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新趋化因子的EST，并克隆了编码CC趋化因子的cDNA，这些趋化因子被称为LARC（肝脏和活化调节趋化因子）、SLC（次级淋巴组织趋化因子）、ELC（EBI 1-配体趋化因子）、PARC（肺和活化调节趋化因子）、LEC（肝脏表达趋化因子）和CX 3C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趋化因子的基因聚集在Chr 17上，而主要对淋巴细胞具有趋化性的CC趋化因子的基因位于其他染色体上。我们还鉴定了PARC基因在Chr 17趋化因子簇中的特征，并发现该基因是由两个MIP-1 α样序列融合产生的。此外，没有人类PARC基因的小鼠对应物。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趋化因子基因产生的Chr 17的连续重复事件的区域含有MIP-1 α基因。因此，位于Chr 17以外的CC趋化因子在Chr 17上的大多数CC趋化因子产生之前已经出现，并且最近通过复制产生的基因如PARC基因位于Chr 17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.