Dataset Information

Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, CYP2D6, from whole-genome sequences.

ABSTRACT: An important component of precision medicine-the use of whole-genome sequencing (WGS) to guide lifelong healthcare-is electronic decision support to inform drug choice and dosing. To achieve this, automated identification of genetic variation in genes involved in drug absorption, distribution, metabolism, excretion and response (ADMER) is required. CYP2D6 is a major enzyme for drug bioactivation and elimination. CYP2D6 activity is predominantly governed by genetic variation; however, it is technically arduous to haplotype. Not only is the nucleotide sequence of CYP2D6 highly polymorphic, but the locus also features diverse structural variations, including gene deletion, duplication, multiplication events and rearrangements with the nonfunctional, neighbouring CYP2D7 and CYP2D8 genes. We developed Constellation, a probabilistic scoring system, enabling automated ascertainment of CYP2D6 activity scores from 2×100 paired-end WGS. The consensus reference method included TaqMan genotyping assays, quantitative copy-number variation determination and Sanger sequencing. When compared with the consensus reference Constellation had an analytic sensitivity of 97% (59 of 61 diplotypes) and analytic specificity of 95% (116 of 122 haplotypes). All extreme phenotypes, i.e., poor and ultrarapid metabolisers were accurately identified by Constellation. Constellation is anticipated to be extensible to functional variation in all ADMER genes, and to be performed at marginal incremental financial and computational costs in the setting of diagnostic WGS.

SUBMITTER: Twist GP

PROVIDER: S-EPMC5685293 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, <i>CYP2D6</i>, from whole-genome sequences.

Twist Greyson P GP Gaedigk Andrea A Miller Neil A NA Farrow Emily G EG Willig Laurel K LK Dinwiddie Darrell L DL Petrikin Josh E JE Soden Sarah E SE Herd Suzanne S Gibson Margaret M Cakici Julie A JA Riffel Amanda K AK Leeder J Steven JS Dinakarpandian Deendayal D Kingsmore Stephen F SF

NPJ genomic medicine 20160113

An important component of precision medicine-the use of whole-genome sequencing (WGS) to guide lifelong healthcare-is electronic decision support to inform drug choice and dosing. To achieve this, automated identification of genetic variation in genes involved in drug absorption, distribution, metabolism, excretion and response (ADMER) is required. <i>CYP2D6</i> is a major enzyme for drug bioactivation and elimination. CYP2D6 activity is predominantly governed by genetic variation; however, it i ...[more]

PMID: 29263805

Similar Datasets

Project description:BackgroundThe high variability in envelope regions of some viruses such as HIV allow the virus to establish infection and to escape subsequent immune surveillance. This variability, as well as increasing incorporation of N-linked glycosylation sites, is fundamental to this evasion. It also creates difficulties for multiple sequence alignment methods (MSA) that provide the first step in their analysis. Existing MSA tools often fail to properly align highly variable HIV envelope sequences requiring extensive manual editing that is impractical with even a moderate number of these variable sequences.ResultsWe developed an automated library building tool NGlyAlign, that organizes similar N-linked glycosylation sites as block constraints and statistically conserved global sites as single site constraints to automatically enforce partial columns in consistency-based MSA methods such as Dialign. This combined method accurately aligns variable HIV-1 envelope sequences. We tested the method on two datasets: a set of 156 founder and chronic gp160 HIV-1 subtype B sequences as well as a set of reference sequences of gp120 in the highly variable region 1. On measures such as entropy scores, sum of pair scores, column score, and similarity heat maps, NGlyAlign+Dialign proved superior against methods such as T-Coffee, ClustalOmega, ClustalW, Praline, HIValign and Muscle. The method is scalable to large sequence sets producing accurate alignments without requiring manual editing. As well as this application to HIV, our method can be used for other highly variable glycoproteins such as hepatitis C virus envelope.ConclusionsNGlyAlign is an automated tool for mapping and building glycosylation motif libraries to accurately align highly variable regions in HIV sequences. It can provide the basis for many studies reliant on single robust alignments. NGlyAlign has been developed as an open-source tool and is freely available at https://github.com/UNSW-Mathematical-Biology/NGlyAlign_v1.0 .

Project description:BACKGROUND:Whole-genome sequencing is performed routinely as a means to identify polymorphic genetic loci such as short tandem repeat loci. We have developed a simple tool, called pSTR Finder, which is freely available as a means of identifying putative polymorphic short tandem repeat (STR) loci from data generated from genome-wide sequences. The program performs cross comparisons on the STR sequences generated using the Tandem Repeats Finder based on multiple-genome samples in a FASTA format. These comparisons generate reports listing identical, polymorphic, and different STR loci when comparing two samples. METHODS:The web site http://forensic.mc.ntu.edu.tw:9000/PSTRWeb/Default has been developed as a means to identify polymorphic STR loci within complex mass genome sequences. The program was developed to generate a series of user-friendly reports. RESULTS:As proof of concept for the program, four FASTA genome sequence samples of human chromosome X (AC_000155.1, CM000685.1, NC_018934.2, and CM000274.1) were obtained from GenBank and were analyzed for the presence of putative STR regions. The sequences within AC-000155.1 were used as an initial reference sequence from which there were 5443 identical and 4305 polymorphic STR loci identified using a repeat unit of 1-6 and 10 bp as the flanking sequence either side of the putative STR loci. A reliability test was used to compare five FASTA samples, which had sections of DNA sequence removed to mimic partial or fragmented DNA sequences, to determine whether pSTR Finder can efficiently and consistently find identical, polymorphic, and different STR loci. CONCLUSIONS:From the mass of DNA sequence data, the project was found to reproducibly identify polymorphic STR loci and generate user-friendly reports detailing the number and location of these potential polymorphic loci. This freely available program was found to be a useful tool to find polymorphic STR within whole-genome sequence data in forensic genetic studies.

Project description:Microsatellites are ubiquitously distributed, polymorphic repeat sequence valuable for association, selection, population structure and identification. They can be mined by genomic library, probe hybridization and sequencing of selected clones. Such approach has many limitations like biased hybridization and selection of larger repeats. In silico mining of polymorphic markers using data of various genotypes can be rapid and economical. Available tools lack in some or other aspects like: targeted user defined primer generation, polymorphism discovery using multiple sequence, size and number limits of input sequence, no option for primer generation and e-PCR evaluation, transferability, lack of complete automation and user-friendliness. They also lack the provision to evaluate published primers in e-PCR mode to generate additional allelic data using re-sequenced data of various genotypes for judicious utilization of previously generated data. We developed the tool (PolyMorphPredict) using Perl, R, Java and launched at Apache which is available at http://webtom.cabgrid.res.in/polypred/. It mines microsatellite loci and computes primers from genome/transcriptome data of any species. It can perform e-PCR using published primers for polymorphism discovery and across species transferability of microsatellite loci. Present tool has been evaluated using five species of different genome size having 21 genotypes. Though server is equipped with genomic data of three species for test run with gel simulation, but can be used for any species. Further, polymorphism predictability has been validated using in silico and in vitro PCR of four rice genotypes. This tool can accelerate the in silico microsatellite polymorphism discovery in re-sequencing projects of any species of plant and animal for their diversity estimation along with variety/breed identification, population structure, MAS, QTL and gene discovery, traceability, parentage testing, fungal diagnostics and genome finishing.

Dataset Information

Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, CYP2D6, from whole-genome sequences.

Publications

Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, <i>CYP2D6</i>, from whole-genome sequences.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets