Gene constellation was acorrelate of a number of functional and evolutionary properties of genes, but its statistical effect was ~1-2 orders of magnitude lower than the effects of recombination, chromosome linkage and protein function.Author:Shuwei Li, Ching-Hua Shih, Michael H KohnPublish Year:2010
What is the constellation view?
The Constellation view presents the genes most closely correlated to a chosen gene, grouped by genomic location or secondary correlation. Dive into a zoom-enabled representation of the genome, with gene expression (microarray) as pseudo-color barcodes positioned along the chromosomes, marking specific genes or differentially expressed regions.
What are the data inputs for Constellation?
Data inputs for Constellation were .vcf files, a gene directory with chromosomal position, and a nomenclature file for each locus to be diplotyped. The position file contained the location of the gene transcript [Chr:start—stop] according to the GRCh37 reference.
Can constellation help us better understand Admer gene variations?
The researchers hope that Constellation can identify variations in other ADMER genes, enabling future uses of WGS for personalized precision medicine. Zhou, S. F. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin. Pharmacokinet. 48, 689–723 (2009).
What is the clinical specificity of constellation?
The clinical specificity of Constellation was 98% (56 of 57 Activity Scores (excluding no calls and unknowns) were concordant with the consensus reference). Importantly, all extreme phenotypes, i.e., poor and ultrarapid metabolisers were correctly identified with Constellation ( Table 1 ).
What is Additional File 5A?
Additional file 5: 5A i.-v.) Prior to the elimination of overrepresented GO terms for the X-chromosome. (Additional file 5B i.-v.) Prior to the elimination of overrepresented GO terms for autosomes. (DOC 721 KB)
What is the codon adaptation index?
The Codon Adaptation Index (CAI) was calculated for D. melanogaster genes using the software CodonW http://codonw.sourceforge.net/. CAI measures the synonymous codon usage bias for a DNA or RNA sequence [ 42 ]. The measurement ranges between 0 and 1, with a value of 1 indicating extreme codon usage bias.
What are co-clustering genes?
Chromatin co-clustering genes include genes that co-locate within 20 kb of another gene on the opposite strand (Group COS, Figure 1C, top) or on the same strand (CSS, Figure 1C, bottom). In Drosophila, concerted access to chromatin during transcription has been inferred for genes spanning 20 kb segments [ 11, 13 ], leading to significant correlation in gene expression within co-called transcriptional territories. We varied the distances separating genes to account for the range of distances over which transcriptional territories can occur (2 kb to 200 kb; median 100 kb) (Additional file 2; Figure 2B ).
What is persistence and turnover of gene constellations?
Persistence and turnover of gene constellations may be indicative of evolutionary processes and/or technical issues related to gene annotation. For example, ~4500 D. melanogaster genes (including duplicated genes) in different constellations have no consensus ortholog in D. pseudoobscura. This might indicate rapid turnover of genes in particular gene constellations and/or, that these genes are more difficult to annotate and assign as orthologs than others. We compared conservation of gene constellations between D. melanogaster and D. pseudoobscura. The latter species was chosen because one-to-one assignment of orthologs to D. melanogaster genes is well established and this information is accessible (Inparanoid; [ 27 ]).
What is the recombination rate?
The recombination rate is a correlate of the effect of genetic drift and selection on levels of genetic variation within species and the rates of molecular evolution between species [ 19, 20 ].
What is the effect of the location of a gene on the X chromosome versus the autosome?
The location of a gene on the X chromosome versus the autosomes may have an effect on its functional properties and evolutionary dynamics [ 17, 18 ]. For example, recessive mutations are exposed to selection in the hemizygous X of males.
What are the biological dimensions of genes?
The biological dimensions of genes are manifold. These include genomic properties, (e.g., X/autosomal linkage, recombination) and functional properties (e.g., expression level, tissue specificity). Multiple properties, each generally of subtle influence individually, may affect the evolution of genes or merely be (auto-)correlates. Results of multidimensional analyses may reveal the relative importance of these properties on the evolution of genes, and therefore help evaluate whether these properties should be considered during analyses. While numerous properties are now considered during studies, most work still assumes the stereotypical solitary gene as commonly depicted in textbooks. Here, we investigate the Drosophila melanogaster genome to determine whether deviations from the stereotypical gene architecture correlate with other properties of genes.
What is the gold standard for CYP2D6?
Despite the central importance for clinical pharmacogenomics and precision medicine, no current ‘gold standard’ method exists for clinical determination of CYP2D6 (or other pharmacogene) diplotypes and their translation into clinically actionable results. 15 Regardless of the genotyping or sequencing methods used considerable knowledge regarding genome sequence nomenclature and conventions, CYP2D6 haplotype (star allele) nomenclature, and CYP2D6 haplotype—CYP2D6 phenotype relationships is required. Furthermore, mappings between these are not necessarily intuitive, 35 one-to-one or fixed with respect to time, which may pose a barrier to the general adoption of interpretation of CYP2D6 genetic results. Other computational methods such as Cypiriri have been developed to assess CYP2D6 genotype from high-throughput sequence data. 36 Although Cypiripi was evaluated on 71 simulated data sets, its validation was limited to a Coriell trio (NA12878, NA12877 and NA12882). Similar to Constellation, the CYP2D6*68+*4 allele was called as CYP2D6*4 missing the additional gene copy. The Cypiripi algorithm also heavily relies on locus-specific analysis techniques such as alignment to custom reference sequences and identification of common spurious variant calls from the CYP2D7 pseudogene. Constellation is advantageous as this tool is a homogenous method that is rapid, scalable and has minimal incremental cost in the setting of a whole-genome sequence through its ability to use the VCF output from the primary alignment and variant detection pipeline without imposing an additional computational burden. This allows for the parallel processing of multiple loci with annotated nomenclature systems without requiring locus-specific reanalysis or any knowledge of related genes and/or pseudogenes. As Constellation adjusts haplotype scoring based on the sensitivity and specificity of the variant detection method being used, any improvement in variant calling in the primary analysis pipeline, either through improved read format or pipeline parameterisation, is immediately available to Constellation to improve locus resolution. Finally, Constellation has minimal requirements for expert domain knowledge for operation, as it performs the intermediate mapping, translation and inference steps.
How many variants are there in CYP2D6?
Fifteen nucleotide variants were identified by WGS and Sanger Sequencing that are not part of currently defined CYP2D6 alleles (haplotypes; Table 1, Supplementary Figure 3 ). These SNPs define five subvariants of CYP2D6*1 ( var1 – 5 ), two subvariants of CYP2D6*2 ( var1, 2) and four subvariants of CYP2D6*4 ( var1 – 4 ). One subvariant of CYP2D6*17 (var1 has previously been described 26 (see Supplementary Information for additional details). Notably, rs267608274 (424C>T) was identified in two related subjects by Sanger (mother and child 2), but only called by NGS using GSNAP-GATK for child 2. This SNP was not identified by the variation caller in the mother owing to a low quality threshold. We also identified a CYP2D6*17 subvariant that is characterised by the lack of three SNPs (family 5, subject CMH438 in Supplementary Figure 3 ).
What is WGS used for?
WGS has successfully been applied for the molecular diagnosis of genetic diseases. 17 – 19 The Illumina HiSeq X Ten, although not FDA-cleared, has the capacity to sequence ~18,000 human genomes per year to ~30-fold coverage at a sequencing cost of ~$1,000 per sample ( www.nature.com/news/is-the-1-000-genome-for-real-1.14530) markedly changing the potential cost effectiveness of WGS in health-care applications. In a pediatric context, WGS is increasingly being used clinically, particularly in neurodevelopmental disorders, to diagnose suspected underlying genetic diseases, 20 and it is not unreasonable to expect that at some point in the not too distant future, WGS data will be the rule rather than the exception. Critical to lifelong, individualised drug choice and dosing is the identification of genetic variation in genes critical to drug absorption, distribution, metabolism, excretion and response (ADMER) obtained at any point along the age continuum. In order to be of broad clinical use, scalable, automated methods are needed for imputation of function and/or activity of ADMER genes, with return of results to support clinical guidance for drug, dose and exposure for individual patients. At present about 100 ADMER genes are relevant for such guidance ( http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm, https://www.pharmgkb.org/gene/PA128#tabview=tab0&subtab=32, and http://pharmaadme.org/ ), and of these, CYP2D6 is the most technically difficult to diplotype. Although it may be somewhat premature to recommend WGS as a platform for routine pharmacogenomic testing, WGS data is becoming increasingly more common as a clinical diagnostic platform, and the pharmacogenome represents ‘secondary findings’ that may have direct applicability to the choice of medication as well as the most appropriate dose for an individual patient. 21, 22 Herein, we describe a system for scalable, automated derivation of diploid functional alleles from unphased WGS using CYP2D6 as a specific example of its utility.
How to adjust for variant call errors?
To adjust for variant call errors, the scores were adjusted by the sensitivity (sens) and specificity (spec) of WGS variant calling. Assuming independence of variant calls, the score for each variant was reported as a likelihood ratio. For instance, a reported variant (type X) that matched a candidate diplotype was scored as P (Predicted|Present)/P (Predicted|Absent)=Sensitivity/ (1?Specificity), type Y scored as P (Predicted|Absent)/P (Predicted/Present)= (1?Specificity)/Sensitivity, and type Z scored as P (Not Predicted|Present)/P (Not Predicted|Absent)= (1?Sensitivity)/Specificity. Thus, X was adjusted by A = [sens/ (1?spec)], Y adjusted by B = [ (1?sens)/spec], and Z adjusted by C = [ (1?spec)/sens]. The overall score was the product of likelihood ratios of a diplotype sample set match [score= ( Ax )* ( By )* ( Cz )]. Resultant diplotypes were returned in a reverse sorted list with the highest index, max ( P ), reported to the output file. The CYP2D6 activity corresponding to the highest scoring diplotype was reported.
What is a WGS in medicine?
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.
How many kb is a CYP2D6 fragment?
CYP2D6 genotyping was performed as described. 37, 39 – 44 Briefly, long-range PCR was used to amplify a 6.6-kb fragment encompassing the entire CYP2D6 gene (fragment A), a 3.5-kb fragment from the intergenic region of CYP2D6 duplication structures (fragment B) and a 5-kb fragment from CYP2D7/2D6 hybrid structures (fragment H). 42 Presence of fragments was determined by band visualisation following agarose gel electrophoresis. The gene regions amplified are shown in Supplementary Figure 1.
What enzymes are involved in the elimination of endogenous and exogenous biochemicals?
Cytochrome P450 family 2, subfamily D, polypeptide 6, CYP2D6 , is one of the most important enzymes of bioactivation or elimination of endogenous and exogenous biochemicals. Specifically, CYP2D6 contributes to hepatic metabolism of ~25% of drugs in clinical use, including many antidepressants, antipsychotics, opioids, antiemetics, anti-arrhythmics, β-blockers, cancer chemotherapeutics and drugs of abuse. 1, 2 The enzymatic activity of CYP2D6 varies widely among individuals, based both on level of expression and on functional genetic variations (alleles), resulting in significant clinical consequences for drug metabolism and individual risk of adverse events or drug efficacy ( www.cypalleles.ki.se/ 3 and www.pharmgkb.org/ ).
What gene gives dragon wings?
The Constellation gene gives a dragon’s wings and crests a swirled, smoky pattern, overlaid with a sparkling stars and a constellation on their wing joints. Eggplant Constellation on a male Bogsneak. Spearmint Constellation on a female Bogsneak. Spruce Constellation on a hatchling Bogsneak. Marigold Constellation on a male Coatl.
What is the secondary counterpart of the Starmap?
Constellation is the secondary counterpart to the Starmap primary.
When was the glow patch patched?
This gene was patched on November 11th, 2021 to fix an art error with Obelisk dragons. Formerly, the "glow" layer around the constellations was misapplied, causing the stars to appear larger and softer than they were supposed to.
Current Issues in Molecular Virology
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The Age of Enlightenment is the period in time when the method of reasoning known as the Scientific Method was developed. This revolution in science began with the description of the sun as the center of our solar system rather than the earth. Natural phenomena previously explained by spiritualists were now described by science.
2. The segmented influenza genome
The Orthomyxoviridae family is comprised of negative-sense, segmented RNA viruses. There are three influenza genera, influenza A, B and C viruses, that belong to the family. Eight negative-sense RNA segments make up the viral genome for the A and B viruses, one more than the influenza C virus genome which has seven segments ( Figure 1).
3. The gene constellation effect
It stands to reason that if a certain gene constellation confers some desirable attribute then viruses containing those segments should occur more often in the population over time than other reassortments.
Understanding the gene constellation effect in influenza is important, especially for vaccine production. The mixing and matching of influenza genomic segments in nature and in the laboratory gives rise to new viruses with phenotypes that differ from the ancestral viruses.
The findings and conclusions in this chapter have not been formally disseminated by the Food and Drug Administration and should not be construed to represent an Agency determination or policy.