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1.
Am J Hum Genet ; 108(10): 1891-1906, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34551312

RESUMO

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.

2.
Am J Hum Genet ; 108(7): 1283-1300, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34214447

RESUMO

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.


Assuntos
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
3.
Cell Syst ; 12(7): 691-693, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34293323

RESUMO

Systematic, high-throughput screening for "dominant-negative" protein fragments is an emerging method for mapping functional regions of the parental protein in vivo. In this issue of Cell Systems, Ford et al. apply this approach to 65 cancer drivers, providing functional insights and demonstrating therapeutic potential for several dominant-negative peptides.

4.
Bioinformatics ; 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33774657

RESUMO

SUMMARY: Multiplexed assays of variant effect (MAVEs) are capable of experimentally testing all possible single nucleotide or amino acid variants in selected genomic regions, generating 'variant effect maps', which provide biochemical insight and functional evidence to enable more rapid and accurate clinical interpretation of human variation. Because the international community applying MAVE approaches is growing rapidly, we developed the online MaveRegistry platform to catalyze collaboration, reduce redundant efforts, allow stakeholders to nominate targets, and enable tracking and sharing of progress on ongoing MAVE projects. AVAILABILITY AND IMPLEMENTATION: MaveRegistry service: https://registry.varianteffect.org. MaveRegistry source code: https://github.com/kvnkuang/maveregistry-front-end. SUPPLEMENTARY INFORMATION: no Supplementary data.

5.
Bioinformatics ; 36(22-23): 5448-5455, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33300982

RESUMO

MOTIVATION: When rare missense variants are clinically interpreted as to their pathogenicity, most are classified as variants of uncertain significance (VUS). Although functional assays can provide strong evidence for variant classification, such results are generally unavailable. Multiplexed assays of variant effect can generate experimental 'variant effect maps' that score nearly all possible missense variants in selected protein targets for their impact on protein function. However, these efforts have not always prioritized proteins for which variant effect maps would have the greatest impact on clinical variant interpretation. RESULTS: Here, we mined databases of clinically interpreted variants and applied three strategies, each building on the previous, to prioritize genes for systematic functional testing of missense variation. The strategies ranked genes (i) by the number of unique missense VUS that had been reported to ClinVar; (ii) by movability- and reappearance-weighted impact scores, to give extra weight to reappearing, movable VUS and (iii) by difficulty-adjusted impact scores, to account for the more resource-intensive nature of generating variant effect maps for longer genes. Our results could be used to guide systematic functional testing of missense variation toward greater impact on clinical variant interpretation. AVAILABILITY AND IMPLEMENTATION: Source code available at: https://github.com/rothlab/mave-gene-prioritization. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Mutação de Sentido Incorreto , Proteínas
6.
J Biol Chem ; 295(50): 16906-16919, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33060198

RESUMO

Kinases are critical components of intracellular signaling pathways and have been extensively investigated with regard to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate PAK1 genetic interactions. En masse transformation of the PAK1 gene into 4,653 homozygous diploid Saccharomyces cerevisiae yeast deletion mutants identified ∼400 candidates that suppressed yeast toxicity. Here we selected 19 candidate PAK1 genetic interactions that had human orthologs and were expressed in glioma for further examination in mammalian cells, brain slice cultures, and orthotopic glioma models. RNAi and pharmacological inhibition of potential PAK1 interactors confirmed that DPP4, KIF11, mTOR, PKM2, SGPP1, TTK, and YWHAE regulate PAK1-induced cell migration and revealed the importance of genes related to the mitotic spindle, proteolysis, autophagy, and metabolism in PAK1-mediated glioma cell migration, drug resistance, and proliferation. AKT1 was further identified as a downstream mediator of the PAK1-TTK genetic interaction. Taken together, these data provide a global view of PAK1-mediated signal transduction pathways and point to potential new drug targets for glioma therapy.


Assuntos
Movimento Celular , Glioma/patologia , Saccharomyces cerevisiae/crescimento & desenvolvimento , Transdução de Sinais , Fuso Acromático/genética , Quinases Ativadas por p21/genética , Animais , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Modelos Animais de Doenças , Epistasia Genética , Feminino , Glioma/genética , Glioma/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitose , Inibidores de Proteínas Quinases/farmacologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Quinases Ativadas por p21/metabolismo
7.
Elife ; 92020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32870157

RESUMO

Vitamin K epoxide reductase (VKOR) drives the vitamin K cycle, activating vitamin K-dependent blood clotting factors. VKOR is also the target of the widely used anticoagulant drug, warfarin. Despite VKOR's pivotal role in coagulation, its structure and active site remain poorly understood. In addition, VKOR variants can cause vitamin K-dependent clotting factor deficiency or alter warfarin response. Here, we used multiplexed, sequencing-based assays to measure the effects of 2,695 VKOR missense variants on abundance and 697 variants on activity in cultured human cells. The large-scale functional data, along with an evolutionary coupling analysis, supports a four transmembrane domain topology, with variants in transmembrane domains exhibiting strongly deleterious effects on abundance and activity. Functionally constrained regions of the protein define the active site, and we find that, of four conserved cysteines putatively critical for function, only three are absolutely required. Finally, 25% of human VKOR missense variants show reduced abundance or activity, possibly conferring warfarin sensitivity or causing disease.


Assuntos
Domínio Catalítico , Variação Genética , Mutação de Sentido Incorreto , Vitamina K Epóxido Redutases/química , Vitamina K Epóxido Redutases/genética , Cisteína/química , Resistência a Medicamentos , Células HEK293 , Humanos , Erros Inatos do Metabolismo , Modelos Moleculares , Análise de Sequência de DNA , Varfarina/farmacologia
8.
Mol Syst Biol ; 16(9): e9828, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32939983

RESUMO

Essential genes tend to be highly conserved across eukaryotes, but, in some cases, their critical roles can be bypassed through genetic rewiring. From a systematic analysis of 728 different essential yeast genes, we discovered that 124 (17%) were dispensable essential genes. Through whole-genome sequencing and detailed genetic analysis, we investigated the genetic interactions and genome alterations underlying bypass suppression. Dispensable essential genes often had paralogs, were enriched for genes encoding membrane-associated proteins, and were depleted for members of protein complexes. Functionally related genes frequently drove the bypass suppression interactions. These gene properties were predictive of essential gene dispensability and of specific suppressors among hundreds of genes on aneuploid chromosomes. Our findings identify yeast's core essential gene set and reveal that the properties of dispensable essential genes are conserved from yeast to human cells, correlating with human genes that display cell line-specific essentiality in the Cancer Dependency Map (DepMap) project.

9.
G3 (Bethesda) ; 10(9): 3399-3402, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32763951

RESUMO

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.


Assuntos
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
10.
Cells ; 9(5)2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32392905

RESUMO

Kinases are critical intracellular signaling proteins. To better understand kinase-mediated signal transduction, a large-scale human-yeast genetic interaction screen was performed. Among 597 human kinase genes tested, 28 displayed strong toxicity in yeast when overexpressed. En masse transformation of these toxic kinase genes into 4653 homozygous diploid yeast deletion mutants followed by barcode sequencing identified yeast toxicity modifiers and thus their human orthologs. Subsequent network analyses and functional grouping revealed that the 28 kinases and their 676 interaction partners (corresponding to a total of 969 genetic interactions) are enriched in cell death and survival (34%), small-molecule biochemistry (18%) and molecular transport (11%), among others. In the subnetwork analyses, a few kinases were commonly associated with glioma, cell migration and cell death/survival. Our analysis enabled the creation of a first draft of the kinase genetic interactome network and identified multiple drug targets for inflammatory diseases and cancer, in which deregulated kinase signaling plays a pathogenic role.


Assuntos
Epistasia Genética , Proteínas Serina-Treonina Quinases/genética , Proteoma/genética , Saccharomyces cerevisiae/genética , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Proteoma/metabolismo
11.
Bioinformatics ; 36(12): 3938-3940, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32251504

RESUMO

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: https://mavequest.varianteffect.org/. MaveQuest source code: https://github.com/kvnkuang/mavequest-front-end/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Software , Humanos , Fenótipo
12.
Nat Cell Biol ; 22(4): 498-511, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203420

RESUMO

Rho GTPases are central regulators of the cytoskeleton and, in humans, are controlled by 145 multidomain guanine nucleotide exchange factors (RhoGEFs) and GTPase-activating proteins (RhoGAPs). How Rho signalling patterns are established in dynamic cell spaces to control cellular morphogenesis is unclear. Through a family-wide characterization of substrate specificities, interactomes and localization, we reveal at the systems level how RhoGEFs and RhoGAPs contextualize and spatiotemporally control Rho signalling. These proteins are widely autoinhibited to allow local regulation, form complexes to jointly coordinate their networks and provide positional information for signalling. RhoGAPs are more promiscuous than RhoGEFs to confine Rho activity gradients. Our resource enabled us to uncover a multi-RhoGEF complex downstream of G-protein-coupled receptors controlling CDC42-RHOA crosstalk. Moreover, we show that integrin adhesions spatially segregate GEFs and GAPs to shape RAC1 activity zones in response to mechanical cues. This mechanism controls the protrusion and contraction dynamics fundamental to cell motility. Our systems analysis of Rho regulators is key to revealing emergent organization principles of Rho signalling.


Assuntos
Citoesqueleto/genética , Proteínas Ativadoras de GTPase/genética , Integrinas/genética , Mecanotransdução Celular/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Proteínas rac1 de Ligação ao GTP/genética , Animais , Células COS , Adesão Celular , Linhagem Celular , Movimento Celular , Chlorocebus aethiops , Biologia Computacional , Citoesqueleto/metabolismo , Citoesqueleto/ultraestrutura , Cães , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Proteínas Ativadoras de GTPase/classificação , Proteínas Ativadoras de GTPase/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Integrinas/metabolismo , Células Madin Darby de Rim Canino , Camundongos , Pan troglodytes , Domínios Proteicos , Ratos , Fatores de Troca de Nucleotídeo Guanina Rho/classificação , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo
13.
Genome Med ; 12(1): 13, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000841

RESUMO

BACKGROUND: For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective. METHODS: Damaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function. RESULTS: Our CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman's ϱ = 0.9) and human clinical response to vitamin B6 (ϱ = 0.93). CONCLUSIONS: We demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.


Assuntos
Cistationina beta-Sintase/genética , Teste de Complementação Genética/métodos , Testes Genéticos/métodos , Homocistinúria/genética , Mutação de Sentido Incorreto , Cistationina beta-Sintase/metabolismo , Genótipo , Humanos , Fenótipo , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/genética
14.
Cell Syst ; 10(1): 25-38.e10, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31668799

RESUMO

Many traits are complex, depending non-additively on variant combinations. Even in model systems, such as the yeast S. cerevisiae, carrying out the high-order variant-combination testing needed to dissect complex traits remains a daunting challenge. Here, we describe "X-gene" genetic analysis (XGA), a strategy for engineering and profiling highly combinatorial gene perturbations. We demonstrate XGA on yeast ABC transporters by engineering 5,353 strains, each deleted for a random subset of 16 transporters, and profiling each strain's resistance to 16 compounds. XGA yielded 85,648 genotype-to-resistance observations, revealing high-order genetic interactions for 13 of the 16 transporters studied. Neural networks yielded intuitive functional models and guided exploration of fluconazole resistance, which was influenced non-additively by five genes. Together, our results showed that highly combinatorial genetic perturbation can functionally dissect complex traits, supporting pursuit of analogous strategies in human cells and other model systems.


Assuntos
Transporte Biológico/genética , Proteínas de Membrana Transportadoras/genética , Humanos
15.
Genome Biol ; 20(1): 223, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31679514

RESUMO

Multiplex assays of variant effect (MAVEs), such as deep mutational scans and massively parallel reporter assays, test thousands of sequence variants in a single experiment. Despite the importance of MAVE data for basic and clinical research, there is no standard resource for their discovery and distribution. Here, we present MaveDB ( https://www.mavedb.org ), a public repository for large-scale measurements of sequence variant impact, designed for interoperability with applications to interpret these datasets. We also describe the first such application, MaveVis, which retrieves, visualizes, and contextualizes variant effect maps. Together, the database and applications will empower the community to mine these powerful datasets.


Assuntos
Bases de Dados Genéticas , Variação Genética , Genômica , Software
16.
Hum Mutat ; 40(9): 1463-1473, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31283071

RESUMO

This paper reports the evaluation of predictions for the "CALM1" challenge in the fifth round of the Critical Assessment of Genome Interpretation held in 2018. In the challenge, the participants were asked to predict effects on yeast growth caused by missense variants of human calmodulin, a highly conserved protein in eukaryotic cells sensing calcium concentration. The performance of predictors implementing different algorithms and methods is similar. Most predictors are able to identify the deleterious or tolerated variants with modest accuracy, with a baseline predictor based purely on sequence conservation slightly outperforming the submitted predictions. Nevertheless, we think that the accuracy of predictions remains far from satisfactory, and the field awaits substantial improvements. The most poorly predicted variants in this round surround functional CALM1 sites that bind calcium or peptide, which suggests that better incorporation of structural analysis may help improve predictions.


Assuntos
Calmodulina/química , Calmodulina/genética , Biologia Computacional/métodos , Mutação de Sentido Incorreto , Leveduras/crescimento & desenvolvimento , Algoritmos , Sítios de Ligação , Cálcio/metabolismo , Calmodulina/metabolismo , Evolução Molecular , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Aptidão Genética , Humanos , Modelos Genéticos , Modelos Moleculares , Conformação Proteica , Engenharia de Proteínas , Leveduras/genética
17.
PLoS Genet ; 15(7): e1008227, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31344031

RESUMO

Somatic mutations in protein-coding regions can generate 'neoantigens' causing developing cancers to be eliminated by the immune system. Quantitative estimates of the strength of this counterselection phenomenon have been lacking. We quantified the extent to which somatic mutations are depleted in peptides that are predicted to be displayed by major histocompatibility complex (MHC) class I proteins. The extent of this depletion depended on expression level of the neoantigenic gene, and on whether the patient had one or two MHC-encoding alleles that can display the peptide, suggesting MHC-encoding alleles are incompletely dominant. This study provides an initial quantitative understanding of counter-selection of identifiable subclasses of neoantigenic somatic variation.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Mutação de Sentido Incorreto , Peptídeos/genética , Alelos , Apresentação do Antígeno , Antígenos de Neoplasias/genética , Humanos
18.
Front Pharmacol ; 10: 448, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31105571

RESUMO

Mutations in ATP Binding Cassette (ABC)-transporter genes can have major effects on the bioavailability and toxicity of the drugs that are ABC-transporter substrates. Consequently, methods to predict if a drug is an ABC-transporter substrate are useful for drug development. Such methods traditionally relied on literature curated collections of ABC-transporter dependent membrane transfer assays. Here, we used a single large-scale dataset of 376 drugs with relative efficacy on an engineered yeast strain with all ABC-transporter genes deleted (ABC-16), to explore the relationship between a drug's chemical structure and ABC-transporter substrate-likeness. We represented a drug's chemical structure by an array of substructure keys and explored several machine learning methods to predict the drug's efficacy in an ABC-16 yeast strain. Gradient-Boosted Random Forest models outperformed all other methods with an AUC of 0.723. We prospectively validated the model using new experimental data and found significant agreement with predictions. Our analysis expands the previously reported chemical substructures associated with ABC-transporter substrates and provides an alternative means to investigate ABC-transporter substrate-likeness.

19.
Elife ; 82019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30747104

RESUMO

Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, 'isogenic' iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD. Heterozygous de novo and rare-inherited presumed-damaging variants were characterized in ASD risk genes/loci. Combinations of putative etiologic variants (GLI3/KIF21A or EHMT2/UBE2I) in separate families were modeled. We used a multi-electrode array, with patch-clamp recordings, to determine a reproducible synaptic phenotype in 25% of the individuals with ASD (other relevant data on the remaining lines was collected). Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient for CNTN5 or EHMT2. The biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research. Editorial note: This article has been through an editorial process in which authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Assuntos
Transtorno Autístico/fisiopatologia , Contactinas/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Células-Tronco Pluripotentes Induzidas/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Adolescente , Adulto , Células Cultivadas , Criança , Contactinas/deficiência , Contactinas/genética , Fenômenos Eletrofisiológicos , Feminino , Heterozigoto , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/genética , Humanos , Cinesina/genética , Cinesina/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Técnicas de Patch-Clamp , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Adulto Jovem , Proteína Gli3 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/metabolismo
20.
Bioinformatics ; 35(17): 3191-3193, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649215

RESUMO

SUMMARY: The promise of personalized genomic medicine depends on our ability to assess the functional impact of rare sequence variation. Multiplexed assays can experimentally measure the functional impact of missense variants on a massive scale. However, even after such assays, many missense variants remain poorly measured. Here we describe a software pipeline and application to impute missing information in experimentally determined variant effect maps. AVAILABILITY AND IMPLEMENTATION: http://impute.varianteffect.org source code: https://github.com/joewuca/imputation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Software , Genoma , Genômica , Mutação de Sentido Incorreto
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