Alignment-Integrated Reconstruction of Ancestral Sequences Improves Accuracy.
Alignment-Integrated Reconstruction of Ancestral Sequences Improves Accuracy.
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DOI：
10.1093/gbe/evaa164
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发表时间：
2020-09-01
影响因子：
3.3
通讯作者：
Kolaczkowski B
中科院分区：
文献类型：
--
作者：
Aadland K;Kolaczkowski B
祖先序列重建（ASR）使用现存蛋白质序列的比对，描述蛋白质家族历史的同源性和分子进化过程的模型来推断古老蛋白质的序列，使研究人员能够直接研究序列进化对蛋白质结构和功能的影响。与所有统计推断一样，ASR可能对违反其基本假设的行为敏感。以前的研究表明，而系统发育的不确定性只有一个非常微弱的影响ASR的准确性，在蛋白质序列比对的不确定性可以更强烈地影响推断的祖先序列。在这里，我们表明，序列比对中的错误可以产生错误的ASR在一系列现实和简化的进化场景。重要的是，序列重建错误可能导致对祖先蛋白质的结构和功能特性的估计错误，从而可能破坏依赖于ASR的分析的可靠性。我们介绍了一个集成的ASR方法，结合了许多不同的序列比对的信息。我们发现，整合对齐不确定性提高了ASR的准确性和下游结构和功能推断的准确性，通常表现为高度准确的结构引导对齐。鉴于越来越多的证据表明序列比对错误会影响ASR研究的可靠性，我们建议未来的研究纳入减轻比对不确定性影响的方法。插入和缺失事件的概率建模有可能从根本上提高ASR的准确性时，模型反映了真正的潜在的进化历史，但需要进一步的研究，以彻底评估这些方法在现实条件下的可靠性。
Ancestral sequence reconstruction (ASR) uses an alignment of extant protein sequences, a phylogeny describing the history of the protein family and a model of the molecular-evolutionary process to infer the sequences of ancient proteins, allowing researchers to directly investigate the impact of sequence evolution on protein structure and function. Like all statistical inferences, ASR can be sensitive to violations of its underlying assumptions. Previous studies have shown that, whereas phylogenetic uncertainty has only a very weak impact on ASR accuracy, uncertainty in the protein sequence alignment can more strongly affect inferred ancestral sequences. Here, we show that errors in sequence alignment can produce errors in ASR across a range of realistic and simplified evolutionary scenarios. Importantly, sequence reconstruction errors can lead to errors in estimates of structural and functional properties of ancestral proteins, potentially undermining the reliability of analyses relying on ASR. We introduce an alignment-integrated ASR approach that combines information from many different sequence alignments. We show that integrating alignment uncertainty improves ASR accuracy and the accuracy of downstream structural and functional inferences, often performing as well as highly accurate structure-guided alignment. Given the growing evidence that sequence alignment errors can impact the reliability of ASR studies, we recommend that future studies incorporate approaches to mitigate the impact of alignment uncertainty. Probabilistic modeling of insertion and deletion events has the potential to radically improve ASR accuracy when the model reflects the true underlying evolutionary history, but further studies are required to thoroughly evaluate the reliability of these approaches under realistic conditions.
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DOI：
10.1093/bioinformatics/8.3.275
发表时间：
1992-06-01
期刊：
COMPUTER APPLICATIONS IN THE BIOSCIENCES
影响因子：
--
作者：
JONES, DT;TAYLOR, WR;THORNTON, JM
通讯作者：
THORNTON, JM
影响因子：
10.7
作者：
Herman, Joseph L.;Challis, Christopher J.;Schmidler, Scott C.
通讯作者：
Schmidler, Scott C.
影响因子：
5.7
作者：
Ingles-Prieto, Alvaro;Ibarra-Molero, Beatriz;Delgado-Delgado, Asuncion;Perez-Jimenez, Raul;Fernandez, Julio M.;Gaucher, Eric A.;Sanchez-Ruiz, Jose M.;Gavira, Jose A.
通讯作者：
Gavira, Jose A.
影响因子：
10.7
作者：
Eick, Geeta N.;Bridgham, Jamie T.;Thornton, Joseph W.
通讯作者：
Thornton, Joseph W.
影响因子：
3.9
作者：
Koshi, JM;Goldstein, RA
通讯作者：
Goldstein, RA