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Am J Hum Genet ; 108(10): 1891-1906, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34551312


The success of personalized genomic medicine depends on our ability to assess the pathogenicity of rare human variants, including the important class of missense variation. There are many challenges in training accurate computational systems, e.g., in finding the balance between quantity, quality, and bias in the variant sets used as training examples and avoiding predictive features that can accentuate the effects of bias. Here, we describe VARITY, which judiciously exploits a larger reservoir of training examples with uncertain accuracy and representativity. To limit circularity and bias, VARITY excludes features informed by variant annotation and protein identity. To provide a rationale for each prediction, we quantified the contribution of features and feature combinations to the pathogenicity inference of each variant. VARITY outperformed all previous computational methods evaluated, identifying at least 10% more pathogenic variants at thresholds achieving high (90% precision) stringency.

Am J Hum Genet ; 108(7): 1283-1300, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34214447


Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.

Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Análise Mutacional de DNA , Diploide , Biblioteca Gênica , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Saccharomyces cerevisiae/genética
G3 (Bethesda) ; 10(9): 3399-3402, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32763951


The world is facing a global pandemic of COVID-19 caused by the SARS-CoV-2 coronavirus. Here we describe a collection of codon-optimized coding sequences for SARS-CoV-2 cloned into Gateway-compatible entry vectors, which enable rapid transfer into a variety of expression and tagging vectors. The collection is freely available. We hope that widespread availability of this SARS-CoV-2 resource will enable many subsequent molecular studies to better understand the viral life cycle and how to block it.

Betacoronavirus/genética , Fases de Leitura Aberta/genética , Betacoronavirus/isolamento & purificação , COVID-19 , Clonagem Molecular , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Escherichia coli/metabolismo , Humanos , Pandemias , Plasmídeos/genética , Plasmídeos/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Potyvirus/genética , SARS-CoV-2
Bioinformatics ; 36(12): 3938-3940, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32251504


SUMMARY: Fully realizing the promise of personalized medicine will require rapid and accurate classification of pathogenic human variation. Multiplexed assays of variant effect (MAVEs) can experimentally test nearly all possible variants in selected gene targets. Planning a MAVE study involves identifying target genes with clinical impact, and identifying scalable functional assays for that target. Here, we describe MaveQuest, a web-based resource enabling systematic variant effect mapping studies by identifying potential functional assays, disease phenotypes and clinical relevance for nearly all human protein-coding genes. AVAILABILITY AND IMPLEMENTATION: MaveQuest service: MaveQuest source code: SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Software , Humanos , Fenótipo
Nat Commun ; 11(1): 731, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024834


The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types that co-occur in the same tumours. However, it remains unclear how mutation processes change during cancer evolution due to the lack of reliable methods to reconstruct evolutionary trajectories of mutational signature activity. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we present TrackSig, a new method that reconstructs these trajectories using optimal, joint segmentation and deconvolution of mutation type and allele frequencies from a single tumour sample. In simulations, we find TrackSig has a 3-5% activity reconstruction error, and 12% false detection rate. It outperforms an aggressive baseline in situations with branching evolution, CNA gain, and neutral mutations. Applied to data from 2658 tumours and 38 cancer types, TrackSig permits pan-cancer insight into evolutionary changes in mutational processes.

Biologia Computacional/métodos , Mutação , Neoplasias/genética , Simulação por Computador , Evolução Molecular , Frequência do Gene , Genoma Humano , Humanos , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma