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PubMed2002

Biplot Analysis of Test Sites and Trait Relations of Soybean in Ontario.

Superior crop cultivars must be identified through multi-environment trials (MET) and on the basis of multiple traits. The objectives of this paper were to describe two types of biplots, the GGE biplot and the GT biplot, which graphically display genotype by environment data and genotype by trait data, respectively, and hence facilitate cultivar evaluation on the basis of MET data and multiple traits. Genotype main effect plus genotype by environment interaction effect (GGE) biplot analysis of the soybean [Glycine max (L.) Merr.] yield data for the 2800 crop heat unit area of Ontario for MET in the period 1994-1999 revealed yearly crossover genotype by site interactions. The eastern Ontario site Winchester showed a different genotype response pattern from the three southwestern Ontario sites in four of the six years. The interactions were not large enough to divide the area into different mega-environments as when analyzed over years, a single cultivar yielded the best in all four sites. The southwestern site, St. Pauls, was found to always group together with at least one of the other three sites; it did not provide unique information on genotype performance. Therefore, in future cultivar evaluations, Winchester should always be used but St. Pauls can be dismissed. Applying GT biplot to the 1994-1999 multiple trait data illustrated that GT biplots graphically displayed the interrelationships among seed yield, oil content, protein content, plant height, and days to maturity, among other traits, and facilitated visual cultivar comparisons and selection. It was found that selection for seed yield alone was not only the simplest, but also the most effective strategy in the early stages of soybean breeding.

Journal Article↗
PubMed2003

Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity.

The identification and characterization of genes that influence the risk of common, complex multifactorial diseases, primarily through interactions with other genes and other environmental factors, remains a statistical and computational challenge in genetic epidemiology. This challenge is partly due to the limitations of parametric statistical methods for detecting genetic effects that are dependent solely or partially on interactions with other genes and environmental exposures. We previously introduced multifactor dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus genotype information to improve the identification of polymorphism combinations associated with disease risk. The MDR approach is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., assumes no particular inheritance model), and is directly applicable to case-control and discordant sib-pair study designs. Both empirical and theoretical studies suggest that MDR has excellent power for identifying high-order gene-gene interactions. However, the power of MDR for identifying gene-gene interactions in the presence of common sources of noise is not currently known. The goal of this study was to evaluate the power of MDR for identifying gene-gene interactions in the presence of noise due to genotyping error, missing data, phenocopy, and genetic or locus heterogeneity. Using simulated data, we show that MDR has high power to identify gene-gene interactions in the presence of 5% genotyping error, 5% missing data, or a combination of both. However, MDR has reduced power for some models in the presence of 50% phenocopy, and very limited power in the presence of 50% genetic heterogeneity. Extending MDR to address genetic heterogeneity should be a priority for the continued methodological development of this new approach.

Algorithms↗
PubMed2026

Family genetic designs in MoBa provide insights into health and functioning.

Genome-wide association studies using large, population-based samples of unrelated individuals have discovered thousands of genetic associations with health and disease1. These studies can help explain genetic and environmental risks. However, increasing evidence suggests that population-based estimates, while precise, can also reflect confounding that affects their use and interpretation. This confounding can be overcome using data from genotyped family members, such as nuclear mother-father-child trios2,3. However, samples of genotyped families are rare4-11. Here we illustrate some of the advantages of familial data using the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based cohort of parents and offspring with extensive genotype data (n ≈ 230,000) (ref. 3), along with broad and longitudinal phenotyping of health and functioning. We provide an overview of MoBa and describe the quality control of genotype data tailored to this extensively related sample. We then use trio data to illustrate how family-based genomic designs can identify distinct direct and indirect sources of genetic influence and structural confounding. As examples, we analyse children's height, educational achievement, depressive symptoms and sleep duration. These demonstrations highlight MoBa as a broadly valuable resource for advancing understanding of health and functioning across the lifecourse and generations.

Journal Article↗
PubMed2006

Integrating large-scale genotype and phenotype data.

With the completion of the Human Genome Project, a new emphasis is focusing on the sequence variation and the resulting phenotype. The number of data available from genomic studies addressing this relationship is rapidly growing. In order to analyze these data as a whole, they need to be integrated, aggregated and annotated in a timely manner. The Pharmacogenetics and Pharmacogenomics Knowledge Base PharmGKB; ( ) assembles and disseminates these data and their associated metadata that are needed for unambiguous identification and replication. Assembling these data in a timely manner is challenging, and the scalability of these data produce major challenges for a knowledge base such as PharmGKB. However, it is only through rapid global meta-annotation of these data that we will understand the relationship between specific genotype(s) and the related phenotype. PharmGKB has confronted these challenges, and these experiences and solutions can benefit all genome communities.

Animals↗
PubMed2005

T.I.M.S: TaqMan Information Management System, tools to organize data flow in a genotyping laboratory.

BACKGROUND: Single Nucleotide Polymorphism (SNP) genotyping is a major activity in biomedical research. The Taqman technology is one of the most commonly used approaches. It produces large amounts of data that are difficult to process by hand. Laboratories not equipped with a Laboratory Information Management System (LIMS) need tools to organize the data flow. RESULTS: We propose a package of Visual Basic programs focused on sample management and on the parsing of input and output TaqMan files. The code is written in Visual Basic, embedded in the Microsoft Office package, and it allows anyone to have access to those tools, without any programming skills and with basic computer requirements. CONCLUSION: We have created useful tools focused on management of TaqMan genotyping data, a critical issue in genotyping laboratories without a more sophisticated and expensive system, such as a LIMS.

Clinical Laboratory Information Systems↗
PubMed2005

Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits.

Forward genetic approaches to identify genes involved in complex traits such as common human diseases have met with limited success. Fine mapping of linkage regions and validation of positional candidates are time-consuming and not always successful. Here we detail a hybrid procedure to map loci involved in complex traits that leverages the strengths of forward and reverse genetic approaches. By integrating genotypic and expression data in a segregating mouse population, we show how clusters of expression quantitative trait loci linking to regions of the genome accurately reflect the underlying perturbation to the transcriptional network induced by DNA variations in genes that control the complex traits. By matching patterns of gene expression in a segregating population with expression responses induced by single-gene perturbation experiments, we show how genes controlling clusters of expression and clinical quantitative trait loci can be mapped directly. We demonstrate the utility of this approach by identifying 5-lipoxygenase as underlying previously identified quantitative trait loci in an F(2) cross between strains C57BL/6J and DBA/2J and showing that it has pleiotropic effects on body fat, lipid levels and bone density.

Animals↗
PubMed1999

Fitting a regression model for genotype-by-environment data on heading dates in grasses by methods for nonlinear mixed models.

The analysis of agricultural crop variety trials is usually complicated by the presence of genotype-by-environment interaction. A number of methods and models have been proposed to tackle this problem. One of the most common methods is the regression approach due to Yates and Cochran (1938, Journal of Agricultural Science 28, 556-580), in which performances of genotypes in the environments are regressed onto environmental means. The underlying regression model contains a multiplicative term with two unknown parameters (one for genotypes and one for environments). In the present paper, the model is modified by exchanging the role of genotypes and environments. Various diagnostic plots show that this modified model is adequate for a data set on heading dates in the grass species Dactylis glomerata. If environments are considered as a random factor while genotypes are taken as fixed, the model falls into the class of nonlinear mixed models. Recently, a number of procedures have been suggested for this class of models, which are based on first-order Taylor series expansion. Alternatively, the model can be estimated by maximum likelihood. This paper discusses the application of these methods for estimating parameters of the model.

Agriculture↗
PubMed2006

Cytogenetic genotype-phenotype studies: improving genotyping, phenotyping and data storage.

High-resolution molecular cytogenetic techniques such as genomic array CGH and MLPA detect submicroscopic chromosome aberrations in patients with unexplained mental retardation. These techniques rapidly change the practice of cytogenetic testing. Additionally, these techniques may improve genotype-phenotype studies of patients with microscopically visible chromosome aberrations, such as Wolf-Hirschhorn syndrome, 18q deletion syndrome and 1p36 deletion syndrome. In order to make the most of high-resolution karyotyping, a similar accuracy of phenotyping is needed to allow researchers and clinicians to make optimal use of the recent advances. International agreements on phenotype nomenclature and the use of computerized 3D face surface models are examples of such improvements in the practice of phenotyping patients with chromosomal anomalies. The combination of high-resolution cytogenetic techniques, a comprehensive, systematic system for phenotyping and optimal data storage will facilitate advances in genotype-phenotype studies and a further deconstruction of chromosomal syndromes. As a result, critical regions or single genes can be determined to be responsible for specific features and malformations.

Chromosome Aberrations↗
PubMed2005

Precision and type I error rate in the presence of genotype errors and missing parental data: a comparison between the original transmission disequilibrium test (TDT) and TDTae statistics.

BACKGROUND: Two factors impacting robustness of the original transmission disequilibrium test (TDT) are: i) missing parental genotypes and ii) undetected genotype errors. While it is known that independently these factors can inflate false-positive rates for the original TDT, no study has considered either the joint impact of these factors on false-positive rates or the precision score of TDT statistics regarding these factors. By precision score, we mean the absolute difference between disease gene position and the position of markers whose TDT statistic exceeds some threshold. METHODS: We apply our transmission disequilibrium test allowing for errors (TDTae) and the original TDT to phenotype and modified single-nucleotide polymorphism genotype simulation data from Genetic Analysis Workshop. We modify genotype data by randomly introducing genotype errors and removing a percentage of parental genotype data. We compute empirical distributions of each statistic's precision score for a chromosome harboring a simulated disease locus. We also consider inflation in type I error by studying markers on a chromosome harboring no disease locus. RESULTS: The TDTae shows median precision scores of approximately 13 cM, 2 cM, 0 cM, and 0 cM at the 5%, 1%, 0.1%, and 0.01% significance levels, respectively. By contrast, the original TDT shows median precision scores of approximately 23 cM, 21 cM, 15 cM, and 7 cM at the corresponding significance levels, respectively. For null chromosomes, the original TDT falsely rejects the null hypothesis for 28.8%, 14.8%, 5.4%, and 1.7% at the 5%, 1%, 0.1% and 0.01%, significance levels, respectively, while TDTae maintains the correct false-positive rate. CONCLUSION: Because missing parental genotypes and undetected genotype errors are unknown to the investigator, but are expected to be increasingly prevalent in multilocus datasets, we strongly recommend TDTae methods as a standard procedure, particularly where stricter significance levels are required.

Chromosomes, Human, Pair 3↗
PubMed2005

A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data.

BACKGROUND: Rapid genetic screening for cytochrome P450 (CYP) 2C9 variants may play a role in improving the efficacy and safety of warfarin in individuals with CYP2C9 variants. The feasibility of prospective CYP2C9 model-based warfarin dosing has not yet been assessed. OBJECTIVES: To evaluate the feasibility of applying a CYP2C9 gene-based warfarin dosing model in clinical practice. DESIGN: Prospective, randomized, single-blinded clinical pilot trial. SETTING: Large multispecialty group practice. PATIENTS: Candidates were recruited from a list of clinic patients eligible for warfarin initiation. This included patients with newly diagnosed thromboembolic disease or atrial arrhythmia, as well as patients anticipating elective valvuloplasty or arthroplasty. Patients who previously received warfarin were excluded. INTERVENTIONS: Subjects were randomized to receive either 1) a standard initiation dose of 5 mg warfarin/day, or 2) rapid CYP2C9 genotyping and an initiation dose determined using parameters estimated from a previously published multivariate model [including age, body size, co-morbidity (e.g., diabetes), clinical indication (e.g., valvuloplasty) and CYP2C9 genotype]. MEASUREMENTS: Primary outcome measurements were patient willingness to participate, physician willingness to refer, sample processing time, ability to administer calculated dosage and adequacy of follow-up. LIMITATIONS: This pilot trial was designed to assess the feasibility of model-based warfarin dosing. Power was insufficient for statistical comparison of adverse event rates. RESULTS: Forty-three of 117 patients had no prior warfarin treatment and were eligible. Five declined to participate. Twenty patients were randomized to a standard initiation dose of 5 mg daily. Eighteen patients were randomized to model-based dosing. All but one participant received the assigned initiation dose. Blood draw to dosage calculation time (including genotyping) required approximately 4 hours. Six adverse events occurred within the standard dosing group, and two adverse events occurred within the model-based dosing group. CONCLUSIONS: Prospective application of a multivariate CYP2C9 gene-based warfarin dosing model is feasible.

Aged↗
PubMed2006

Hepatitis B virus genotypes in acute and fulminant hepatitis patients from north India using two different molecular genotyping approaches.

Data from India on hepatitis B virus (HBV) genotype related differences in clinical progression and outcome of acute and fulminant hepatitis B are limited. Sera from patients with acute hepatitis B (AHB) (n=80), fulminant hepatitis B (FHB) (n=40) and asymptomatic HBsAg carriers (ASC) (n=40) were tested for HBV genotype using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and type-specific primers-based PCR (TSP-PCR). The genotype distribution for 160 patients with HBV related hepatitis/carriers were as follows: A, 3/80 (3.7%) in AHB, 2/40 (5%) in FHB and 7/40 (17.5%) in ASC; D, 77/80 (96.2%) in AHB, 38/40 (95%) in FHB and 33/40 (82.5%) in ASC. C, 0; B, 0; E, 0; F, 0 (p<0.01, genotype D versus A). Compared with genotype D, genotype A patients had no significant clinical or biochemical differences (p>0.05). HBV genotypes A and D were found to be prevalent in patients with HBV related acute and fulminant hepatitis from New Delhi, India. Genotype D was the dominant genotype prevalent in all patient categories while genotype A was solely responsible for AHB leading to chronic hepatitis B in 3.7% of the cases from this region.

Journal Article↗
PubMed2002

Discriminative quantification of cytochrome P4502D6 and 2D7/8 pseudogene expression by TaqMan real-time reverse transcriptase polymerase chain reaction.

The human drug oxidizing cytochrome P450, CYP2D6, is expressed at highly variable levels mainly due to a common genetic polymorphism which leads to the poor metabolizer phenotype in carriers of two nonfunctional alleles and to the extensive metabolizer phenotype in carriers of one or more functional alleles. Investigation of the role of CYP2D6 mRNA for expression and the possibility of using mRNA expression as a surrogate marker has been hampered by the presence of two pseudogenes, CYP2D7P and CYP2D8P. We therefore developed highly specific TaqMan real-time reverse transcriptase-PCR assays for the discriminative quantification of CYP2D6 and CYP2D7/8P transcripts. By in vitro transcription of plasmids containing the CYP2D6 cDNA or a hybrid CYP2D6/7 cDNA constructed by in vitro mutagenesis, authentic cRNAs were synthesized to be used for specificity testing and for absolute quantification. The method was used to determine CYP2D transcripts in a large number of human livers samples. CYP2D6 was not normally distributed with a median mRNA content of 3.2 transcripts per picogram of total RNA in all livers (range 0.32-14.8, N = 74). Expression in genetic poor metabolizers (1.81, N = 6) was significantly lower compared to extensive metabolizers (3.33, N = 68, P = 0.022). Similar expression levels were found for CYP2D7/8P (median 3.38 transcripts/pg, range 0.46-14.3), which were correlated to CYP2D6 mRNA (r(S) = 0.46, P < 0.0001) but did not depend on CYP2D6 genotype. These data demonstrate genotype-dependent mRNA expression for CYP2D6 and they emphasize the necessity of differentiating between the functional CYP2D6 and the CYP2D pseudogenes.

Base Sequence↗
PubMed2006

Susceptibility to antiretroviral drugs of CRF01_AE, CRF02_AG, and subtype C viruses from untreated patients of Africa and Asia: comparative genotypic and phenotypic data.

Non-B HIV-1 viruses are predominant in developing countries where access to antiretroviral drugs (ARVs) is progressively being intensified. It is important to obtain more data on the susceptibility of these viruses to available ARVs. CRF01_AE, CRF02_AG, and subtype C strains of HIV-1 obtained from untreated patients from Vietnam, Cote d'Ivoire, and India were analyzed for their in vitro susceptibility to NRTIs, NNRTIs, PIs, and an entry inhibitor (T-20) using a recombinant viral assay (PHENOSCRIPT). The corresponding viruses, which had been previously sequenced in reverse transcriptase (RT), protease (prot), plus envelope (env) C2/V3 genes and had therefore been fully characterized, were further sequenced in env HR1 + HR2 regions. CRF01_AE isolates are sensitive to NRTIs and NNRTIs with the exception of one isolate that exhibits a decreased susceptibility to NNRTIs associated with a I135T substitution in RT. CRF02_AG and subtype C viruses are sensitive to NRTIs and NNRTIs but some CRF02_AG isolates tend to be resistant to abacavir, potentially related to associated substitutions of RT at positions 123 (D123N) plus 135 (I135V). Whereas all but one CRF01_AE isolates are fully susceptible to PIs, some CRF02_AG and, more frequently, some subtype C isolates are resistant to atazanavir. The role of substitutions in prot at positions of secondary resistance mutations 20, 36, 63, and 82 is raised with a potentially crucial role of the V82I substitution. Finally, all viruses tested, regardless of the CRF or subtype, are fully susceptible to T-20.

Anti-HIV Agents↗
PubMed2024

Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.

PURPOSE: Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations. METHODS: A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups. RESULTS: The study models the natural history of the HPDL-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span. CONCLUSION: Quantitative and unbiased natural history modeling in HPDL-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies.

Humans↗
PubMed2025

SISTEM: simulation of tumor evolution, metastasis, and DNA-seq data under genotype-driven selection.

SUMMARY: SISTEM is a software package and mathematical framework for simulating tumor evolution and cell migrations at single-cell resolution. Unlike existing frameworks which simulate cancer cell populations under the neutral coalescent or using simple birth-death models, SISTEM simulates tumor populations under somatic clonal selection using an agent-based framework. SISTEM can generate mutation profiles, read counts, and DNA sequencing reads along with ground truth cell lineages and migration graphs under a number of easily customizable mutation and selection models. For improved realism, SISTEM allows for cell fitness to be driven by genomic events of various scales including single nucleotide variants, segmental gains and losses, whole-chromosomal and chromosome-arm aberrations, and whole-genome duplications. SISTEM also includes numerous migration models to simulate metastatic cancers, facilitating the exploration and evaluation of diverse migration patterns. AVAILABILITY AND IMPLEMENTATION: SISTEM is written in Python and is freely available open-source under GNU GPLv3 from: https://github.com/samsonweiner/sistem.

Software↗
PubMed2004

Williamsia maris sp. nov., a novel actinomycete isolated from the Sea of Japan.

The taxonomic position of a marine actinomycete, strain SJS0289/JS1T, was determined using a polyphasic taxonomic approach. The organism, which had phenotypic properties consistent with its classification in the genus Williamsia, formed a distinct clade in the 16S rRNA gene tree together with the type strain of Williamsia muralis, but was readily distinguished from this species using DNA-DNA relatedness and phenotypic data. The genotypic and phenotypic data show that the organism merits recognition as a new species of Williamsia. The name proposed for the new species is Williamsia maris; the type strain is SJS0289/JS1T (=DSM 44693T=JCM 12070T=KCTC 9945T=NCIMB 13945T).

Actinomycetales↗
PubMed1996

Typing multidrug-resistant Staphylococcus aureus: conflicting epidemiological data produced by genotypic and phenotypic methods clarified by phylogenetic analysis.

An outbreak of an unusual tetracycline-sensitive, rifampicin- and ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus (MRSA) strain at a large teaching hospital was investigated. Two typing methods, phage typing and restriction fragment length polymorphism (RFLP) by pulsed-field gel electrophoresis (RFLP-PFGE), gave conflicting results which were clarified by phylogenetic analysis. Phage typing identified all the "epidemic-associated" strains as identical, while RFLP-PFGE further divided these strains into four pulsotypes. Phylogenetic analysis showed these four pulsotypes were related genetically and also recognized a second strain of MRSA causing a continuing cross-infection problem. Variation in the RFLP-PFGE pattern was shown to occur following lysogenization of phage-sensitive MRSA. These results indicate that in analyzing outbreaks caused by subgroups of clonal organisms like MRSA, it is necessary to use at least two typing methods and that conflicts between these could be resolved by phylogenetic analysis.

Bacterial Typing Techniques↗