Boyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ, United Kingdom
Institute of Applied Mathematics and Statistics, University of Hohenheim, 70593 Stuttgart, Germany.
Genetics. 2019 Jun;212(2):553-564. doi: 10.1534/genetics.119.302022. Epub 2019 Apr 5.
The Major Histocompatibility Complex (MHC) is the most genetically diverse region of the genome in most vertebrates. Some form of balancing selection is necessary to account for the extreme diversity, but the precise mechanism of balancing selection is unknown. Due to the way MHC molecules determine immune recognition, overdominance (also referred to as heterozygote advantage) has been suggested as the main driving force behind this unrivalled diversity. However, both theoretical results and simulation models have shown that overdominance in its classical form cannot maintain large numbers of alleles unless all alleles confer unrealistically similar levels of fitness. There is increasing evidence that heterozygotes containing genetically divergent alleles allow for broader antigen presentation to immune cells, providing a selective mechanism for MHC polymorphism. By framing competing models of overdominance within a general framework, we show that a model based on Divergent Allele Advantage (DAA) provides a superior mechanism for maintaining alleles with a wide range of intrinsic merits, as intrinsically less-fit MHC alleles that are more divergent can survive under DAA. Specifically, our results demonstrate that a quantitative mechanism built from the DAA hypothesis is able to maintain polymorphism in the MHC. Applying such a model to both livestock breeding and conservation could provide a better way of identifying superior heterozygotes, and quantifying the advantages of genetic diversity at the MHC.
主要组织相容性复合体 (MHC) 是大多数脊椎动物基因组中遗传多样性最高的区域。为了解释这种极端的多样性，某种形式的平衡选择是必要的，但平衡选择的确切机制尚不清楚。由于 MHC 分子决定免疫识别的方式，超显性（也称为杂合优势）已被认为是这种无与伦比的多样性的主要驱动力。然而，理论结果和模拟模型都表明，经典形式的超显性不能维持大量的等位基因，除非所有等位基因赋予不切实际的相似适应度水平。越来越多的证据表明，含有遗传上不同等位基因的杂合体允许更广泛的抗原呈递给免疫细胞，为 MHC 多态性提供了一种选择性机制。通过在一般框架内构建超显性的竞争模型，我们表明，基于分歧等位基因优势 (DAA) 的模型为维持具有广泛内在优势的等位基因提供了一种优越的机制，因为在 DAA 下，更具分歧但内在适应度较低的 MHC 等位基因可以存活下来。具体来说，我们的结果表明，基于 DAA 假设的定量机制能够维持 MHC 中的多态性。将这种模型应用于家畜养殖和保护，可以提供一种更好的方法来识别优秀的杂合体，并量化 MHC 中遗传多样性的优势。
