De Boer Rob J, Borghans José A M, van Boven Michiel, Keşmir Can, Weissing Franz J
Theoretical Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Immunogenetics. 2004 Feb;55(11):725-31. doi: 10.1007/s00251-003-0629-y. Epub 2004 Jan 13.
Major histocompatibility (MHC) molecules are encoded by extremely polymorphic genes and play a crucial role in vertebrate immunity. Natural selection favors MHC heterozygous hosts because individuals heterozygous at the MHC can present a larger diversity of peptides from infectious pathogens than homozygous individuals. Whether or not heterozygote advantage is sufficient to account for a high degree of polymorphism is controversial, however. Using mathematical models we studied the degree of MHC polymorphism arising when heterozygote advantage is the only selection pressure. We argue that existing models are misleading in that the fitness of heterozygotes is not related to the MHC alleles they harbor. To correct for this, we have developed novel models in which the genotypic fitness of a host directly reflects the fitness contributions of its MHC alleles. The mathematical analysis suggests that a high degree of polymorphism can only be accounted for if the different MHC alleles confer unrealistically similar fitnesses. This conclusion was confirmed by stochastic simulations, including mutation, genetic drift, and a finite population size. Heterozygote advantage on its own is insufficient to explain the high population diversity of the MHC.
主要组织相容性（MHC）分子由高度多态性的基因编码，在脊椎动物免疫中起关键作用。自然选择有利于MHC杂合宿主，因为MHC杂合个体比纯合个体能呈现来自感染性病原体的更多样化的肽段。然而，杂合优势是否足以解释高度多态性存在争议。我们使用数学模型研究了仅在杂合优势作为唯一选择压力时产生的MHC多态性程度。我们认为现有模型具有误导性，因为杂合子的适应性与其所携带的MHC等位基因无关。为纠正这一点，我们开发了新模型，其中宿主的基因型适应性直接反映其MHC等位基因的适应性贡献。数学分析表明，只有当不同的MHC等位基因赋予不切实际的相似适应性时，才能解释高度多态性。包括突变、遗传漂变和有限种群大小在内的随机模拟证实了这一结论。仅杂合优势不足以解释MHC的高种群多样性。
