polygenic disorders such as autoimmunity. This premise is supported by recent correlations of CNVs with inter-individual variation in immune defense and disease resistance/susceptibility among humans. In spite of the biomedical relevance of CNVs, the fine-scale structure of the majority of CNV regions remains unknown with only a fraction resolved at the sequence level. CNV regions involving short-range segmental duplications of DNA with near-identical sequence, often representing multi-allelic and highly polymorphic systems, have proven particularly difficult to characterize and present a challenge to high-throughput analysis. The KIR complex on chromosome 19 is an immune gene family exhibiting substantial segmental CNVs. The complex offers a unique opportunity to gain insight into the processes operating in multicopy gene families and segmental CNV regions because over the last 15 years KIRs have been extensively studied in terms of gene structures and haplotype content due to increasing awareness of their broad medical relevance. We have been focused on studying the patterns of variation and the underlying recombination processes in the KIR complex to better understand its relationship with disease and evolutionary history The KIR receptor family differs markedly among species and even between primates suggesting that KIR haplotypes evolve rapidly in ways that cannot be accounted for solely by divergence in MHC class I molecules. The evolutionary plasticity of the KIRs and their biomedical relevance makes it important to understand the dynamics of how these receptors evolve. It has been previously proposed that the arrangement of KIR genes in close head-to-tail orientation and their high sequence similarity facilitates gene gain and loss by unidirectional alignment and sequential meiotic non-allelic homologous recombination (NAHR). Consistent with this, we have identified by segregation analysis unusual KIR haplotypes possessing aberrant gene content in families comprising Caucasian individuals of European origin. These rare KIR haplotypes can help expound the rapid evolution and the genomic and physiological regulation of this gene family. In collaboration with our colleagues at University of Cambridge, two unusual, extremely truncated KIR haplotypes were sequenced. The data provide insight into CNV in general, as well as special mutational processes that shape the KIR complex.
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