Analysis of the estimators of the average coefficient of dominance of deleterious mutations
Analysis of the estimators of the average coefficient of dominance of deleterious mutations
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DOI：
10.1534/genetics.104.027706
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发表时间：
2004-10-01
期刊：
影响因子：
3.3
通讯作者：
Caballero, A
中科院分区：
文献类型：
--
作者：
Fernández, B;García-Dorado, A;Caballero, A
我们研究了影响最常用的有害突变平均显性程度（h）估计方法的偏差来源，重点关注隔离群体的估计。主要强调的是人口数量有限的影响，但也考虑了其他偏差来源。使用有限群体中基因频率分布的扩散近似以及随机模拟，我们评估了从突变-选择-漂移平衡中的群体获得的估计量的行为，这些平衡触发了不同的突变场景，并比较了新出现和分离突变的 h 平均值。由于遗传漂变，基于突变选择平衡理论的关于新出现的模仿的推论可能具有显着的向上偏差，具体取决于 h 的分布。此外，估计值通常是指以不同方式通过纯合有害效应加权的h，因此当这两个变量负相关时，推论变得复杂。由于这两种偏差来源，广泛使用的杂合对纯合均值的回归低估了用于分离突变的 h 的算术平均值，这与文献中反复假设的相等相反。我们的结论是，在一般条件下，来自隔离群体的估计量都不能提供有用的工具来确定显性程度的特性，无论是对于隔离还是对于新出现的有害突变。突变累积实验对平均 h 的直接估计显示出会受到清除选择引起的一些偏差，但由于它们不需要对维持分离变异的原因进行假设，因此它们似乎为新出现的突变提供了更可靠的平均优势。
We investigate the sources of bias that affect the most commonly used methods of estimation of the average degree of dominance (h) of deleterious mutations, focusing on estimates from segregating populations. The main emphasis is on the effect of the finite size of the populations, but other sources of bias are also considered. Using diffusion approximations to the distribution of gene frequencies in finite populations as well as stochastic simulations, we assess the behavior of the estimators obtained from populations at mutation-selection-drift balance tinder different Mutational scenarios and compare averages of h for newly arisen and segregating mutations. Because of genetic drift, the inferences concerning newly arisen imitations based on the mutation-selection balance theory can have substantial upward bias depending upon the distribution of h. In addition, estimates usually refer to h weighted by the homozygous deleterious effect in different ways, so that inferences are complicated when these two variables are negatively correlated. Due to both sources of bias, the widely used regression of heterozygous on homozygous means underestimates the arithmetic mean of h for segregating mutations, in contrast to their repeatedly assumed equality in the literature. We conclude that none of the estimators from segregating populations provides, under general conditions, a useful tool to ascertain the properties of the degree of dominance, either for segregating or for newly arisen deleterious mutations. Direct estimates of the average h from mutation-accumulation experiments are shown to suffer some bias caused by purging selection but, because they do not require assumptions on the causes maintaining segregating variation, they appear to give a more reliable average dominance for newly arisen mutations.