Arvidsson A K, Svensson A C, Widmark E, Andersson G, Rask L, Larhammar D
Ludwig Institute for Cancer Research, Uppsala, Sweden.
Hum Immunol. 1995 Mar;42(3):254-64. doi: 10.1016/0198-8859(94)00102-v.
The human major histocompatibility complex, HLA, is a highly polymorphic gene region which includes the DRA and DRB genes. The number of DRB genes differs between haplotypes. The DR4 haplotype seems to be one of the most complex with five DRB loci, DRB1, DRB4, DRB7, DRB8, and DRB9, in addition to the single DRA locus. We determined the nucleotide sequences of three separated DRB exons located between the DRB4 locus and the DRA locus in the DR4 haplotype, two DRB signal-peptide exons (S1 and S3) and one DRB first-domain exon (locus designation DRB9). Sequence comparisons suggest the following order of events for the origin of these exons: DRB9 seems to be the oldest exon and has previously been detected in multiple HLA haplotypes. DRB9 is more divergent than the three other known DRB pseudogenes, all of which have been found in apes. This suggests that DRB9 arose prior to the hominoid divergence. An L1 repeat has been inserted 3' to DRB9. Subsequently, a LTR of the ERV9 retrovirus-like family was inserted into the L1 repeat. Such LTRs have recently been observed in some of the other DRB genes. The pseudogenes DRB7 and DRB8 (containing only exons 3-6) arose after DRB9. Finally, the separated signal peptide exons S1 and S3 were formed. The molecular characterization of these separated DRB exons and insertion elements further clarifies the complex evolutionary history of the HLA-DR region. These selectively neutral exons may serve as useful markers for tracing the phylogeny of HLA haplotypes.
人类主要组织相容性复合体HLA是一个高度多态的基因区域，其中包括DRA和DRB基因。不同单倍型之间DRB基因的数量有所不同。DR4单倍型似乎是最复杂的单倍型之一，除了单个DRA基因座外，还有五个DRB基因座，即DRB1、DRB4、DRB7、DRB8和DRB9。我们确定了位于DR4单倍型中DRB4基因座和DRA基因座之间的三个分离的DRB外显子的核苷酸序列，即两个DRB信号肽外显子（S1和S3）和一个DRB第一结构域外显子（基因座命名为DRB9）。序列比较表明这些外显子起源的事件顺序如下：DRB9似乎是最古老的外显子，之前已在多种HLA单倍型中检测到。DRB9比其他三个已知的DRB假基因差异更大，这三个假基因均在猿类中发现。这表明DRB9在类人猿分化之前就已出现。一个L1重复序列已插入到DRB9的3'端。随后，ERV9逆转录病毒样家族的一个长末端重复序列（LTR）插入到L1重复序列中。最近在其他一些DRB基因中也观察到了这种LTR。DRB7和DRB8假基因（仅包含外显子3 - 6）在DRB9之后出现。最后，形成了分离的信号肽外显子S1和S3。这些分离的DRB外显子和插入元件的分子特征进一步阐明了HLA - DR区域复杂的进化历史。这些选择性中性外显子可作为追踪HLA单倍型系统发育的有用标记。
