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Wednesday, 19 September 2012
Tuesday, 18 September 2012
Article series : Nature Reviews Genetics
http://www.nature.com/nrg/series/nextgeneration/index.html
Applications of next-generation sequencing
The power of high–throughput DNA sequencing technologies is being harnessed by researchers to address an increasingly diverse range of biological problems. The scale and efficiency of sequencing that can now be achieved is providing unprecedented progress in areas from the analysis of genomes themselves to how proteins interact with nucleic acids. This series highlights the breadth of next–generation sequencing applications and the importance of the insights that are being gained through these methods.
Monday, 17 September 2012
Localization of association signal from risk and protective variants in sequencing studies.
Front Genet. 2012;3:173. Epub 2012 Sep 6.
Localization of association signal from risk and protective variants in sequencing studies.
Source
Department of Health Sciences Research, Mayo Clinic Rochester, MN, USA.
Abstract
Aggregating information across multiple variants in a gene or region can improve power for rare variant association testing. Power is maximized when the aggregation region contains many causal variants and few neutral variants. In this paper, we present a method for the localization of the association signal in a region using a sliding-window based approach to rare variant association testing in a region. We first introduce a novel method for analysis of rare variants, the Difference in Minor Allele Frequency test (DMAF), which allows combined analysis of common and rare variants, and makes no assumptions about the direction of effects. In whole-region analyses of simulated data with risk and protective variants, DMAF and other methods which pool data across individuals were found to outperform methods which pool data across variants. We then implement a sliding-window version of DMAF, using a step-down permutation approach to control type I error with the testing of multiple windows. In simulations, the sliding-window DMAF improved power to detect a causal sub-region, compared to applying DMAF to the whole region. Sliding-window DMAF was also effective in localizing the causal sub-region. We also applied the DMAF sliding-window approach to test for an association between response to the drug gemcitabine and variants in the gene FKBP5 sequenced in 91 lymphoblastoid cell lines derived from white non-Hispanic individuals. The application of the sliding-window test procedure detected an association in a sub-region spanning an exon and two introns, when rare and common variants were analyzed together.
- PMID:
- 22973297
- [PubMed - in process]
Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants.
N Engl J Med. 2012 Sep 12. [Epub ahead of print]
Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants.
Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, Filipink RA, McConnell JS, Angle B, Meschino WS, Nezarati MM, Asamoah A, Jackson KE, Gowans GC, Martin JA, Carmany EP, Stockton DW, Schnur RE, Penney LS, Martin DM, Raskin S, Leppig K, Thiese H, Smith R, Aberg E, Niyazov DM,Escobar LF, El-Khechen D, Johnson KD, Lebel RR, Siefkas K, Ball S, Shur N, McGuire M, Brasington CK, Spence JE, Martin LS, Clericuzio C, Ballif BC, Shaffer LG, Eichler EE.
Source
The authors' affiliations are listed in the Appendix.
Abstract
Background Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. Methods We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. Results Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; ...
- PMID:
- 22970919
- [PubMed - as supplied by publisher]
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Sunday, 16 September 2012
Phylogenetic and functional metagenomic profiling for assessing microbial biodiversity in environmental monitoring.
PLoS One. 2012;7(8):e43630. Epub 2012 Aug 27.
Phylogenetic and functional metagenomic profiling for assessing microbial biodiversity in environmental monitoring.
Source
University of Tartu, Institute of Technology, Tartu, Estonia.
Abstract
Decisions guiding environmental management need to be based on a broad and comprehensive understanding of the biodiversity and functional capability within ecosystems. Microbes are of particular importance since they drive biogeochemical cycles, being both producers and decomposers. Their quick and direct responses to changes in environmental conditions modulate the ecosystem accordingly, thus providing a sensitive readout. Here we have used direct sequencing of total DNA from water samples to compare the microbial communities of two distinct coastal regions exposed to different anthropogenic pressures: the highly polluted Port of Genoa and the protected area of Montecristo Island in the Mediterranean Sea. Analysis of the metagenomes revealed significant differences in both microbial diversity and abundance between the two areas, reflecting their distinct ecological habitats and anthropogenic stress conditions. Our results indicate that the combination of next generation sequencing (NGS) technologies and bioinformatics tools presents a new approach to monitor the diversity and the ecological status of aquatic ecosystems. Integration of metagenomics into environmental monitoring campaigns should enable the impact of the anthropogenic pressure on microbial biodiversity in various ecosystems to be better assessed and also predicted.
- PMID:
- 22952724
- [PubMed - in process]
- PMCID:
- PMC3428334
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[pub]: Extra-binomial variation approach for analysis of pooled DNA sequencing data.
| 1. | Bioinformatics. 2012 Sep 12. [Epub ahead of print]Extra-binomial variation approach for analysis of pooled DNA sequencing data.Yang X, Todd JA, Clayton D, Wallace C.SourceJuvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK. AbstractMOTIVATION:The invention of next generation sequencing technology has made it possible to study the rare variants which are more likely to pinpoint causal disease genes. To make such experiments financially viable, DNA samples from several subjects are often pooled before sequencing. This induces large between-pool variation which, together with other sources of experimental error, creates over-dispersed data. Statistical analysis of pooled sequencing data needs to appropriately model this additional variance to avoid inflating the false positive rate. RESULTS:We propose a new statistical method based on an extra-binomial model to address the over-dispersion and apply it to pooled case control data. We demonstrate that our model provides a better fit to the data than either a standard binomial model or a traditional extra-binomial model proposed by Williams, and can analyse both rare and common variants with lower or more variable pool depths compared to the other methods. AVAILABILITY:Package "extraBinomial" is on http://cran.r-project.org/ CONTACT: |
| PMID: 22976083 [PubMed - as supplied by publisher] | |
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