Heterozygote advantage can explain the extraordinary diversity of immune genes

The majority of highly polymorphic genes are related to immune functions and with over 100 alleles within a population, genes of the major histocompatibility complex (MHC) are the most polymorphic loci in vertebrates. How such extraordinary polymorphism arose and is maintained is controversial. One possibility is heterozygote advantage (HA), which can in principle maintain any number of alleles, but biologically explicit models based on this mechanism have so far failed to reliably predict the coexistence of significantly more than ten alleles. We here present an eco-evolutionary model showing that under HA evolution can result in the emergence and maintenance of more than 100 alleles if the following two assumptions are fulfilled: first, pathogens are lethal in the absence of an appropriate immune defense; second, the combined effect of multiple pathogens on host survival exceeds the sum of the effects of each pathogen alone. Thus, our results show that HA can be a more potent force in..., MATLAB script used for individual-based simulation presented in the main paper. This script simulates a diploid Wright-Fisher model with mutation and selection to study the evolutionary dynamics of allelic values x for both the Gaussian and the bit-string model. It considers a diploid population of fixed size N with non-overlapping generations and random mating. Individuals produce a large number of offspring, independent of their genotype, resulting in deterministic Hardy-Weinberg proportions before viability selection. After viability selection (based on Equation 5 from the main paper), which adjusts the proportion of genotypes, stochasticity is introduced via random multinomial sampling of N surviving offspring to form the next generation's adult population. This model tracks the fate of recurrent mutations occurring with a per-capita mutation probability mu. , , # Heterozygote advantage can explain the extraordinary diversity of immune genes MATLAB script used for individual based simulation presented in the main paper. This script simulates a diploid Wright-Fisher model with mutation and selection to study the evolutionary dynamics of allelic values x for both the Gaussian and the bit-string model. It considers a diploid population of fixed size N with non-overlapping generations and random mating. Individuals produce a large number of offspring, independent of their genotype, resulting in deterministic Hardy-Weinberg proportions before viability selection. After viability selection (based on Equation 5 from the main paper), which adjusts the proportion of genotypes, stochasticity is introduced via random multinomial sampling of N surviving offspring to form the next generation's adult population. This model tracks the fate of recurrent mutations occurring with a per-capita mutation probability mu. ## Workflow Run the `MHC_sim_Dryad.m` f...绝大多数高度多态性基因均与免疫功能相关，而主要组织相容性复合体（major histocompatibility complex, MHC）基因在种群内拥有超过100个等位基因，是脊椎动物中多态性最高的基因座。这类极端多态性的起源与维持机制至今仍存在争议。其中一种候选机制为杂合子优势（heterozygote advantage, HA），该理论原则上可维持任意数量的等位基因，但迄今为止基于该机制的生物学显式模型均无法可靠预测10个以上等位基因的共存。本文提出了一项生态进化模型，结果显示，当满足以下两项假设时，杂合子优势驱动的进化可促成超过100个等位基因的出现与维持：其一，缺乏适配免疫防御的宿主会被病原体致死；其二，多种病原体对宿主存活率的联合效应超出单个病原体效应的总和。据此，本研究结果表明，杂合子优势或许是一种更为强效的进化力量……，本文同时附上主论文中用于基于个体的模拟的MATLAB脚本。 该脚本模拟了一个带有突变与选择的二倍体赖特-费希尔（Wright-Fisher）模型，用于研究高斯模型（Gaussian model）与位串模型（bit-string model）下等位基因值x的进化动力学。模型考虑了一个固定种群规模N、世代不重叠且随机交配的二倍体群体。个体产生大量与自身基因型无关的后代，在存活选择前会呈现出符合哈迪-温伯格（Hardy-Weinberg）比例的确定性分布。在基于主论文公式5的存活选择调整基因型比例后，通过对N个存活后代进行随机多项抽样来引入随机性，以此构建下一代的成年种群。该模型会追踪以个体突变速率mu复发性发生的突变的命运。 , , # 杂合子优势可解释免疫基因的极端多样性 该脚本模拟了一个带有突变与选择的二倍体赖特-费希尔（Wright-Fisher）模型，用于研究高斯模型（Gaussian model）与位串模型（bit-string model）下等位基因值x的进化动力学。模型考虑了一个固定种群规模N、世代不重叠且随机交配的二倍体群体。个体产生大量与自身基因型无关的后代，在存活选择前会呈现出符合哈迪-温伯格（Hardy-Weinberg）比例的确定性分布。在基于主论文公式5的存活选择调整基因型比例后，通过对N个存活后代进行随机多项抽样来引入随机性，以此构建下一代的成年种群。该模型会追踪以个体突变速率mu复发性发生的突变的命运。 ## 工作流程 运行`MHC_sim_Dryad.m`文件……