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等位基因年龄提供的关于负选择强度的信息有限。

Allele ages provide limited information about the strength of negative selection.

作者信息

Shastry Vivaswat, Berg Jeremy J

机构信息

Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA.

Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.

出版信息

Genetics. 2025 Mar 17;229(3). doi: 10.1093/genetics/iyae211.

Abstract

For many problems in population genetics, it is useful to characterize the distribution of fitness effects (DFE) of de novo mutations among a certain class of sites. A DFE is typically estimated by fitting an observed site frequency spectrum (SFS) to an expected SFS given a hypothesized distribution of selection coefficients and demographic history. The development of tools to infer gene trees from haplotype alignments, along with ancient DNA resources, provides us with additional information about the frequency trajectories of segregating mutations. Here, we ask how useful this additional information is for learning about the DFE, using the joint distribution on allele frequency and age to summarize information about the trajectory. To this end, we introduce an accurate and efficient numerical method for computing the density on the age of a segregating variant found at a given sample frequency, given the strength of selection and an arbitrarily complex population size history. We then use this framework to show that the unconditional age distribution of negatively selected alleles is very closely approximated by reweighting the neutral age distribution in terms of the negatively selected SFS, suggesting that allele ages provide little information about the DFE beyond that already contained in the present day frequency. To confirm this prediction, we extended the standard Poisson random field method to incorporate the joint distribution of frequency and age in estimating selection coefficients, and test its performance using simulations. We find that when the full SFS is observed and the true allele ages are known, including ages in the estimation provides only small increases in the accuracy of estimated selection coefficients. However, if only sites with frequencies above a certain threshold are observed, then the true ages can provide substantial information about the selection coefficients, especially when the selection coefficient is large. When ages are estimated from haplotype data using state-of-the-art tools, uncertainty about the age abrogates most of the additional information in the fully observed SFS case, while the neutral prior assumed in these tools when estimating ages induces a downward bias in the case of the thresholded SFS.

摘要

对于群体遗传学中的许多问题,刻画某类位点上新发突变的适合度效应分布(DFE)是很有用的。DFE通常是通过将观察到的位点频率谱(SFS)与给定选择系数分布和群体历史假设下的预期SFS进行拟合来估计的。从单倍型比对推断基因树的工具的发展,以及古DNA资源,为我们提供了关于分离突变频率轨迹的额外信息。在这里,我们通过使用等位基因频率和年龄的联合分布来总结关于轨迹的信息,来探讨这些额外信息对于了解DFE有多大用处。为此,在给定选择强度和任意复杂的群体大小历史的情况下,我们引入了一种准确且高效的数值方法,用于计算在给定样本频率下发现的分离变异年龄的密度。然后,我们使用这个框架来表明,通过根据负选择的SFS对中性年龄分布进行重新加权,负选择等位基因的无条件年龄分布能得到非常接近的近似,这表明等位基因年龄提供的关于DFE的信息,除了现今频率中已经包含的信息之外,几乎没有其他信息。为了证实这一预测,我们扩展了标准泊松随机场方法,在估计选择系数时纳入频率和年龄的联合分布,并使用模拟测试其性能。我们发现,当观察到完整的SFS且真实等位基因年龄已知时,在估计中纳入年龄只会使估计的选择系数的准确性略有提高。然而,如果只观察到频率高于某个阈值的位点,那么真实年龄可以提供关于选择系数的大量信息,特别是当选择系数很大时。当使用最先进的工具从单倍型数据估计年龄时,年龄的不确定性消除了完全观察到的SFS情况下的大部分额外信息,而这些工具在估计年龄时假设的中性先验在阈值化SFS的情况下会导致向下偏差。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b046/11912868/09f1e1c6a684/iyae211f1.jpg

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