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PubMed2004

Haplotype structure and allele frequencies of CYP2B6 in a Korean population.

Cytochrome P450 2B6 (CYP2B6) metabolizes a number of therapeutic drugs and its metabolic activity varies markedly in human liver. Although genetic polymorphisms of CYP2B6 have been reported in noncoding and coding regions, little information is available regarding single nucleotide polymorphisms (SNPs) and their haplotypes in noncoding regions in Asians. Fourteen previously reported SNPs were determined by polymerase chain reaction-restriction fragment length polymorphism or SNaPshot analysis in a Korean population and their haplotypes were inferred from genotype data using an expectation-maximization algorithm. The most common haplotypes were haplotype I, the reference sequence (frequency 0.35), haplotype II (0.19), haplotype III (0.19), and haplotype V (0.12), which together accounted for 85% of all haplotypes. The frequency of haplotype III, which contains -2320C, -1778G, -1186G, -750C, and 15582T, was found to be 2.4-fold higher than that of the *1J allele in Caucasians, and the frequency of haplotype V, which contains -8207C, -1456C, -750C, 516T, and 785G, was 55% of that of the *6B allele in Caucasians. Moreover, haplotype V, the *6B allele, appeared to be completely linked to -8207 within a putative nuclear receptor binding motif, suggesting that lower expressions of the *6B allele may be associated with the presence of noncoding SNPs such as -8207G>C linked to nonsynonymous SNPs. In conclusion, we found 11 previously described polymorphisms and identified four major haplotypes of CYP2B6 in Koreans. The frequencies of the *1J or *6B alleles, which may reduce CYP2B6 enzyme expression, were found to be significantly different between Koreans and Caucasians.

Adult↗
PubMed2006

The K101P and K103R/V179D mutations in human immunodeficiency virus type 1 reverse transcriptase confer resistance to nonnucleoside reverse transcriptase inhibitors.

Genotypic patterns associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in the absence of well-characterized resistance mutations were identified using a database (n > 47,000) of phenotype-genotype data. Among samples with no known NNRTI mutations, the most resistant samples contained K101P (n = 35) or a combination of K103R and V179D (n = 41). Site-directed mutagenesis confirmed the importance of these mutations.

Amino Acid Substitution↗
PubMed2006

Salicylic acid activates sigma factor B by rsbU-dependent and -independent mechanisms.

Salicylic acid (SAL) may impact Staphylococcus aureus virulence by activating the sigB operon (rsbU-V-W-sigB), thus leading to reductions in alpha-toxin production and decreased fibronectin binding (L. I. Kupferwasser et al., J. Clin. Investig. 112:222-233, 2003). As these prior studies were performed in strain RN6390 (an rsbU mutant) and its rsbU-repaired variant, SH1000, the current investigation was designed to determine if the SAL effect occurs via rsbU- and/or rsbV-dependent pathways in an rsbU-intact S. aureus strain (FDA486). We thus quantified the transcription from two sigB-dependent promoters (asp23 and sarA P3) in FDA486 in response to SAL exposure in vitro, using isogenic single-knockout constructs of rsbU, rsbV, or rsbW and a green fluorescent protein reporter system. SAL induced sarA P3 and asp23 promoter activities in a dose-dependent manner in the parental strain. In contrast, sigB activation by SAL was progressively more mitigated in the rsbU and rsbV mutants. As predicted, SAL caused significant reductions in both alpha-toxin production and fibrinogen and fibronectin binding in the parental strain. The extent of these reductions, compared with the parent, was reduced in the rsb mutants (rsbV > rsbU), especially at low SAL concentrations. Since generation of the free SigB protein usually requires a sequential rsbU-V-W-sigB activation cascade, the present phenotypic and genotypic data suggest key roles for both rsbU and rsbV in SAL-mediated activation of sigB in strains with a fully intact sigB operon.

Bacterial Proteins↗
PubMed1993

Epidemiological analysis of Candida albicans strains by multilocus enzyme electrophoresis.

Genotypic diversity in a collection of 98 isolates of Candida albicans was assessed by multilocus enzyme electrophoresis. Four of the 10 enzyme loci studied were polymorphic. The electrophoretic patterns observed were compatible with those expected for a diploid organism. The 98 isolates were assigned to 14 electrophoretic types, each of which was represented by from 1 to 21 isolates. Samples from various clinical sites of seven bone marrow transplant patients treated in the same unit within a 13-month period were obtained repeatedly. Three patients were found to be colonized with more than one strain. In one patient, flucytosine-resistant strains were isolated after systemic antifungal treatment was started. These isolates had electrophoretic types different from those of the strains that colonized the patient before treatment. There was no evidence that cross-infection between these patients occurred in the hospital. The population structure of C. albicans is discussed in regard to the multilocus genotype data.

Antifungal Agents↗
PubMed1996

Clinical isolates of Histoplasma capsulatum from Indianapolis, Indiana, have a recombining population structure.

A sample of 30 clinical isolates of Histoplasma capsulatum was analyzed to determine (i) whether genetic exchange is important in the life cycle of this fungus and (ii) whether distinct subpopulations which correlate with disease severity or host immune status exist. Eleven biallelic molecular markers were developed, with the frequency of the least common allele at each molecular locus ranging from 10 to 50%. Every isolate had a different, unique multilocus genotype. Data analysis indicated that frequent recombination occurs within the Indianapolis, Ind., population. There were no associations between isolates from the immunocompromised population or from those with different clinical manifestations of histoplasmosis.

Genes, Fungal↗
PubMed2004

Clonal expansion of a globally disseminated lineage of Mycobacterium tuberculosis with low IS6110 copy numbers.

Knowledge of the clonal expansion of Mycobacterium tuberculosis and accurate identification of predominant evolutionary lineages in this species remain limited, especially with regard to low-IS6110-copy-number strains. In this study, 170 M. tuberculosis isolates with </=6 IS6110 insertions identified in Cape Town, South Africa, were characterized by principal genetic grouping, restriction fragment length polymorphism analysis, spoligotyping, IS6110 insertion site mapping, and variable-number tandem repeat (VNTR) typing. These analyses indicated that all but one of the isolates analyzed were members of principal genetic group 2 and of the same low-IS6110-copy-number lineage. The remaining isolate was a member of principal genetic group 1 and a different low-IS6110-copy-number lineage. Phylogenetic reconstruction suggests clonal expansion through sequential acquisition of additional IS6110 copies, expansion and contraction of VNTR sequences, and the deletion of specific direct-variable-repeat sequences. Furthermore, comparison of the genotypic data of 91 representative low-IS6110-copy-number isolates from Cape Town, other southern African regions, Europe, and the United States suggests that certain low-IS6110-copy-number strain spoligotypes and IS6110 fingerprints were acquired in the distant past. These clones have subsequently become widely disseminated and now play an important role in the global tuberculosis epidemic.

DNA Transposable Elements↗
PubMed2005

Use of rapid genomic deletion typing to monitor a tuberculosis outbreak within an urban homeless population.

Beginning in mid-2002, a large tuberculosis outbreak occurred among homeless persons in King County, Washington. In order to further monitor the outbreak following its peak in 2003, Mycobacterium tuberculosis isolates from all new King County tuberculosis (TB) patients in 2004 and the first half of 2005 (n = 220) were genotyped by using a rapid comparative genomics-based (genomic deletion-typing) approach, with confirmation by mycobacterial interspersed repetitive units and repetitive-sequence-based PCR (rep-PCR). Results were compared to retrospective genotypic data from 1995 to 2003. The outbreak strain SBRI9, which was not seen among King County homeless persons prior to 2002, accounted for 16 out of 30 TB cases (53%) within this population in 2002. This trend continued with 27 out of 35 cases (77%) caused by the outbreak strain in 2003, 11 out of 13 cases (85%) caused by the outbreak strain in 2004, and 4 out of 10 cases (40%) caused by the outbreak strain in the first 5 months of 2005. Thus, the outbreak strain remained well established within this homeless population throughout the study period. At least four SBRI9 cases were in people who had previously been infected by other strains. The novel PCR-based strain-typing approach used in this investigation proved to be cost-effective and very rapid. In most cases, it was possible to analyze DNA extracted directly from primary isolation (Mycobacterium growth indicator tube) cultures submitted by clinical laboratories, a feature that markedly reduced the delay between diagnosis and strain typing results. This rapid turnaround facilitated public health efforts to prevent new outbreaks involving this strain.

Bacterial Typing Techniques↗
PubMed2005

Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the DFNB53 locus.

BACKGROUND: Allele variants of COL11A2, encoding collagen type XI alpha2, cause autosomal dominant non-syndromic hearing loss (ARNSHL) at the DFNA13 locus (MIM 601868) and various syndromes that include a deafness phenotype. OBJECTIVE: To describe a genome-wide scan carried out on a consanguineous Iranian family segregating ARNSHL. RESULTS: Genotyping data identified a novel locus for ARNSHL on chromosome 6p21.3, which was designated DFNB53. Homozygosity for the P621T mutation of COL11A2 was present in all deaf persons in this family; this same variation was absent in 269 Iranian controls. Sequence comparison of collagen type XI alpha1 and alpha2 peptides across species shows that the replaced proline is an evolutionarily conserved amino acid. CONCLUSIONS: The P621T mutation of COL11A2 affects the Y position of the canonical -Gly-X-Y- repeat in collagens. It lies near the amino-terminus of the triple helical region and causes ARNSHL. This finding suggests that mutation type and location are critical determinants in defining the phenotype of COL11A2 associated diseases.

Amino Acid Sequence↗
PubMed1994

Molecular evidence for non-penetrance in Best's disease.

The present study provides evidence for a possible case of non-penetrance in Best's disease. We have analysed the at risk members of a three generation family with an established history of Best's disease by ophthalmoscopic examination, electrophysiological tests, and genetic analysis. The clinical examination identified 10 affected and five unaffected persons in this family. Genetic linkage analysis strongly supports linkage of the disease locus to DNA microsatellite markers from proximal 11q. The genotyping data were used to construct the familial haplotype associated with Best's disease. One person was identified who has inherited the Best's disease haplotype from his affected mother. Fundus examination and electrophysiological tests have repeatedly been performed in this patient but failed to show any signs of the disease. Based on these findings we have jointly estimated the most likely order of the Best's disease locus relative to the closet flanking markers at various penetrance values. A maximum likelihood estimate for the heterozygote penetrance was reached for the locus order D11S903-Best's disease-PYGM at a penetrance value of 0.96.

Adult↗
PubMed2004

No association between interferon-gamma receptor-1 gene polymorphism and pulmonary tuberculosis in a Gambian population sample.

BACKGROUND: Tuberculosis (TB) is a major global cause of mortality and morbidity, and host genetic factors influence disease susceptibility. Interferon-gamma mediates immunity to mycobacteria and rare mutations in the interferon-gamma receptor-1 gene (IFNGR1) result in increased susceptibility to mycobacterial infection, including TB, in affected families. The role of genetic variation in IFNGR1 in susceptibility to common mycobacterial diseases such as pulmonary TB in outbred populations has not previously been investigated. METHODS: The association between IFNGR1 and susceptibility to pulmonary TB was investigated in a Gambian adult population sample using a case-control study design. The coding and promoter regions of IFNGR1 were sequenced in 32 patients with pulmonary TB, and the frequencies of six common IFNGR1 polymorphisms were determined using PCR based methods in 320 smear positive TB cases and 320 matched controls. Haplotypes were estimated from the genotype data using the expectation-maximisation algorithm. RESULTS: There was no association between the IFNGR1 variants studied and TB in this Gambian population sample. Three common haplotypes were identified within the study population, none of which was associated with TB. CONCLUSIONS: These data represent an important negative finding and suggest that, while IFNGR1 is implicated in rare Mendelian susceptibility to mycobacterial disease, the common variants studied here do not have a major influence on susceptibility to pulmonary TB in The Gambian population.

Cohort Studies↗
PubMed2006

Analysis of QTLs for yield components, agronomic traits, and disease resistance in an advanced backcross population of spring barley.

Hordeum vulgare subsp. spontaneum, the wild progenitor of barley, is a potential source of useful genetic variation for barley breeding programs. The objective of this study was to map quantitative trait loci (QTLs) in an advanced backcross population of barley. A total of 207 BC3 lines were developed using the 2-rowed German spring cultivar Hordeum vulgare subsp. vulgare 'Brenda' as a recurrent parent and the H. vulgare subsp. spontaneum accession HS584 as a donor parent. The lines were genotyped by 108 simple-sequence repeat (SSR) markers and evaluated in field tests for the measurement of grain yield and its components, such as ear length, spikelet number per spike, grain number per spike, spike number, and 1000-grain mass, as well as heading date and plant height. A total of 100 QTLs were detected. Ten QTLs with increasing effects were found for ear length, spikelet number, and grain number per spike. Three QTLs contributed by HS584 were found to significantly decrease days to heading across all years at 2 locations. In addition, 2 QTLs from HS584 on chromosomes 2H and 3H were associated with resistance to leaf rust. Based on genotypic data obtained from this population, 55 introgression lines carrying 1 or 2 donor segments were selected to develop a set of doubled-haploid lines, which will be used to reconfirm and investigate the effects of 100 QTLs for future genetic studies.

Chromosome Segregation↗
PubMed1989

Linkage maps of human chromosomes.

Finding the chromosomal location of human genes that heretofore have been defined solely by phenotypes, in particular clinical phenotypes that are transmitted in Mendelian fashion in families, is an early and often crucial step in the process of identifying the molecular basis of a disease. Recent progress in construction of chromosomal maps of genetically linked DNA markers has made almost the entire human genome accessible to linkage studies in families that are segregating genetic defects. Construction of linkage maps requires a panel of three-generation families for genotyping, a large number of polymorphic markers, and sophisticated computer programs for analysis of genotypic data. After a locus harboring a deleterious mutation has been identified by linkage to a mapped marker, a high-resolution map of the region can be constructed with new markers derived from cosmid libraries, to narrow the search for the gene in question. For example, this strategy has been pursued in the effort to characterize the gene responsible for familial adenomatous polyposis. When a target region has been narrowed to about 1 centiMorgan, corresponding to roughly a million base pairs in physical distance, other techniques of molecular biology can be brought to bear to isolate and clone the actual gene.

Chromosome Mapping↗
PubMed2005

Molecular features of adult glioma associated with patient race/ethnicity, age, and a polymorphism in O6-methylguanine-DNA-methyltransferase.

BACKGROUND: Risk factors for adult glioma in the San Francisco Bay Area include well-known demographic features such as age and race/ethnicity, and our previous studies indicated that these characteristics are associated with the TP53 mutation status of patients' tumors. We enlarged our study to assess the relationships of risk factors with TP53 as well as epidermal growth factor receptor (EGFR) and murine double minute-2 (MDM2) gene amplification and expression and the germ line Leu84Phe polymorphism in the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT). MGMT expression may depend on the TP53 status of cells. METHODS: Molecular analyses were carried out on 556 incident astrocytic tumors. MGMT genotype data were collected on germ line DNA from 260 of these cases. RESULTS: The tumor data confirm the inverse relationships between TP53 mutation and MDM2 (P = 0.04) or EGFR (P = 0.004) amplification and that patients whose tumors contain TP53 mutations are younger than those without (P < 0.001). Although there was little difference in age of patient by EGFR amplification or expression among glioblastoma multiforme cases, EGFR gene amplification was associated with much older age of onset of anaplastic astrocytoma; for example, EGFR-amplified anaplastic astrocytoma cases were on average 63 years old compared with 48 years for nonamplified cases (P = 0.005). An increased prevalence of TP53 mutation positive glioblastoma multiforme was noted among nonwhites (African American and Asian) compared with whites (Latino and non-Latino; P = 0.004). Carriers of the MGMT variant 84Phe allele were significantly less likely to have tumors with TP53 overexpression (odds ratio, 0.30; 95% confidence interval, 0.13-0.71) and somewhat less likely to have tumors with any TP53 mutation (odds ratio, 0.47; 95% confidence interval, 0.13-1.69) after adjusting for age, gender, and ethnicity. Interestingly, EGFR gene amplification and EGFR protein overexpression were also inversely associated with the MGMT 84Phe allele. CONCLUSIONS: Our results are consistent with ethnic variation in glioma pathogenesis. The data on MGMT show that an inherited factor involving the repair of methylation and other alkylation damage, specifically to the O6 position of guanine, may be associated with the development of tumors that proceed in their development without TP53 mutations or accumulation of TP53 protein and possibly also those that do not involve amplification of the EGFR locus.

Astrocytoma↗
PubMedDate not supplied

Haplotyping in pedigrees via a genetic algorithm.

Genome-wide screening for localization of disease genes necessitates the efficient reconstruction of haplotypes of members of a pedigree from genotype data at multiple loci. We propose a genetic algorithmic approach to haplotyping and show that it works fast, efficiently and reliably. This algorithm uses certain principles of biological evolution to find optimal solutions to complex problems. The optimality criterion used in the present problem is the minimum number of recombinations over possible haplotype configurations of members of a pedigree. The proposed algorithm is much less demanding in terms of data and assumption requirements compared to the currently used likelihood-based methods of haplotype reconstruction. It also provides multiple optimal haplotype configurations of a pedigree, if such multiple optima exist.

Algorithms↗
PubMed2000

Molecular genetics of cancer susceptibility.

Studies on the role of genetically polymorphic enzymes like cytochrome P450 1A1, arylamine N-acetyltransferase 2 or glutathione S-transferase M1 as cancer susceptibility factors date back more than 20 years, and some associations have been confirmed in several studies and meta-analyses. Overall, the extent of risk modulation due to these polymorphisms is only moderate but remains epidemiologically relevant. The role of some of these polymorphisms in human health may even be ambiguous: rapid acetylation, for example, protects from urinary bladder cancer but appears to increase the risk of laryngeal, lung and colon cancer. The first genetic polymorphisms in xenobiotics transporters such as P-gp (MDR1) and MRP2 have recently been identified. These polymorphisms may have great impact as cancer susceptibility factors as well as factors modulating the outcome of cancer treatment. Enzymes involved in generation or detoxification of reactive oxygen species also have to be considered; one of these enzymes, myeloperoxidase, constitutes a relatively strong lung cancer risk factor, as confirmed in 4 independent studies. Other genes, including those coding for DNA repair enzymes, signal transduction and cell growth regulation, may ultimately prove more important than the metabolic enzymes as cancer susceptibility factors. Study designs in molecular genetic epidemiology are evolving; large ongoing prospective trials increasingly allow confirmatory nested case control studies to be performed. However, carefully controlled, large case-control studies will remain the mainstay in molecular genetic epidemiology. Molecular genetic epidemiological evaluation of response to chemoprevention as well as response to the adverse events of cancer chemotherapy are likely to provide results that may be useful for individualized prevention and treatment in the near future. Since routine genotyping of all persons is now feasible, something like a genotype passport may soon become reality, and molecular and clinical epidemiological studies will have to provide the basis for understanding how to use genotype data for the benefit of the population.

Animals↗
PubMed2001

Statistical considerations for genome-wide scans: design and application of a novel software package POLYMORPHISM.

OBJECTIVE: Given the cost and complexity of genome-wide scans, optimization of study design is of critical importance. Available algorithms only partially satisfy this need. We designed a software package called 'POLYMORPHISM' to meet these needs. METHODS: The program is designed to calculate linkage parameters for both 'single-point' and 'two-point' settings that are applicable also to incompletely informative microsatellite markers. In single-point analysis, the heterozygosity, polymorphism information content (PIC) and linkage information content (LIC) statistics based on marker allele frequencies are provided. In two-point analysis, joint PIC values for two markers, the conditional probability of detecting linkage phase, the frequency of double heterozygotes and the expected number of informative meioses are calculated. RESULTS: Results were obtained using S.A.G.E./DESPAIR (Design of Linkage Studies Based on Pairs of Relatives) in addition to applying this program to a Centre d'Etude du Polymorphisme pedigree-derived genotyping data set, which estimated critical parameters used in a two-stage genome scan. A single nucleotide polymorphism (SNP)-based one-stage genomic screen strategy is also considered. CONCLUSIONS: LIC values are crucial for getting accurate estimates on those parameters that are important for a two-stage genome screening study. Optimization of the cost-effectiveness of an SNP-based genomic screen strategy is possible by modeling a balance between marker information content and marker density.

Alleles↗
PubMed2003

Bayesian spatial modeling of haplotype associations.

We review methods for relating the risk of disease to a collection of single nucleotide polymorphisms (SNPs) within a small region. Association studies using case-control designs with unrelated individuals could be used either to test for a direct effect of a candidate gene and characterize the responsible variant(s), or to fine map an unknown gene by exploiting the pattern of linkage disequilibrium (LD). We consider a flexible class of logistic penetrance models based on haplotypes and compare them with an alternative formulation based on unphased multilocus genotypes. The likelihood for haplotype-based models requires summation over all possible haplotype assignments consistent with the observed genotype data, and can be fitted using either Expectation-Maximization (E-M) or Markov chain Monte Carlo (MCMC) methods. Subtleties involving ascertainment correction for case-control studies are discussed. There has been great interest in methods for LD mapping based on the coalescent or ancestral recombination graphs as well as methods based on haplotype sharing, both of which we review briefly. Because of their computational complexity, we propose some alternative empirical modeling approaches using techniques borrowed from the Bayesian spatial statistics literature. Here, space is interpreted in terms of a distance metric describing the similarity of any pair of haplotypes to each other, and hence their presumed common ancestry. Specifically, we discuss the conditional autoregressive model and two spatial clustering models: Potts and Voronoi. We conclude with a discussion of the implications of these methods for modeling cryptic relatedness, haplotype blocks, and haplotype tagging SNPs, and suggest a Bayesian framework for the HapMap project.

Algorithms↗
PubMed2004

An integrative genomics approach to the reconstruction of gene networks in segregating populations.

The reconstruction of genetic networks in mammalian systems is one of the primary goals in biological research, especially as such reconstructions relate to elucidating not only common, polygenic human diseases, but living systems more generally. Here we propose a novel gene network reconstruction algorithm, derived from classic Bayesian network methods, that utilizes naturally occurring genetic variations as a source of perturbations to elucidate the network. This algorithm incorporates relative transcript abundance and genotypic data from segregating populations by employing a generalized scoring function of maximum likelihood commonly used in Bayesian network reconstruction problems. The utility of this novel algorithm is demonstrated via application to liver gene expression data from a segregating mouse population. We demonstrate that the network derived from these data using our novel network reconstruction algorithm is able to capture causal associations between genes that result in increased predictive power, compared to more classically reconstructed networks derived from the same data.

11-beta-Hydroxysteroid Dehydrogenases↗