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Prediction of Deleterious Non-synonymous Single-Nucleotide Polymorphisms of H... Related Articles
Prediction of Deleterious Non-synonymous Single-Nucleotide Polymorphisms of Human Uridine Diphosphate Glucuronosyltransferase Genes.
AAPS J. 2009 Jul 2;
Authors: Di YM, Chan E, Wei MQ, Liu JP, Zhou SF
UDP glucuronosyltransferases (UGTs) are an important class of Phase II enzymes involved in the metabolism and detoxification of numerous xenobiotics including therapeutic drugs and endogenous compounds (e.g. bilirubin). To date, there are 21 human UGT genes identified, and most of them contain single-nucleotide polymorphisms (SNPs). Non-synonymous SNPs (nsSNPs) of the human UGT genes may cause absent or reduced enzyme activity and polymorphisms of UGT have been found to be closely related to altered drug clearance and/or drug response, hyperbilirubinemia, Gilbert's syndrome, and Crigler-Najjar syndrome. However, it is unlikely to study the functional impact of all identified nsSNPs in humans using laboratory approach due to its giant number. We have investigated the potential for bioinformatics approach for the prediction of phenotype based on known nsSNPs. We have identified a total of 248 nsSNPs from human UGT genes. The two algorithms tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), were used to predict the impact of these nsSNPs on protein function. SIFT classified 35.5% of the UGT nsSNPs as "deleterious"; while PolyPhen identified 46.0% of the UGT nsSNPs as "potentially damaging" and "damaging". The results from the two algorithms were highly associated. Among 63 functionally characterized nsSNPs in the UGTs, 24 showed altered enzyme expression/activities and 45 were associated with disease susceptibility. SIFT and Polyphen had a correct prediction rate of 57.1% and 66.7%, respectively. These findings demonstrate the potential use of bioinformatics techniques to predict genotype-phenotype relationships which may constitute the basis for future functional studies.
PMID: 19572200 [PubMed - as supplied by publisher]
k-link EST Clustering: evaluating error introduced by chimeric sequences under different degrees of linkage.
Bioinformatics. 2009 Jul 1;
Authors: Bragg LM, Stone G
MOTIVATION: The clustering of expressed sequence tags (ESTs) is a crucial step in many sequence analysis studies that require a high level of redundancy. Chimeric sequences, while uncommon, can make achieving the optimal EST clustering a challenge. Single-linkage algorithms are particularly vulnerable to the effects of chimeras. To avoid chimerafacilitated erroneous merges, researchers using single-linkage algorithms are forced to use stringent sequence-similarity thresholds. Such thresholds reduce the sensitivity of the clustering algorithm. RESULTS: We introduce the concept of k-link clustering for EST data. We evaluate how clustering error rates vary over a range of linkage thresholds. Using k-link, we show that type II error decreases in response to increasing the number of shared ESTs (ie. links) required. We observe a base level of type II error likely caused by the presence of unmasked low-complexity or repetitive sequence.We find that Type I error increases gradually with increased linkage. To minimise the type I error introduced by increased linkage requirements, we propose an extension to k-link which modifies the required number of links with respect to the size of clusters being compared. AVAILABILITY: The implementation of k-link is available under the terms of the GPL from http://www.bioinformatics.csiro.au/products.shtml CONTACT: lauren.bragg@csiro.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
PMID: 19570806 [PubMed - as supplied by publisher]
Genome-wide maps of mono- and di-nucleosomes of Aspergillus fumigatus.
Bioinformatics. 2009 Jul 1;
Authors: Nishida H, Motoyama T, Yamamoto S, Aburatani H, Osada H
We identified 6 499 428 mono- and 7 545 410 di-nucleosome positions of the fungus Aspergillus fumigatus, which was detected at high resolution based on the DNA sequence data obtained from both mono- and dinucleosomal DNA fragments. We show that the distribution of lengths of the mononucleosomal DNA fragments has two peaks at 134 nt and 149 nt, whereas the distribution of di-nucleosomal DNA fragment lengths has a single peak at 285 nt. Although the gene bodies of the active and inactive genes and the inactive gene promoters had the two peaks of the mono-nucleosomal DNA fragment lengths, the active gene promoter lost the longer peak at 149-nt. Our findings strongly suggest that the nucleosomes protecting longer DNA fragments against MNase at the promoters, thereby inhibiting high gene expression. CONTACT: hnishida@iu.a.u-tokyo.ac.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
PMID: 19570804 [PubMed - as supplied by publisher]
[Study of the metastasis-associated genes and its copy numbers variation in highly metastatic epithelial ovarian cancer.]
Zhonghua Fu Chan Ke Za Zhi. 2009 Feb;44(2):126-30
Authors: Ying LS, Xu SH, Su D, Mou HZ, Gu LH, Zhu CH, Liu XL
OBJECTIVE: To investigate the relationship of the metastasis-associated genes and its copy numbers variation in the highly metastatic human epithelial ovarian cancer cell line HO-8910PM. METHODS: The differentially expressed genes and its copy number variation between HO-8910PM cell line and normal ovarian tissues was detected by human genome U133A 2.0 gene chip and human mapping 10K array 2.0 gene chip, and the data was analyzed by bioinformatics. Some of metastasis-associated genes were validated the results of single nucleotide polymorphism (SNP) and cDNA chips by fluorescence in situ hybridization (FISH) and real-time quantitative PCR. RESULTS: Integrate analysis of two gene chips data showed that there were 385 differentially expressed genes in the same and 379 SNP positional point (6 of them, included 2 genes) between HO-8910PM cell line and normal ovarian tissues, these copy number amplification of 379 SNP positional point of chromosome were >/= 3, which had 240, deletion </= 1 had 139. Chromosome location analysis showed that there were 385 differentially expressed genes located at all chromosomes, and 261 of them (67.8%, 261/385) located at 10 chromosomes, included that 34 (8.8%), 33 (8.6%), 28 (7.3%), 27 (7.0%), 25 (6.5%), 24 (6.2%) of them located at chromosome 3, 2, 9, 10, 1 and 11 respectively, and 23 (6.0%) of them at chromosome 6 and 12 each, 22 (5.7%) of them at chromosome 4 and 5 each. For the function of differentially expressed genes, the results showed that 99 (25.7%) genes belonged to the family of enzymes and their regulators, 54 (14.0%) genes associated with signal transduction, 50 (13.0%) genes associated with nucleic acid binding, and 36 (9.4%) genes associated with protein binding. CONCLUSION: We have demonstrated that there are 4 kinds of differentially expressed genes related to metastasis of ovarian cancer, which belonged to the families enzyme and its regulator, nucleic acid binding, signal transduction and protein binding, and located at chromosome 1, 2, 3, 4, 5, 6, 9, 10, 11 and 12.
PMID: 19570424 [PubMed - in process]
Construction and analysis of cotton (Gossypium arboreum L.) drought-related cDNA library.
BMC Res Notes. 2009 Jul 2;2(1):120
Authors: Zhang L, Li FG, Liu CL, Zhang CJ, Zhang XY
ABSTRACT: BACKGROUND: Drought is one of the most important environmental factors causing water stress for cotton, and it greatly limits cotton growth and crop productivity. So far only a few drought-tolerance genes have been functionally characterized in details, and most efforts on this topic have been made in model organisms. Therefore, to identify more drought-related genes in cotton plays a crucial role in elucidating the underlying mechanisms of drought tolerance as well as utilizing bioengineering techniques to improve the tolerance in this organism. FINDINGS: Here we constructed a subtractive drought-tolerance cDNA library using suppressive subtractive hybridization (SSH). Through differential screening and bioinformatics analysis, we identified 392 positive clones with differential expression, corresponding 265 unique genes. By BLAST search against Genbank, we found that more than half of these EST sequences were homologous to those previously known drought-related genes and that there were 57 sequences with unknown functions, suggesting that many more genes are involved in this complex trait. Moreover, using RT-PCR, we examined the expression of nine representative candidate genes and confirmed that their expression levels were increased at different levels under drought stress. CONCLUSIONS: Our results show that drought tolerance is a complex trait in cotton, which involves the coordination of many genes and multiple metabolism pathways. The candidate EST sequences we identified here would facilitate further functional studies of drought-related genes and provide important insights into the molecular mechanisms of drought-stress tolerance and genetic breeding in cotton.
PMID: 19570239 [PubMed - as supplied by publisher]
Integration of Bayesian molecular clock methods and fossil-based soft bounds reveals early Cenozoic origin of African lacertid lizards.
BMC Evol Biol. 2009 Jul 1;9(1):151
Authors: Hipsley CA, Himmelmann L, Metzler D, Mueller J
ABSTRACT: BACKGROUND: Although current molecular clock methods offer greater flexibility in modelling historical evolutionary events, calibration of the clock with dates from the fossil record is still problematic for many groups. Here we implement several new approaches in molecular dating to estimate evolutionary ages of Lacertidae, an Old World family of lizards with a poor fossil record and uncertain phylogeny. Four different models of rate variation are tested in a new program for Bayesian phylogenetic analysis called TreeTime, based on a combination of mitochondrial and nuclear gene sequences. We incorporate paleontological uncertainty into divergence estimates by expressing multiple calibration dates as a range of probabilistic distributions. We also test the reliability of our proposed calibrations by exploring effects of individual priors on posterior estimates. RESULTS: According to the most reliable model, as indicated by Bayes factor comparison, modern lacertids arose shortly after the K/T transition and entered Africa about 45 million years ago, with the majority of their African radiation occurring in the Eocene and Oligocene. Our findings indicate much earlier origins for these clades than previously reported, and we discuss our results in light of paleogeographic trends during the Cenozoic. CONCLUSIONS: This study represents the first attempt to estimate evolutionary ages of a specific group of reptiles exhibiting uncertain phylogenetic relationships, molecular rate variation and a poor fossil record. Our results emphasize the sensitivity of molecular divergence dates to fossil calibrations, and support the use of combined molecular data sets and multiple, well-spaced dates from the fossil record as minimum node constraints. The bioinformatics program used here, TreeTime, is publicly available, and we recommend its use for molecular dating of taxa faced with similar challenges.
PMID: 19570207 [PubMed - as supplied by publisher]
Comprehensive identification of essential Staphylococcus aureus genes using Transposon-Mediated Differential Hybridisation (TMDH).
BMC Genomics. 2009 Jul 1;10(1):291
Authors: Chaudhuri RR, Allen AG, Owen PJ, Shalom G, Stone K, Harrison M, Burgis TA, Lockyer M, Garcia-Lara J, Foster SJ, Pleasance SJ, Peters SE, Maskell DJ, Charles IG
ABSTRACT: BACKGROUND: In recent years there has been an increasing problem with Staphylococcus aureus strains that are resistant to treatment with existing antibiotics. An important starting point for the development of new antimicrobial drugs is the identification of "essential" genes that are important for bacterial survival and growth. RESULTS: We have developed a robust microarray and PCR-based method, Transposon-Mediated Differential Hybridisation (TMDH), that uses novel bioinformatics to identify transposon inserts in genome-wide libraries. Following a microarray-based screen, genes lacking transposon inserts are re-tested using a PCR and sequencing-based approach. We carried out a TMDH analysis of the S. aureus genome using a large random mariner transposon library of around a million mutants, and identified a total of 351 S. aureus genes important for survival and growth in culture. A comparison with the essential gene list experimentally derived for Bacillus subtilis highlighted interesting differences in both pathways and individual genes. CONCLUSIONS: We have determined the first comprehensive list of S. aureus essential genes. This should act as a useful starting point for the identification of potential targets for novel antimicrobial compounds. The TMDH methodolgy we have developed is generic and could be applied to identify essential genes in other bacterial pathogens.
PMID: 19570206 [PubMed - as supplied by publisher]
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