Vincek V, Klein D, Figueroa F, Hauptfeld V, Kasahara M, O'hUigin C, Mach B, Klein J
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33101.
Immunogenetics. 1992;35(4):263-71. doi: 10.1007/BF00166832.
The human HLA-DR3 haplotype consists of two functional genes (DRB103 and DRB301) and one pseudogene (DRB2), arranged in the order DRB1...DRB2...DRB3 on the chromosome. To shed light on the origin of the haplotype, we sequenced 1480 nucleotides of the HLA-DRB2 gene and long stretches of two other genes, Gogo-DRB2 from a gorilla, "Sylvia" and Patr-DRB2 from a chimpanzee, "Hugo". All three sequences (HLA-DRB2, Gogo-DRB2, Patr-DRB2) are pseudogenes. The HLA-DRB2 and Gogo-DRB2 pseudogenes lack exon 2 and contain a twenty-nucleotide deletion in exon 3, which destroys the correct translational reading frame and obliterates the highly conserved cysteine residue at position 173. The Patr-DRB2 pseudogene lacks exons 1 and 2; it does not contain the twenty-nucleotide deletion, but does contain a characteristic duplication of that part of exon 6 which codes for the last four amino acid residues of the cytoplasmic region. When the nucleotide sequences of these three genes are compared to those of all other known DRB genes, the HLA-DRB2 is seen as most closely related to Gogo-DRB2, indicating orthologous relationship between the two sequences. The Patr-DRB2 gene is more distantly related to these two DRB2 genes and whether it is orthologous to them is uncertain. The three genes are in turn most closely related to HLA-DRBVI (the pseudogene of the DR2 haplotype) and Patr-DRB6 (another pseudogene of the Hugo haplotype), followed by HLA-DRB4 (the functional but nonpolymorphic gene of the DR4 haplotype). These relationships suggest that these six genes evolved from a common ancestor which existed before the separation of the human, gorilla, and chimpanzee lineages. The DRB2 and DRB6 have apparently been pseudogenes for at least six million years (myr). In the human and the gorilla haplotype, the DRB2 pseudogene is flanked on each side by what appear to be related genes. Apparently, the DR3 haplotype has existed in its present form for more than six myr.
人类HLA - DR3单倍型由两个功能基因（DRB103和DRB301）和一个假基因（DRB2）组成，在染色体上按DRB1...DRB2...DRB3的顺序排列。为了阐明该单倍型的起源，我们对HLA - DRB2基因的1480个核苷酸以及另外两个基因的长片段进行了测序，这两个基因分别是来自大猩猩“西尔维亚”的Gogo - DRB2和来自黑猩猩“雨果”的Patr - DRB2。所有这三个序列（HLA - DRB2、Gogo - DRB2、Patr - DRB2）都是假基因。HLA - DRB2和Gogo - DRB2假基因缺少外显子2，并且在外显子3中有一个20个核苷酸的缺失，这破坏了正确的翻译阅读框，并消除了第173位高度保守的半胱氨酸残基。Patr - DRB2假基因缺少外显子1和2；它不包含20个核苷酸的缺失，但确实包含外显子6中编码细胞质区域最后四个氨基酸残基的那部分的特征性重复。当将这三个基因的核苷酸序列与所有其他已知的DRB基因的序列进行比较时，HLA - DRB2被视为与Gogo - DRB2关系最密切，表明这两个序列之间存在直系同源关系。Patr - DRB2基因与这两个DRB2基因的关系更远，它是否与它们直系同源尚不确定。这三个基因依次与HLA - DRBVI（DR2单倍型的假基因）和Patr - DRB6（雨果单倍型的另一个假基因）关系最密切，其次是HLA - DRB4（DR4单倍型的功能性但非多态性基因）。这些关系表明这六个基因是从人类、大猩猩和黑猩猩谱系分离之前存在的一个共同祖先进化而来的。DRB2和DRB6显然至少在600万年前（myr）就已经是假基因了。在人类和大猩猩单倍型中，DRB2假基因两侧似乎都是相关基因。显然，DR3单倍型以其目前的形式已经存在了超过600万年。
