Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models.
Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models.
复制标题
DOI：
10.1002/humu.22225
复制
发表时间：
2013-01
期刊：
影响因子：
3.9
通讯作者：
Gaunt, Tom R.
中科院分区：
文献类型：
--
作者：
Shihab, Hashem A.;Gough, Julian;Cooper, David N.;Stenson, Peter D.;Barker, Gary L. A.;Edwards, Keith J.;Day, Ian N. M.;Gaunt, Tom R.
由于全基因组/全外显子组测序技术的进步，在人类基因组中发现非同义单核苷酸多态(NsSNPs)的速度正在急剧增加。因此，能够准确和可靠地区分致病和功能中性nsSNPs的自动化方法正变得越来越重要。在这里，我们描述了通过隐马尔可夫模型的功能分析(FATHMM)软件和服务器：一种物种无关的方法，具有可选的物种特定权重，用于预测蛋白质错义变体的功能效应。使用对人类突变进行加权的模型，我们在两个单独的基准上获得了优于传统预测方法(即SIFT、PolyPhen和Panther)的性能精度。此外，在一个基准测试中，我们获得了比当前最先进的预测方法(即SNPs&Go和MutPred)更高的性能精度。我们证明，FATHMM可以有效地应用于高通量/大规模的人类和非人类基因组测序项目，并增加表型结果关联的好处。为了说明这一点，我们评估了小麦(Triticum spp.)鉴定在驯化过程中由密集选择引入的表型差异的一些重要的遗传变异。FATHMM的基于网络的实现，包括一个高吞吐量的批处理设施和一个可下载的独立包，可在http://fathmm.biocompute.org.uk.上获得
The rate at which nonsynonymous single nucleotide polymorphisms (nsSNPs) are being identified in the human genome is increasing dramatically owing to advances in whole-genome/whole-exome sequencing technologies. Automated methods capable of accurately and reliably distinguishing between pathogenic and functionally neutral nsSNPs are therefore assuming ever-increasing importance. Here, we describe the Functional Analysis Through Hidden Markov Models (FATHMM) software and server: a species-independent method with optional species-specific weightings for the prediction of the functional effects of protein missense variants. Using a model weighted for human mutations, we obtained performance accuracies that outperformed traditional prediction methods (i.e., SIFT, PolyPhen, and PANTHER) on two separate benchmarks. Furthermore, in one benchmark, we achieve performance accuracies that outperform current state-of-the-art prediction methods (i.e., SNPs&GO and MutPred). We demonstrate that FATHMM can be efficiently applied to high-throughput/large-scale human and nonhuman genome sequencing projects with the added benefit of phenotypic outcome associations. To illustrate this, we evaluated nsSNPs in wheat (Triticum spp.) to identify some of the important genetic variants responsible for the phenotypic differences introduced by intense selection during domestication. A Web-based implementation of FATHMM, including a high-throughput batch facility and a downloadable standalone package, is available at http://fathmm.biocompute.org.uk.
登录
查看更多内容
影响因子：
14.9
作者：
Bromberg Y;Rost B
通讯作者：
Rost B
影响因子：
3.9
作者：
Hicks, Stephanie;Wheeler, David A.;Plon, Sharon E.;Kimmel, Marek
通讯作者：
Kimmel, Marek
影响因子：
5.6
作者：
KROGH, A;BROWN, M;HAUSSLER, D
通讯作者：
HAUSSLER, D
影响因子：
--
作者：
KULLBACK, S;LEIBLER, RA
通讯作者：
LEIBLER, RA
影响因子：
5.8
作者：
Mottaz, Anais;David, Fabrice P. A.;Yip, Yum L.
通讯作者：
Yip, Yum L.