Data_Sheet_1_Influence of Dominance and Drift on Lethal Mutations in Human Populations.PDF

We consider disease-causing mutations that are lethal when homozygous. Lethality involves the very strongest form of negative selection, with the selection coefficient against the disease-carrying homozygote having its maximum value of unity. We determine results for the behavior of the frequency of a lethal allele in an effectively infinite population. This includes an estimate of the time it takes to achieve equilibrium, and a description of transient behavior associated with a sudden change in the fitness of the heterozygote. We determine analogous results for a finite population, showing that a lethal disease-causing allele needs to be described by a modified Wright-Fisher model, which deviates from the standard model, where selection coefficients are assumed small compared with 1. We show that a by-product of the dynamics, resulting from the absence of the disease-allele carrying homozygote in adults, is the general constraint that the frequency of the disease-causing allele cannot exceed 12. The results presented in this work should prove useful to a number of areas including analysis of lethal/near lethal mutations in Mendelian disorders and, in particular, for exploring how mutation-selection-drift balance explains the current spectrum of mutation frequencies in humans. While the number of empirical examples of overdominance in lethal genetic disorders is not large, relatively high observed heterozygote frequencies may be a hint of transient heterozygous advantage in nature. For lethal disorders with anomalous frequencies, such as cystic fibrosis and Tay-Sachs, our analysis lends further support to the role that transitory episodes of weak overdominance may play in the evolution of lethal mutations.

本研究聚焦于研究那些纯合状态下致病的突变，此类突变涉及极为强烈的负选择，对携带疾病纯合子的选择系数达到最大值一。我们探讨了在有效无限种群中，致死等位基因频率的行为，包括达到平衡状态所需时间的估算以及与杂合子适应度突然变化相关的瞬时行为的描述。对于有限种群，我们得出类似的结果，表明致死疾病致病的等位基因需要通过改进的Wright-Fisher模型进行描述，该模型与标准模型不同，其中选择系数相对于一被认为是小的。我们展示了动力学过程中的一个副产品，即由于成年个体中不存在携带疾病等位基因的纯合子，导致对疾病致因等位基因频率的一般限制，即其频率不能超过12。本研究呈现的结果应被证明对多个领域具有实用性，包括孟德尔遗传病中致死/近致死突变的分析，特别是探索突变-选择-漂变平衡如何解释人类当前突变频率谱。尽管在致死遗传疾病中过度显性（overdominance）的实证例子数量不多，但相对较高的观察到的杂合子频率可能是自然界中瞬时杂合子优势的暗示。对于具有异常频率的致死疾病，如囊性纤维化和泰-萨克斯病，我们的分析进一步支持了过渡期弱过度显性可能在致死突变进化中发挥的作用。