Whole-exome sequencing on the Illumina Genome AnalyzerIIx in conjunction with homozygosity mapping enabled discovery of a causative allele for hearing loss in the DFNB82 region of chromosome 1p13.1. This nonsense mutation leads to early truncation of the G protein signaling modulator GPSM2, an essential protein for maintenance of cell polarity and spindle orientation, suggesting dysregulation of cell polarity as a mechanism underlying hearing loss.
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Walsh T, Shahin H, Elkan-Miller T, Lee MK, Thornton AM, et al.
Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82. Am J Hum Genet
High-throughput transcriptome sequencing (RNA-Seq) on the Genome Analyzer was used to analyze transcripts expressed in the human, chimpanzee, and rhesus macaque brain. Intergenic transcripts show more expression differences among species and exons show less, indicating the existence of yet uncharacterized evolutionarily conserved transcripts in the human brain. These transcripts may play roles in transcriptional regulation and contribute to the evolution of human-specific phenotypic traits.
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Xu AG, He L, Li Z, Xu Y, Li M, et al.
Intergenic and repeat transcription in human, chimpanzee and macaque brains measured by RNA-Seq. PLoS Comput Biol
Paired-end transcriptome sequencing of tumor samples with the Genome Analyzer identified rare, recurrent gene fusion rearrangements in the RAF pathway in 1–2% of advanced prostate cancers, gastric cancers, and melanoma. Sequencing of tumor transcriptions and genomes may lead to the identification of rare targetable fusions across cancer types.
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Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pflueger D, Ramnarayanan K
Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer, and melanoma. Nature Medicine
Scientists developed a metagenomics analysis method that delivers longer read lengths at a fraction of the cost of pyrosequencing. Using a Shortread Error-reducing Aligner (SHERA) software tool, in combination with an automatable gel-less library construction step and paired-end sequencing on the Genome Analyzer, the approach yielded millions of reads exceeding 200bp with quality scores approaching that of traditional Sanger sequencing. The strategy could be broadly applicable to any sequencing applications that require longer read lengths.
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Rodrigue S, Materna AC, Timberlake SC, Blackburn MC, Malmstrom RR
Unlocking short read sequencing for metagenomics. PLoS One
To investigate the role on intragenic methylation in transcription, scientists used the Genome Analyzer to generate a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. DNA methylation appears to regulate intragenic promoter activity in vitro and in vivo. These alternative transcripts are expressed in a tissue- and cell type–specific manner, as well as differentially within a single cell type from distinct brain regions. The results support a major role for intragenic methylation in regulating cell context–specific alternative promoters in gene bodies.
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Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C
Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature
Transcriptional profiling can be used to detect subclinical heart disease, and provide insight into disease etiology and functional status. Scientists used the Genome Analyzer to perform comprehensive analysis of individual cardiac transcriptomes in the Gαq transgenic mouse model, as an alternative to tiling array-based transcriptional profiling. They found RNA sequencing provides a rapid, accurate, and sensitive method for identifying abundant and rare cardiac transcripts.
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Matkovich SJ, Zhang Y, Van Booven DJ, Dorn GW
Deep mRNA sequencing for in vivo functional analysis of cardiac transcriptional regulators: application to Gαq. Circulation Research
Misregulation of neuronal migration can lead to lissencephaly and behavioral and cognitive defects. Using high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP), researchers found that the neuronspecific RNA-binding protein Nova2 regulates an RNA switch that affects a key signaling pathway associated with neuronal migration. These findings suggest new links between splicing regulation, brain disease, and development.
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Yano M, Hayakawa-Yano Y, Mele A, Damell R
Nova2 regulates neuronal migration through an RNA switch in disabled-1 signaling. Neuron
The genomes of 21 strains representative of the global diversity and six major lineages of the M. tuberculosis complex (MTBC) were sequenced on the Genome Analyzer. A genome-wide phylogeny based on these sequences revealed that most of the 491 experimentally confirmed human T cell epitopes showed little sequence variation and had a relatively low ratio of nonsynonymous to synonymous changes, suggesting that MTBC might benefit from recognition by human T cells.
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Comas I, Chakravartti J, Small P, Galagan J, Niemann S, et al.
Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat Genet
Deep sequencing of chromatin-associated RNAs (CARs) from human fibroblast cells identified a number of associated intronic and intergenic regions. The CARs in these regions were found to be highly conserved across 44 placental mammalian species. Functional characterization of one intergenic CAR revealed that it regulates gene expression of neighboring genes by modulating the chromatin structure in cis, suggesting that such ncRNAs may regulate various biological functions through fine-tuning of the chromatin architecture.
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Mondal T, Rasmussen M, Pandey G, Isaksson A, Kanduri C
Characterization of the RNA content of chromatin. Genome Res
The molecular basis of resistance and small colony variants formation were investigated on the Genome Analyzer using S. aureus isolates from a patient who had a persistent and recurrent infection. Two point mutations were identified in key staphylococcal genes that dramatically affected clinical behavior of the bacterium, altering virulence and antimicrobial resistance. These findings show how subtle molecular changes can cause major alterations in bacterial behavior and highlight potential weaknesses of current antibiotic treatment regimens.
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Gao W, Chua K, Davies J, Newton H, Seemann T, et al.
Two novel point mutations in clinical Staphylococcus aureus reduce linezolid susceptibility and switch on the stringent response to promote persistent infections. PLoS Pathog
