Polymorphism and balancing selection at major histocompatibility complex loci.
Polymorphism and balancing selection at major histocompatibility complex loci.
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发表时间：
1992-04
期刊：
影响因子：
3.3
通讯作者：
N. Takahata;Y. Satta;J. Klein
中科院分区：
文献类型：
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作者：
N. Takahata;Y. Satta;J. Klein
氨基酸替换的肽结合区（PBR）的功能性主要组织相容性复合体（MHC）基因似乎是由平衡选择驱动。在各种类型的平衡选择中，我们已经研究了一种赋予杂合子优势的超显性模型。正如A.罗伯逊，超显性选择倾向于保持具有或多或少相同程度的杂合子优势的等位基因。由于这种对称性，该模型对不同等位基因之间的系谱关系做出了各种可检验的预测，并提供了分析Mhc等位基因DNA序列的方法。在本文中，我们分析了85个等位基因的DNA序列在HLA-A，-B，-C，-DRB 1和-DQB 1基因座的等位基因的数量和程度的核苷酸差异在PBR，以及在同义（大概中性）的网站。理论表明，在选择所针对的位点（可能是PBR中的非同义位点）上不同的等位基因的数量应该等于等位基因对之间核苷酸取代的平均数量。我们还证明了相对于中性位点，靶位点的核苷酸取代率可能远大于1。所提出的模型的预测是令人惊讶的良好协议与实际数据，从而提供了推断某些人口参数的手段。在有限平衡群体中，超显性选择对纯合子的选择强度与有效群体大小的乘积约为350-3000，其中B位点最大，C位点最小。我们认为，如果每代每个位点的突变率为10（-8），则N为10（5）的数量级，s最多为百分之几。
Amino acid replacements in the peptide-binding region (PBR) of the functional major histocompatibility complex (Mhc) genes appear to be driven by balancing selection. Of the various types of balancing selection, we have examined a model equivalent to overdominance that confers heterozygote advantage. As discussed by A. Robertson, overdominance selection tends to maintain alleles that have more or less the same degree of heterozygote advantage. Because of this symmetry, the model makes various testable predictions about the genealogical relationships among different alleles and provides ways of analyzing DNA sequences of Mhc alleles. In this paper, we analyze DNA sequences of 85 alleles at the HLA-A, -B, -C, -DRB1 and -DQB1 loci with respect to the number of alleles and extent of nucleotide differences at the PBR, as well as at the synonymous (presumably neutral) sites. Theory suggests that the number of alleles that differ at the sites targeted by selection (presumably the nonsynonymous sites in the PBR) should be equal to the mean number of nucleotide substitutions among pairs of alleles. We also demonstrate that the nucleotide substitution rate at the targeted sites relative to that of neutral sites may be much larger than 1. The predictions of the presented model are in surprisingly good agreement with the actual data and thus provide means for inferring certain population parameters. For overdominance selection in a finite population at equilibrium, the product of selection intensity (s) against homozygotes and the effective population size (N) is estimated to be 350-3000, being largest at the B locus and smallest at the C locus. We argue that N is of the order of 10(5) and s is several percent at most, if the mutation rate per site per generation is 10(-8).