Bergström T F, Josefsson A, Erlich H A, Gyllensten U
Department of Genetics and Pathology, University of Uppsala, Biomedical Center, Sweden.
Nat Genet. 1998 Mar;18(3):237-42. doi: 10.1038/ng0398-237.
The HLA class I and class II loci are the most highly polymorphic coding regions in the human genome. Based on the similarity of the coding sequences of alleles between species, it has been claimed that the HLA polymorphism is ancient and predates the separation of human (Homo) and chimpanzee (Pan), 4-7.4 Myr ago. Analysis of intron sequences, however, provides support for a more recent origin and for rapid generation of alleles at the HLA class II DRB1 locus. The human DRB1 alleles can be divided into groups (allelic lineages); most of these lineages have diverged from each other before the separation of Homo and Pan. Alleles within such a lineage, however, appear to be, on average, 250,000 years old, implying that the vast majority (greater than 90%) of the more than 135 contemporary human DRB1 alleles have been generated after the separation of Homo and Pan. The coalescence time of alleles within allelic lineages indicates that the effective population size (Ne) for early hominids (over the last 1 Myr) was approximately 10(4) individuals, similar to estimates based on other nuclear loci and mitochondrial DNA. With a single exception, the genetic mechanisms (gene conversion and point mutation) that have diversified the exon-2 sequences do not appear to extend into the adjacent intron sequences. The part of exon 2 encoding the beta-sheet evolves in concert with the surrounding introns, while the alpha-helix appears to have been subjected to gene conversion-like events, suggesting that such exchange events are highly localised and occur over extremely short sequence tracts.
HLA I类和II类基因座是人类基因组中多态性最高的编码区域。基于物种间等位基因编码序列的相似性，有人认为HLA多态性是古老的，早于人类（智人属）和黑猩猩（黑猩猩属）在400万至740万年前的分化。然而，对内含子序列的分析支持了HLA II类DRB1基因座的起源更近且等位基因快速产生的观点。人类DRB1等位基因可分为若干组（等位基因谱系）；这些谱系中的大多数在智人和黑猩猩分化之前就已相互分化。然而，同一谱系内的等位基因平均年龄似乎为25万年，这意味着在超过135个当代人类DRB1等位基因中，绝大多数（超过90%）是在智人和黑猩猩分化之后产生的。等位基因谱系中等位基因的合并时间表明，早期人类（过去100万年）的有效种群大小（Ne）约为10⁴个个体，这与基于其他核基因座和线粒体DNA的估计相似。除了一个例外，使外显子2序列多样化的遗传机制（基因转换和点突变）似乎并未延伸到相邻的内含子序列。编码β折叠的外显子2部分与周围内含子协同进化，而α螺旋似乎经历了类似基因转换的事件，这表明此类交换事件高度局部化，且发生在极短的序列片段上。
