|1.||Next-generation human genetics.|
ABSTRACT: The field of human genetics is being reshaped by exome and genome sequencing. Several lessons are evident from observing the rapid development of this area over the past 2 years, and these may be instructive with respect to what we should expect from 'next-generation human genetics' in the next few years.
|Genome Biol. 2011 Sep 14;12(9):408. [Epub ahead of print]|
|PMID: 21920048 [PubMed - as supplied by publisher]|
|2.||Next-generation diagnostics for inherited skin disorders.|
|Lai-Cheong JE, McGrath JA.|
|J Invest Dermatol. 2011 Oct;131(10):1971-3. doi: 10.1038/jid.2011.253.|
|PMID: 21918571 [PubMed - in process] Free Article |
AbstractIdentifying genes and mutations in the monogenic inherited skin diseases is a challenging task. Discoveries are cherished but often gene-hunting efforts have gone unrewarded because technology has failed to keep pace with investigators' enthusiasm and clinical resources. But times are changing. The recent arrival of next-generation sequencing has transformed what can now be achieved.
|3.||Whole cancer genome sequencing by next-generation methods.|
|Ross JS, Cronin M.|
AbstractTraditional approaches to sequence analysis are widely used to guide therapy for patients with lung and colorectal cancer and for patients with melanoma, sarcomas (eg, gastrointestinal stromal tumor), and subtypes of leukemia and lymphoma. The next-generation sequencing (NGS) approach holds a number of potential advantages over traditional methods, including the ability to fully sequence large numbers of genes (hundreds to thousands) in a single test and simultaneously detect deletions, insertions, copy number alterations, translocations, and exome-wide base substitutions (including known "hot-spot mutations") in all known cancer-related genes. Adoption of clinical NGS testing will place significant demands on laboratory infrastructure and will require extensive computational expertise and a deep knowledge of cancer medicine and biology to generate truly useful "clinically actionable" reports. It is anticipated that continuing advances in NGS technology will lower the overall cost, speed the turnaround time, increase the breadth of genome sequencing, detect epigenetic markers and other important genomic parameters, and become applicable to smaller and smaller specimens, including circulating tumor cells and circulating free DNA in plasma.
|Am J Clin Pathol. 2011 Oct;136(4):527-39.|
|PMID: 21917674 [PubMed - in process]|
|4.||A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: Targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population.|
|Pelleymounter LL, Moon I, Johnson JA, Laederach A, Halvorsen M, Eckloff B, Abo R, Rossetti S.|
|Mol Genet Metab. 2011 Aug 24. [Epub ahead of print] |
AbstractThe detection of single nucleotide polymorphisms (SNPs) and insertion/deletions (indels) with precision from high-throughput data remains a significant bioinformatics challenge. Accurate detection is necessary before next-generation sequencing can routinely be used in the clinic. In research, scientific advances are inhibited by gaps in data, exemplified by the underrepresented discovery of rare variants, variants in non-coding regions and indels. The continued presence of false positives and false negatives prevents full automation and requires additional manual verification steps. Our methodology presents applications of both pattern recognition and sensitivity analysis to eliminate false positives and aid in the detection of SNP/indel loci and genotypes from high-throughput data. We chose FK506-binding protein 51(FKBP5) (6p21.31) for our clinical target because of its role in modulating pharmacological responses to physiological and synthetic glucocorticoids and because of the complexity of the genomic region. We detected genetic variation across a 160kb region encompassing FKBP5. 613 SNPs and 57 indels, including a 3.3kb deletion were discovered. We validated our method using three independent data sets and, with Sanger sequencing and Affymetrix and Illumina microarrays, achieved 99% concordance. Furthermore we were able to detect 267 novel rare variants and assess linkage disequilibrium. Our results showed both a sensitivity and specificity of 98%, indicating near perfect classification between true and false variants. The process is scalable and amenable to automation, with the downstream filters taking only 1.5h to analyze 96 individuals simultaneously. We provide examples of how our level of precision uncovered the interactions of multiple loci, their predicted influences on mRNA stability, perturbations of the hsp90 binding site, and individual variation in FKBP5 expression. Finally we show how our discovery of rare variants may change current conceptions of evolution at this locus.
|PMID: 21917492 [PubMed - as supplied by publisher]|