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Dive into the research topics where Douglas E. V. Pires is active.

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Featured researches published by Douglas E. V. Pires.


BMC Medicine | 2016

Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance

Jody Phelan; Francesc Coll; Ruth McNerney; David B. Ascher; Douglas E. V. Pires; Nick Furnham; Nele Coeck; Grant A. Hill-Cawthorne; Mridul Nair; Kim Mallard; Andrew Ramsay; Susana Campino; Martin L. Hibberd; Arnab Pain; Leen Rigouts; Taane G. Clark

BackgroundCombating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance.MethodsTo investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods.ResultsThe analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites.ConclusionsUsing the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel resistance mutations to improve the design of tuberculosis control measures, such as diagnostics, and inform patient management.


Nucleic Acids Research | 2016

mCSM-AB: a web server for predicting antibody-antigen affinity changes upon mutation with graph-based signatures

Douglas E. V. Pires; David B. Ascher

Computational methods have traditionally struggled to predict the effect of mutations in antibody–antigen complexes on binding affinity. This has limited their usefulness during antibody engineering and development, and their ability to predict biologically relevant escape mutations. Here we present mCSM-AB, a user-friendly web server for accurately predicting antibody–antigen affinity changes upon mutation which relies on graph-based signatures. We show that mCSM-AB performs better than comparable methods that have been previously used for antibody engineering. mCSM-AB web server is available at http://structure.bioc.cam.ac.uk/mcsm_ab.


Molecular Genetics & Genomic Medicine | 2017

SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity

Ruth Casey; David B. Ascher; Eleanor Rattenberry; Louise Izatt; Katrina A. Andrews; Helen L. Simpson; Benjamen G Challis; Soo-Mi Park; Venkata R. Bulusu; Fiona Lalloo; Douglas E. V. Pires; Hannah West; Graeme R. Clark; Philip Smith; James Whitworth; Thomas G. Papathomas; Phillipe Taniere; Rosina Savisaar; Laurence D. Hurst; Emma R. Woodward; Eamonn R. Maher

To evaluate the role of germline SDHA mutation analysis by (1) comprehensive literature review, (2) description of novel germline SDHA mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA.


Nucleic Acids Research | 2017

mCSM-NA: predicting the effects of mutations on protein-nucleic acids interactions.

Douglas E. V. Pires; David B. Ascher

Abstract Over the past two decades, several computational methods have been proposed to predict how missense mutations can affect protein structure and function, either by altering protein stability or interactions with its partners, shedding light into potential molecular mechanisms giving rise to different phenotypes. Effectively and efficiently predicting consequences of mutations on protein–nucleic acid interactions, however, remained until recently a great and unmet challenge. Here we report an updated webserver for mCSM–NA, the only scalable method we are aware of capable of quantitatively predicting the effects of mutations in protein coding regions on nucleic acid binding affinities. We have significantly enhanced the original method by including a pharmacophore modelling and information of nucleic acid properties into our graph-based signatures, considering the reverse mutation and by using a refined, more reliable data set, based on a new release of the ProNIT database, which has significantly improved the reliability and applicability of the methodology. Our new predictive model was capable of achieving a correlation coefficient of up to 0.70 on cross-validation and 0.68 on blind-tests, outperforming its previous version. The server is freely available via a user-friendly web interface at: http://structure.bioc.cam.ac.uk/mcsm_na.


PLOS ONE | 2016

Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses

Ana Carolina Rios Silvino; Gabriel Luíz Costa; Flávia Carolina Faustino de Araújo; David B. Ascher; Douglas E. V. Pires; Cor Jesus Fernandes Fontes; Luzia H. Carvalho; Cristiana Ferreira Alves de Brito; Taís Nóbrega de Sousa

Although Plasmodium vivax relapses are classically associated with hypnozoite activation, it has been proposed that a proportion of these cases are due to primaquine (PQ) treatment failure caused by polymorphisms in cytochrome P-450 2D6 (CYP2D6). Here, we present evidence that CYP2D6 polymorphisms are implicated in PQ failure, which was reinforced by findings in genetically similar parasites, and may explain a number of vivax relapses. Using a computational approach, these polymorphisms were predicted to affect the activity of CYP2D6 through changes in the structural stability that could lead to disruption of the PQ-enzyme interactions. Furthermore, because PQ is co-administered with chloroquine (CQ), we investigated whether CQ-impaired metabolism by cytochrome P-450 2C8 (CYP2C8) could also contribute to vivax recurrences. Our results show that CYP2C8-mutated patients frequently relapsed early (<42 days) and had a higher proportion of genetically similar parasites, suggesting the possibility of recrudescence due to CQ therapeutic failure. These results highlight the importance of pharmacogenetic studies as a tool to monitor the efficacy of antimalarial therapy.


npj Genomic Medicine | 2017

Familial STAG2 germline mutation defines a new human cohesinopathy

Fernanda C. Soardi; Alice Machado-Silva; Natália D. Linhares; Ge Zheng; Qianhui Qu; Heloísa B. Pena; Thaís Maria da Mata Martins; Helaine Graziele Santos Vieira; Núbia Braga Pereira; Raquel C. Melo-Minardi; Carolina Cavaliéri Gomes; Ricardo Santiago Gomez; Dawidson Assis Gomes; Douglas E. V. Pires; David B. Ascher; Hongtao Yu; Sérgio D.J. Pena

We characterize a novel human cohesinopathy originated from a familial germline mutation of the gene encoding the cohesin subunit STAG2, which we propose to call STAG2-related X-linked Intellectual Deficiency. Five individuals carry a STAG2 p.Ser327Asn (c.980u2009Gu2009>u2009A) variant that perfectly cosegregates with a phenotype of syndromic mental retardation in a characteristic X-linked recessive pattern. Although patient-derived cells did not show overt sister-chromatid cohesion defects, they exhibited altered cell cycle profiles and gene expression patterns that were consistent with cohesin deficiency. The protein level of STAG2 in patient cells was normal. Interestingly, STAG2 S327 is located at a conserved site crucial for binding to SCC1 and cohesin regulators. When expressed in human cells, the STAG2 p.Ser327Asn mutant is defective in binding to SCC1 and other cohesin subunits and regulators. Thus, decreased amount of intact cohesin likely underlies the phenotypes of STAG2-SXLID. Intriguingly, recombinant STAG2 p.Ser327Asn binds normally to SCC1, WAPL, and SGO1 in vitro, suggesting the existence of unknown in vivo mechanisms that regulate the interaction between STAG2 and SCC1.Intellectual disability: mutation in cell cycle protein causes developmental diseaseA newly discovered developmental disease is characterized by mutations in a subunit of the cohesin protein involved in cell division. A team led by Sérgio Pena from GENE—Núcleo de Genética Médica, Brazil, and Hongtao Yu from the University of Texas Southwestern Medical Center, USA, describe a Brazilian family with five male relatives, all with intellectual deficiency, short stature, and other abnormalities. The family tree pointed toward an X-linked pattern of inheritance, so the researchers performed a network analysis of 24 genes on the X chromosome known to contribute to mental retardation. They found that all five individuals had a mutation in a gene called STAG2, which encodes a subunit of cohesin. The mutant STAG2 did not bind properly to other cohesin subunits in human cells, and patient-derived cells exhibited altered cell cycle profiles. The researchers propose calling the disease “STAG2-related X-linked intellectual deficiency”.


Journal of Medical Genetics | 2018

Tumour risks and genotype–phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD

Katrina A. Andrews; David B. Ascher; Douglas E. V. Pires; Daniel R. Barnes; Lindsey Vialard; Ruth Casey; Nicola Bradshaw; Julian Adlard; Simon Aylwin; Paul Brennan; Carole Brewer; Trevor Cole; Jackie Cook; Rosemarie Davidson; Alan Donaldson; Alan Fryer; Lynn Greenhalgh; Shirley Hodgson; Richard Irving; Fiona Lalloo; Michelle McConachie; Vivienne McConnell; Patrick J. Morrison; Victoria Murday; Soo-Mi Park; Helen L. Simpson; Katie Snape; Susan Stewart; Susan Tomkins; Yvonne Wallis

Background Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype–phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. Methods A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. Results Tumour risks analysis provided novel penetrance estimates and genotype–phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). Conclusions Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype–tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.


Investigative Ophthalmology & Visual Science | 2017

A Computational Approach From Gene to Structure Analysis of the Human ABCA4 Transporter Involved in Genetic Retinal Diseases.

Alfonso Trezza; Andrea Bernini; Andrea Langella; David B. Ascher; Douglas E. V. Pires; Andrea Sodi; Ilaria Passerini; Elisabetta Pelo; Stanislao Rizzo; Neri Niccolai; Ottavia Spiga

PurposenThe aim of this article is to report the investigation of the structural features of ABCA4, a protein associated with a genetic retinal disease. A new database collecting knowledge of ABCA4 structure may facilitate predictions about the possible functional consequences of gene mutations observed in clinical practice.nnnMethodsnIn order to correlate structural and functional effects of the observed mutations, the structure of mouse P-glycoprotein was used as a template for homology modeling. The obtained structural information and genetic data are the basis of our relational database (ABCA4Database).nnnResultsnSequence variability among all ABCA4-deposited entries was calculated and reported as Shannon entropy score at the residue level. The three-dimensional model of ABCA4 structure was used to locate the spatial distribution of the observed variable regions. Our predictions from structural in silico tools were able to accurately link the functional effects of mutations to phenotype. The development of the ABCA4Database gathers all the available genetic and structural information, yielding a global view of the molecular basis of some retinal diseases.nnnConclusionsnABCA4 modeled structure provides a molecular basis on which to analyze protein sequence mutations related to genetic retinal disease in order to predict the risk of retinal disease across all possible ABCA4 mutations. Additionally, our ABCA4 predicted structure is a good starting point for the creation of a new data analysis model, appropriate for precision medicine, in order to develop a deeper knowledge network of the disease and to improve the management of patients.


Bioinformatics | 2015

PDBest: a user-friendly platform for manipulating and enhancing protein structures

Wellisson R. S. Gonçalves; Valdete M. Gonçalves-Almeida; Aleksander L. Arruda; Wagner Meira; Carlos H. da Silveira; Douglas E. V. Pires; Raquel C. de Melo-Minardi

UNLABELLEDnPDBest (PDB Enhanced Structures Toolkit) is a user-friendly, freely available platform for acquiring, manipulating and normalizing protein structures in a high-throughput and seamless fashion. With an intuitive graphical interface it allows users with no programming background to download and manipulate their files. The platform also exports protocols, enabling users to easily share PDB searching and filtering criteria, enhancing analysis reproducibility.nnnAVAILABILITY AND IMPLEMENTATIONnPDBest installation packages are freely available for several platforms at http://[email protected], [email protected], [email protected] INFORMATIONnSupplementary data are available at Bioinformatics online.


bioRxiv | 2018

TAG.ME: Taxonomic Assignment of Genetic Markers for Ecology

Douglas E. V. Pires; Francislon S. Oliveira; Felipe B. Correa; Daniel Kumazawa Morais; Gabriel da Rocha Fernandes

Background Sequencing of amplified genetic markers, such as the 16S rRNA gene, have been extensively used to characterize microbial community composition. Recent studies suggested that Amplicon Sequences Variants (ASV) should replace the Operational Taxonomic Units (OTU), given the arbitrary definition of sequence identity thresholds used to define units. Alignment-free methods are an interesting alternative for the taxonomic classification of the ASVs, preventing the introduction of biases from sequence identity thresholds. Results Here we present TAG.ME, a novel alignment-independent and amplicon-specific method for taxonomic assignment based on genetic markers. TAG.ME uses a multilevel supervised learning approach to create predictive models based on user-defined genetic marker genes. The predictive method can assign taxonomy to sequenced amplicons efficiently and effectively. We applied our method to assess gut and soil sample classification, and it outperformed alternative approaches, identifying a substantially larger proportion of species. Benchmark tests performed using the RDP database, and Mock communities reinforced the precise classification into deep taxonomic levels. Conclusion TAG.ME presents a new approach to assign taxonomy to amplicon sequences accurately. Our classification model, trained with amplicon specific sequences, can address resolution issues not solved by other methods and approaches that use the whole 16S rRNA gene sequence. TAG.ME is implemented as an R package and is freely available at http://gabrielrfernandes.github.io/tagme/

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