An estimate of unique DNA sequence heterozygosity in the human genome

Cooper, David Neil; Smith, Barbara A.; Cooke, Howard J.; Niemann, Susanne; Schmidtke, Jörg

doi:10.1007/bf00293024

Cited by 257 publications

(125 citation statements)

References 20 publications

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“…So, too, the response of individual patients to drug therapy is expected to be influenced by genomic variation, for example, because of differences in drug metabolism or the structure or function of drug receptor molecules. The most common type of DNA sequence variation, SNPs, are observed at a frequency of Ϸ1͞500-1,000 nucleotides in humans (31), and large-scale screening for SNPs (32) is now under way to advance efforts to identify disease susceptibility genes or to predict the response of individuals to drug therapies (33). Previous studies have indicated that a prolonged QT interval on a baseline electrocardiogram identifies individuals at increased risk for drug-induced arrhythmia, especially when administered medications that block cardiac potassium channels (9,11).…”

Section: Resultsmentioning

confidence: 99%

A common polymorphism associated with antibiotic-induced cardiac arrhythmia

Sesti

Abbott

Wei

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

439

281

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Drug-induced long QT syndrome (LQTS) is a prevalent disorder of uncertain etiology that predisposes to sudden death. KCNE2 encodes MinK-related peptide 1 (MiRP1), a subunit of the cardiac potassium channel IKr that has been associated previously with inherited LQTS. Here, we examine KCNE2 in 98 patients with drug-induced LQTS, identifying three individuals with sporadic mutations and a patient with sulfamethoxazole-associated LQTS who carried a single-nucleotide polymorphism (SNP) found in Ϸ1.6% of the general population. While mutant channels showed diminished potassium flux at baseline and wild-type drug sensitivity, channels with the SNP were normal at baseline but inhibited by sulfamethoxazole at therapeutic levels that did not affect wild-type channels. We conclude that allelic variants of MiRP1 contribute to a significant fraction of cases of drug-induced LQTS through multiple mechanisms and that common sequence variations that increase the risk of life-threatening drug reactions can be clinically silent before drug exposure.MiRP1 ͉ LQTS ͉ SNP ͉ Bactrim ͉ sulfamethoxazole I nherited long QT syndrome (LQTS) is an uncommon cardiac arrhythmia that predisposes to torsades de pointes (TdP), ventricular fibrillation, and sudden death (1-4). The molecular basis for LQTS is known: delayed repolarization of the myocardium prolongs the cardiac action potential increasing the QT interval measured on the surface electrocardiogram. Mutations in five ion channel genes cause the majority of cases of inherited LQTS. LQTS mutations in SCN5A increase activity of the sodium channel that depolarizes the myocardium to initiate the cardiac action potential (5); LQTS mutations in KCNE1 or KvLQT1 (encoding subunits of I Ks channels) and KCNE2 or HERG (encoding subunits of I Kr channels) diminish potassium fluxes that repolarize the heart to end each beat (6-9).Acquired LQTS is a common disorder caused by drugs and metabolic abnormalities. The risk for acquired LQTS increases when factors that decrease potassium flux act concurrently to impair the ability of the myocardium to repolarize. Wellrecognized conditions that diminish ''repolarization reserve'' include female gender, hypokalemia, and drugs that inhibit cardiac potassium channels (10). Several lines of evidence suggest that patients with drug-induced LQTS have an underlying predisposition to dysrrhythmia. The QT interval measured before drug exposure tends to be longer in patients who later develop drug-induced LQTS than in individuals who receive the same agent safely (11, 12). Moreover, sporadic mutations have been identified in patients with drug-induced TdP (9,13,14). Thus, we demonstrated previously that patients with ''acquired'' LQTS can have a genetic predisposition to arrhythmia because of mutation in the MinK-related peptide 1 (MiRP1) subunit of their I Kr potassium channels (9). In that study, a woman with clarithromycin-induced TdP was found to carry a sporadic missense mutation in KCNE2; channels formed with the altered subunit (Q9E-MiRP1) were abnormal at bas...

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Section: Resultsmentioning

confidence: 99%

A common polymorphism associated with antibiotic-induced cardiac arrhythmia

Sesti

Abbott

Wei

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

439

281

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“…Three kinds of libraries have been used for cloning polymorphic DNA fragments: 1) a genomic library as we used in this report; 2) a genomic library prepared from a specific human chromosome or chromosome fragment, for instance a library from human-mouse hybrid cell DNA (Cavenee et al, 1984) or from DNA of flow sorted metaphase chromosomes (Cooper et al, 1985); 3) and a cDNA library of gene transcripts (Helentjaris and Gesteland, 1983). Using a library prepared from hybrid cell DNA or DNA of flow sorted metaphase chromosomes has the advantage of obtaining fragments from specific chromosomes.…”

Section: Discussionmentioning

confidence: 99%

Isolation of DNA clones revealing restriction fragment length polymorphisms in the human genome

et al. 1986

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SummaryA recombinant human DNA library was constructed using pUC 18 as the cloning vector. Plasmid DNA isolated from a small scale culture was used as the hybridization probe; many recombinant clones could be easily tested for their ability to detect restriction fragment length polymorphisms (RFLPs). Forty-five arbitrary single copy DNA fragments were isolated from this library and five clones revealed RFLPs. Probe OS-5 had three alleles and probe OS-7, which detected insertion/deletion polymorphisms, had several alleles.Apart from these clones, two polymorphic DNA fragments were isolated from the pBR322 plasmid library and another two from the Charon 4A phage library. Although only four restriction enzymes were employed to detect polymorphisms, the efficiency of detecting polymorphisms was reasonable.These nine clones will serve as useful markers for linkage studies.

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“…2,3 Single nucleotide polymorphisms (SNPs) are highly abundant sequence variations present within human populations that are estimated to occur on average one every 1000 base pairs. 34,35 Although the information content of each biallelic SNP marker is less than that of multiallelic microsatellite markers, this information can be rescued by examining moderately larger numbers of SNPs. A genetic map of 1500-3000 biallelic SNPs (with allele frequencies skewed as much as 80:20) should provide greater information content for traditional linkage studies relative to a current set of 300-400 microsatellite marker sets.…”

Section: Gene Mapping and Identificationmentioning

confidence: 99%

Applications of DNA chips for genomic analysis

1998

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A major frontier in medical genetics is the definition of the molecular basis of multifactorial diseases. This is especially relevant in the field of clinical psychiatry where the majority of common disorders display complex inheritance patterns, and are further influenced by environmental interactions. New technologies are needed to help address the pressing needs for discovering and deciphering the nature of such disease-associated genes. One such technology which has emerged within the past 3 years involves hybridization-based nucleic acid array (DNA chip) analysis. This technology has the potential to have a lasting impact on diverse genomic-based applications such as large-scale gene mapping studies, mutational analysis, and global expression level monitoring of all human genes. In this review we will describe the fundamental principles behind nucleic acid array-based assays, while focusing on their applications towards genome-wide DNA and RNA analysis. The current capabilities and limitations of these technologies will be discussed, with a focus on areas where future development will be needed for DNA chip-based assays to achieve their full potential.

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An estimate of unique DNA sequence heterozygosity in the human genome

Cited by 257 publications

References 20 publications

A common polymorphism associated with antibiotic-induced cardiac arrhythmia

A common polymorphism associated with antibiotic-induced cardiac arrhythmia

Isolation of DNA clones revealing restriction fragment length polymorphisms in the human genome

Applications of DNA chips for genomic analysis

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