Toward More Accurate Ancestral Protein Genotype-Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees
Toward More Accurate Ancestral Protein Genotype-Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees
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DOI：
10.1093/molbev/msu305
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发表时间：
2015-01-01
影响因子：
10.7
通讯作者：
Gouy, Manolo
中科院分区：
文献类型：
--
作者：
Groussin, Mathieu;Hobbs, Joanne K.;Gouy, Manolo
祖先蛋白质的复活提供了对自然选择如何塑造自然界蛋白质的直接见解。通过沿着基因系统发育追踪取代，可以在计算机中重建祖先蛋白质，然后在体外合成。这种优雅的策略揭示了蛋白质功能和结构进化的复杂机制。然而，迄今为止，所有蛋白质复活研究都使用简单化的方法进行祖先序列重建（ASR），包括假设仅单个序列比对就足以准确重建基因家族的历史。这种捷径对祖先功能结论的影响尚未得到研究。在这里，我们通过模拟证明，利用物种历史信息，使用一个模型来解释基因的重复、水平转移和丢失 (DTL)，统计上可以提高 ASR 的准确性。这强调了树拓扑在推定祖先的推理中的重要性。我们使用厚壁菌门（一种主要且古老的细菌门）祖先的 LeuB 酶的体外复活来验证我们的计算机预测。对于这种特殊的蛋白质，我们的实验结果表明，有关物种系统发育的信息会产生生化上更真实、动力学上更稳定的祖先蛋白质。需要使用不同蛋白质进行额外的复活实验，以统计量化使用物种树感知基因树对祖先蛋白质表型的影响。尽管如此，我们的结果表明，在未来的蛋白质复活研究中需要结合序列和 DTL 信息，以准确定义蛋白质多样化的基因型-表型空间。
The resurrection of ancestral proteins provides direct insight into how natural selection has shaped proteins found in nature. By tracing substitutions along a gene phylogeny, ancestral proteins can be reconstructed in silico and subsequently synthesized in vitro. This elegant strategy reveals the complex mechanisms responsible for the evolution of protein functions and structures. However, to date, all protein resurrection studies have used simplistic approaches for ancestral sequence reconstruction (ASR), including the assumption that a single sequence alignment alone is sufficient toaccurately reconstruct the history of the gene family. The impact of such shortcuts on conclusions about ancestral functions has not been investigated. Here, we show with simulations that utilizing information on species history using a model that accounts for the duplication, horizontal transfer, and loss (DTL) of genes statistically increases ASR accuracy. This underscores the importance of the tree topology in the inference of putative ancestors. We validate our in silico predictions using in vitro resurrection of the LeuB enzyme for the ancestor of the Firmicutes, a major and ancient bacterial phylum. With this particular protein, our experimental results demonstrate that information on the species phylogeny results in a biochemicallymore realistic and kinetically more stable ancestral protein. Additional resurrection experiments with different proteins are necessary to statistically quantify the impact of using species tree-aware gene trees on ancestral protein phenotypes. Nonetheless, our results suggest the need for incorporating both sequence and DTL information in future studies of protein resurrections to accurately define the genotype-phenotype space in which proteins diversify.