Inferring the molecular and phenotypic impact of amino acid variants with MutPred2.
Inferring the molecular and phenotypic impact of amino acid variants with MutPred2.
复制标题
推断氨基酸变体与MUTPRED2的分子和表型影响。
DOI：
10.1038/s41467-020-19669-x
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发表时间：
2020-11-20
影响因子：
16.6
通讯作者：
Radivojac P
中科院分区：
文献类型：
--
作者：
Pejaver V;Urresti J;Lugo-Martinez J;Pagel KA;Lin GN;Nam HJ;Mort M;Cooper DN;Sebat J;Iakoucheva LM;Mooney SD;Radivojac P
Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants. Identifying variants capable of causing genetic disease is challenging. The authors use semisupervised learning to predict pathogenic missense variants and their impacts on protein structure and function, enabling a molecular mechanism-driven approach to studying different types of human disease.
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DOI：
10.1016/s1474-4422(15)00044-7
发表时间：
2015-11
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Geschwind DH;State MW
通讯作者：
State MW
影响因子：
30.8
作者：
Francioli, Laurent C.;Menelaou, Andronild;Wijmenga, Cisca
通讯作者：
Wijmenga, Cisca
影响因子：
4.4
作者：
Carter H;Douville C;Stenson PD;Cooper DN;Karchin R
通讯作者：
Karchin R
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
16.2
作者：
Buxbaum JD;Daly MJ;Devlin B;Lehner T;Roeder K;State MW;Autism Sequencing Consortium
通讯作者：
Autism Sequencing Consortium