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DNA Sequence Variants (dna + sequence_variants)
Selected AbstractsHuman alcoholism studies of genes identified through mouse quantitative trait locus analysisADDICTION BIOLOGY, Issue 4 2002Marissa A. Ehringer Coding region DNA sequence variants have been recently identified in several QTL candidate genes in a mouse model of differential sensitivity to alcohol [inbred long-sleep (ILS) and inbred short-sleep (ISS)]. This work has been extended into a human population characterized for their initial level of response to alcohol (LR). The coding region of one of the most promising of these candidate genes, zinc finger 133 (Znf133), has been sequenced completely in 50 individuals who participated in alcohol challenges at approximately age 20 and have been followed subsequently for the last 15 years. PCR products were obtained for the protein coding region of ZNF133 using human genomic DNA and directly sequenced using automated sequencers. Novel single nucleotide polymorphisms (SNPs) were detected by analyzing the sequence data using a suite of bioinformatics programs including Consed, Phred, Phrap and Polyphred. Five human SNPs were detected, two that correspond to amino acid changes in the protein, two that are silent DNA changes and one located in an intron. In this small sample, no significant association between any of the SNPs and alcohol diagnosis was detected. A follow-up of these SNPs in a larger sample should allow a more definitive conclusion to be reached. Significantly, the data presented here demonstrate the feasibility of directly testing genes in human alcoholic populations that had been identified first by comparative DNA sequencing of candidate genes located within mouse alcohol-related QTLs, even without detailed knowledge of the gene's function. [source] Systematic evaluation of the effect of common SNPs on pre-mRNA splicing,HUMAN MUTATION, Issue 4 2009Abdou ElSharawy Abstract The evolutionary and biomedical importance of differential mRNA splicing is well established. Numerous studies have assessed patterns of differential splicing in different genes and correlated these patterns to the genotypes for adjacent single-nucleotide polymorphisms (SNPs). Here, we have chosen a reverse approach and screened dbSNP for common SNPs at either canonical splice sites or exonic splice enhancers (ESEs) that would be classified as putatively splicing-relevant by bioinformatic tools. The 223 candidate SNPs retrieved from dbSNP were experimentally tested using a previously established panel of 92 matching DNAs and cDNAs. For each SNP, 16 cDNAs providing a balanced representation of the genotypes at the respective SNP were investigated by nested RT-PCR and subsequent sequencing. Putative allele-dependent splicing was verified by the cloning of PCR products. The positive predictive value of the bioinformatics tools turned out to be low, ranging from 0% for ESEfinder to 9% (in the case of acceptor-site SNPs) for a recently reported neural network. The results highlight the need for a better understanding of the sequence characteristics of functional splice-sites to improve our ability to predict in silico the splicing relevance of empirically observed DNA sequence variants. Hum Mutat 0, 1,9, 2009. © 2009 Wiley-Liss, Inc. [source] Association of HPV16 E6 variants with diagnostic severity in cervical cytology samples of 354 women in a US populationINTERNATIONAL JOURNAL OF CANCER, Issue 11 2009Rosemary E. Zuna Abstract It has been suggested that DNA sequence variants of HPV16 contribute to differences in the behavior of individual cervical lesions. To address this question, we have analyzed the association of HPV16 variants with diagnostic severity in 354 HPV16-positive Oklahoman women. HPV16 variant status was determined by PCR amplification and DNA sequencing of the E6 open reading frame. European sequences were identified in 86% of samples and 14% were non-European. Of the 51 non-European cases, 61% were Asian-American, 23% African and 16% were Native American variants. European prototype and related variants were present in comparable numbers (43% each) but the relative proportion of each differed with diagnostic category. In general, the proportion of European variants and non-European variants increased with diagnostic severity while the European prototype decreased. When adjusted for age and race (white, black or Hispanic), the increased risk for carcinoma/severe dysplasia for non-European variants was statistically significant with an odds ratio of 3.8 (1.3,10.7). However, the analogous comparison for the European variants, although also showing increased association with carcinoma/severe dysplasia, did not reach statistical significance (OR = 1.6 (95% CI 0.7,3.6). Overall, HPV16 European sequences (both prototype and related variants), were predominant in Oklahoman women including those with cancers. This suggests that while there appear to be differences among the HPV16-variant categories in risk for progression to invasive cancer, all variant categories are associated with the development of invasive cancer. © 2009 UICC [source] Consulting the source code: prospects for gene-based medical diagnosticsJOURNAL OF INTERNAL MEDICINE, Issue S741 2001U. Landegren Abstract. Landegren U (Rudbeck Laboratory, Uppsala, Sweden) Gene-based diagnostics (Internal Medicine in the 21st Century). J Intern Med 2000; 248: 271,276. Gene-based diagnostics has been slow to enter medical routine practice in a grand way, but it is now spurred on by three important developments: the total genetic informational content of humans and most of our pathogens is rapidly becoming available; a very large number of genetic factors of diagnostic value in disease are being identified; and such factors include the identity of genes frequently targeted by mutations in specific diseases, common DNA sequence variants associated with disease or responses to therapy, and copy number alterations at the level of DNA or RNA that are characteristic of specific diseases. Finally, improved methodology for genetic analysis now brings all of these genetic factors within reach in clinical practice. The increasing opportunities for genetic diagnostics may gradually influence views on health and normality, and on the genetic plasticity of human beings, provoking discussions about some of the central attributes of genetics. 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