尽管进化生物学家长期以来一直认为 DNA 修复功效的变化可能解释了物种间寿命和癌症发病率的一些多样性，但我们对人类以外正常种系突变的变异性的数据很少。在这里，我们通过使用来自 13 种小鼠、猿、熊、狼和鲸类动物的多态性数据来量化突变序列背景偏差，揭示了哺乳动物诱变的谱系和病因学。在对参考基因组可及性和 k-mer 含量的突变谱进行归一化后，我们使用 Mantel 检验推断突变谱分歧与物种之间的遗传分歧高度相关，而生育年龄等生活史特征是突变谱分歧的较弱预测因素。潜在的生物信息学混杂因素仅与一小部分突变谱特征微弱相关。我们发现，之前从人类癌症推断出的类时钟突变特征无法解释哺乳动物突变谱所表现出的系统发育信号，尽管这些特征能够以高度余弦相似性拟合每个物种的 3 聚体谱。相比之下，从人类从头突变数据推断出的父母衰老特征似乎可以解释大部分 1-mer 谱的系统发育信号与新的突变特征的结合。我们假设未来的模型旨在解释哺乳动物诱变的病因学，需要捕捉这样一个事实：更密切相关的物种具有更相似的突变谱；以高余弦相似度拟合每个边缘谱的模型不能保证捕获物种间突变谱变异的层次结构。© 作者 2023。由牛津大学出版社代表分子生物学与进化学会出版。

Although evolutionary biologists have long theorized that variation in DNA repair efficacy might explain some of the diversity of lifespan and cancer incidence across species, we have little data on the variability of normal germline mutagenesis outside of humans. Here, we shed light on the spectrum and etiology of mutagenesis across mammals by quantifying mutational sequence context biases using polymorphism data from thirteen species of mice, apes, bears, wolves, and cetaceans. After normalizing the mutation spectrum for reference genome accessibility and k-mer content, we use the Mantel test to deduce that mutation spectrum divergence is highly correlated with genetic divergence between species, whereas life history traits like reproductive age are weaker predictors of mutation spectrum divergence. Potential bioinformatic confounders are only weakly related to a small set of mutation spectrum features. We find that clock-like mutational signatures previously inferred from human cancers cannot explain the phylogenetic signal exhibited by the mammalian mutation spectrum, despite the ability of these signatures to fit each species' 3-mer spectrum with high cosine similarity. In contrast, parental aging signatures inferred from human de novo mutation data appear to explain much of the 1-mer spectrum's phylogenetic signal in combination with a novel mutational signature. We posit that future models purporting to explain the etiology of mammalian mutagenesis need to capture the fact that more closely related species have more similar mutation spectra; a model that fits each marginal spectrum with high cosine similarity is not guaranteed to capture this hierarchy of mutation spectrum variation among species.© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.