Generation Mechanism of Human Chemokine Gene Family

趋化因子家族是一组参与炎症、病毒感染和细胞生长的细胞因子。现在有超过40种趋化因子，包括我们小组克隆的那些。我们在EST数据库中发现了几个编码趋化因子的新EST，并克隆了编码CC趋化因子的cDNA，分别命名为LARC(肝脏和激活调节的趋化因子)、SLC(次级淋巴组织趋化因子)、ELC(EBI 1配体趋化因子)、PARC(肺和激活调节的趋化因子)、LEC(肝脏表达的趋化因子)和CX3C趋化因子Fractalkine。我们确定了他们的基因位点。从这些结果可以看出，主要吸引单核细胞的CC趋化因子基因聚集在Chr17上，而主要对淋巴细胞趋化的CC趋化因子基因位于另一条染色体上。我们还鉴定了Chr 17趋化因子簇中的ParC基因，发现该基因是由两个类似MIP-1α的序列融合而成的。此外，没有与人类parc基因对应的小鼠。这表明ParC基因是在人类和啮齿动物分化后产生的。这些结果表明，CC趋化因子基因是通过包含MIP-α基因的区域的连续重复事件而在Chr17上产生的。因此，位于Chr17上的CC趋化因子在大多数Chr17上的CC趋化因子产生之前就已经出现，而最近通过重复产生的基因如Parc基因位于Chr17上的大趋化因子簇中。

Chemokine family is a group of cytokines involved in inflammation, virus infection and cell growth. There are now well over 40 chemokines including those cloned by our group. We found several ESTs encoding novel chemokines in the EST database and cloned the cDNAs encoding CC chemokines termed LARC (liver and activation-regulated chemokine), SLC (secondary lymphoid tissue chemokine), ELC (EBI 1-ligand chemokine), PARC (pulmonary and activation-regulated chemokine), LEC (liver-expressed chemokine) and CX3C chemokine fractalkine. We determined their gene loci. From these results, it is apparent that the genes for the CC chemokines which mainly attract monocytes cluster on Chr 17, whereas the genes for the CC chemokines which are mainly chemotactic for lymphocytes reside on the other chromosomes. We also characterized the PARC gene in the Chr 17 chemokine cluster, and found that the gene had been generated by fusion of two MIP-1alpha-like sequences. In addition, there is no mouse counterpart of the human PARC gene. This indicates that the PARC gene was generated after humans and rodents had diverged. These results suggest that CC chemokine genes were generated on Chr 17 by successive duplication events of the region containing the MIP-lalpha gene. Hence, the CC chemokines located on other than Chr 17 had emerged before most of the CC chemokines on Chr 17 were generated, and the genes recently generated by duplication such as the PARC gene are located in the large chemokine cluster on Chr 17.