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Evolution of natural killer cell receptor genes

by 1975- Hao, Li

Abstract (Summary)
Natural killer (NK) cells play important roles in the early immune response against tumor and virus-infected cells. Their activity is controlled by the interaction of the receptors on the NK-cell surface with major histocompatibility complex (MHC) class I molecules. Genes encoding families of NK receptors are organized into two chromosomal complexes: the leukocyte receptor complex (LRC) and the natural killer gene complex (NKC). To understand the diversity and evolution of these different gene families of NK receptors, the following three related studies were conducted. (1) Belonging to the immunoglobulin-like superfamily, the family of killer cell immunoglobulin-like receptors (KIR) is tandemly clustered in the LRC. I examined the evolutionary relationships of primate KIR genes and showed that the KIR gene family has experienced a rapid expansion in primate species. I also identified the positive selection at the MHC-binding sites (MBS) of KIR genes. Estimates of divergence times between duplicate genes suggested that KIR genes and their ligand, MHC class I genes, coevolved in primates. (2) The KLRA (previously known as Ly49) gene family in rodents belongs to the C-type lectin-like superfamily but performs the same function as that of KIR in primates. They are tandemly clustered in the NKC. I characterized the entire KLRA gene cluster in rats and identified a total of 33 genes, which is approximately twice as large as the KLRA repertoire in mice. The phylogenetic analysis of rodent KLRA genes suggested that this gene family expanded very quickly in rodents and the majority of these genes were generated after divergence of mice and rats. The similarity of the evolutionary pattern between primate KIR and rodent KLRA genes suggests that their rapid evolution is iii caused by the functional divergence of the genes and the interaction with MHC class I molecules. (3) In addition to the KLRA gene family, the NKC contains a large number of other C-type lectin-like receptor genes which are expressed on NK and other immunerelated cells. I characterized all the C-type lectin-like NKC genes and their organization from four major orders of placental mammals, primates (human), rodents (mouse and rat), carnivores (dog), and artiodactyls (cattle). Phylogenetic analysis of these genes indicated that the genes within the NKC are highly heterogeneous with respect to the rate of birthand-death evolution within and between different mammalian species, but the NKC is also remarkably conserved in the gene organization and persistence of orthologous genes. Searching for putative NKC sequences in opossum and chicken genomes suggested that the expansion of the NKC gene families might have occurred before the radiation of placental mammals but after the divergence between birds and mammals. iv
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School:Pennsylvania State University

School Location:USA - Pennsylvania

Source Type:Master's Thesis

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