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Genomics In The Journals: Dec 27, 2012

NEW YORK (GenomeWeb News) – Direct transmission of Clostridium difficile from one patient to another may be a less common mode of infection than anticipated in some healthcare settings, according to a new Genome Biology study. Researchers from the University of Oxford and elsewhere used genome sequencing to study C. difficile transmission at four British hospitals. By sequencing isolates collected from 486 individuals infected at the centers between 2006 and 2010, the team got genetic clues to relationships between the isolates — information that proved useful for assessing potential transmission events. While some patient-to-patient transmissions were identified, other isolates showing up at a given hospital within a relatively short time frame were too distantly related to have been transmitted directly from one patient to another, hinting at more complicated transmission routes.

"The reduced cost of sequencing whole bacterial genomes means we now have the technology for identifying very recent transmissions of infection," co-corresponding author Xavier Didelot, a statistics researcher with the University of Oxford, said in a statement. "Moreover, we can apply this technology even in cases when infection control teams have no suspicion that routes of contact between patients might exist."

Earlier this month, another UK-led team published a Nature Genetics study that used whole genome sequencing to look at the origins and global spread of epidemic, healthcare-associated C. difficile lineages.

A genome-wide association study meta-analysis in Nature Genetics unearthed 18 new loci linked to blood levels of uric acid, a partly heritable trait that influences individuals' risk of developing gout. Members of the Global Urate Genetics Consortium brought together data for more than 140,000 individuals of European descent, searching for variants associated with either blood urate concentrations or directly with gout, an inflammatory arthritic condition caused by uric acid crystal buildup in tissues and around joints. The team's discovery and validation analyses uncovered 10 loci with known ties to blood urate levels and 18 new blood urate-associated loci. Along with genes involved in urate transport, researchers reported, their subsequent network analyses suggested that gout-related variants tended to fall in genes from glucose metabolism pathways or signaling pathways mediated by inhibins-activins.

"Existing therapies to avoid attacks of gout sometimes cause side effects," the Queen Mary University of London's Mark Caulfield, a co-senior author on the study, said in a statement. "Our findings identify new potential mechanisms for gout and offer opportunities for new therapies which may improve prevention of this debilitating condition in the future."

Previous GWAS helped delineate some of the more common variants associated. And last year, researchers from Decode Genetics and elsewhere described two lower-frequency variants with ties to serum uric acid levels and/or gout, found using an association study that included genotyping data imputed from whole-genome sequence data on hundreds of Icelanders.

Also in Nature Genetics, an international team led by investigators in Belgium profiled mutation patterns in pediatric and adult T-cell acute lymphoblastic leukemias. Using exome sequence information for matched tumor-normal samples from 67 individuals with T-ALL, coupled with targeted testing on another 144 T-ALL samples, the researchers sniffed out seven new suspected driver genes in T-ALL. They also saw some distinct mutational patterns within the T-ALL samples from adults compared to those from children. For instance, adult tumors tended to have more mutations, on average. And nearly 8 percent of the adult T-ALLs tested contained mutations affecting the apparent tumor suppressor-coding gene CNOT3. On the other hand, mutations to the ribosomal protein-coding genes RPL5 and RPL10 were more common in T-ALL samples from children, turning up in almost 10 percent of the pediatric T-ALL cases.

"We have discovered that there is a clear genetic difference between T-ALL in children and in adults," co-corresponding author Jan Cools, a human genetics researcher affiliated with KU Leuven and VIB, Leuven, both in Belgium, said in a statement. "This could be an explanation why adults do not respond as well to the current therapy."

In BMC Genomics this week, Broad Institute researchers presented a guide for investigators who are trying to determine what sequencing depth they need to obtain for their RNA-seq studies. The researchers noted that a main challenge in conducting RNA-seq experiments is determining ahead of time the number of reads needed to detect transcripts within a range of abundance.

To try to tease out what biological knowledge is gained or lost at various sequencing depths, the researchers set out to establish how many reads they would need to fully cover the Escherichia coli transcriptome and how altering the sequencing depth changed their capability to detect transcripts and to compare expression levels between samples.

Though they noted that the depth of coverage a study needs depends on the biological question at hand, the researchers reported that, for most studies, the reads produced by a single Illumina HiSeq lane — typically 150 million paired end read, the researchers noted — is enough.

"Thus, multiplexing 15 [to] 30 samples per lane will yield the 5 [million to] 10 million reads per sample that are sufficient for most applications of bacterial RNA-Seq," the Broad researchers reported. "Indeed, our findings suggest that for studies of differential gene expression, even significantly higher levels of multiplexing result in relatively modest decreases in sensitivity."

Stanford University researchers led by Stephen Quake developed a physical interaction map to try to figure out the function of bacterial proteins, many of which are conserved, that researchers had not been able to annotate, as they reported in the Proceedings of the National Academy of Sciences this week.

They began with a set of 112 conserved proteins in Streptococcus pneumoniae. For those proteins, the researchers first predicted likely functional interaction partners. Then, using a microfluidic high-throughput assay technology, the researchers measured binary protein-protein interactions between the unknown proteins and others. Lastly, the researchers screened the interaction partners determined from the previous steps against the expressed S. pneumoniae proteome. From this, the researchers identified 163 new protein interactions, and were able to determine the function of 50 conserved proteins of unknown function.

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.

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