Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci.
Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci.
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作者：
N. Takahata;M. Nei
为了解释啮齿动物和灵长类动物主要组织相容性复合体（MHC）位点上多态性等位基因（反式特异性多态性）的长期持续性，对不同形式选择下采样的不同等位基因的合并时间进行了计算机模拟研究。同时，通过检查平均杂合度、样本中等位基因的数量和密码子取代率来解释MHC位点多态性的维持机制。得到的结果如下。 (1) 中性等位基因的合并时间太短，无法解释 MHC 位点的反式特异性多态性。 (2) 在主导选择下，合并时间可能长达数千万年，具体取决于所使用的参数值。观察到的平均杂合度和等位基因数量也足够高，足以解释 MHC 多态性。 (3)Snell提出的病原体适应模型无法解释MHC多态性，因为该模型的合并时间太短，预期杂合度和预期等位基因数太小。 (4)从数学角度来看，频率依赖选择的少数优势模型能够解释高度的多态性和反式特异性多态性。 (5)当宿主的突变率较低但寄生虫的突变率非常高时，分子拟态假说也给出了足够长的聚结时间。然而，预期的杂合性和预期的等位基因数量往往太小。 (6)考虑MHC分子功能的分子机制和其他生物学观察表明，MHC多态性维持的最重要因素是超显性选择。然而，需要进行一些实验来区分过度显性选择假设和频率依赖选择假设。
To explain the long-term persistence of polymorphic alleles (trans-specific polymorphism) at the major histocompatibility complex (MHC) loci in rodents and primates, a computer simulation study was conducted about the coalescence time of different alleles sampled under various forms of selection. At the same time, average heterozygosity, the number of alleles in a sample, and the rate of codon substitution were examined to explain the mechanism of maintenance of polymorphism at the MHC loci. The results obtained are as follows. (1) The coalescence time for neutral alleles is too short to explain the trans-specific polymorphism at the MHC loci. (2) Under overdominant selection, the coalescence time can be tens of millions of years, depending on the parameter values used. The average heterozygosity and the number of alleles observed are also high enough to explain MHC polymorphism. (3) The pathogen adaptation model proposed by Snell is incapable of explaining MHC polymorphism, since the coalescence time for this model is too short and the expected heterozygosity and the expected number of alleles are too small. (4) From the mathematical point of view, the minority advantage model of frequency-dependent selection is capable of explaining a high degree of polymorphism and trans-specific polymorphism. (5) The molecular mimicry hypothesis also gives a sufficiently long coalescence time when the mutation rate is low in the host but very high in the parasite. However, the expected heterozygosity and the expected number of alleles tend to be too small. (6) Consideration of the molecular mechanism of the function of MHC molecules and other biological observations suggest that the most important factor for the maintenance of MHC polymorphism is overdominant selection. However, some experiments are necessary to distinguish between the overdominance and frequency-dependent selection hypotheses.