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Genomics in the Journals: Nov 13, 2014

NEW YORK (GenomeWeb) – In Nature Genetics, an international team described its sequencing-based efforts to find and track global strains of enterotoxigenic Escherichia coli, or ETEC, the culprit in some 400 million infectious diarrhea cases annually.

The researchers characterized hundreds of ETEC isolates collected in 20 countries globally between 1980 and 2011 using whole-genome sequencing, phylogenetics, and other analyses.

With data for more than 1,400 genes in the genomes of 362 newly sequenced ETEC isolates, for instance, they uncovered a set of main ETEC lineages that appear to account for most of the ETEC isolates collected in Asia, Africa, and the Americas over the time period considered.

In general, ETEC bugs are known for producing toxin types with different heat stability or sensitivity profiles and can be classified as having more than two dozen colonization factors with distinct antigenic profiles.

In their new analysis, the researchers determined that both colonization factor profiles and enterotoxin types are intimately linked to ETEC lineage. In particular, they documented a "clear signature of several globally distributed ETEC lineages that show consistent long-term association with a specific O antigen and virulence gene repertoire."

A BMC Biology study suggests microbial contamination of laboratory reagents and DNA extraction kits may skew findings in microbiome studies based on 16S ribosomal RNA gene sequence and/or metagenomic sequence data.

A research group led by investigators with the Wellcome Trust Sanger Institute's pathogen genomics group and a microbiology group at the University of Aberdeen's Rowett Institute of Nutrition and Health began by doing 16S sequencing on samples from a serially diluted culture of Salmonella bongori that started off pure.

Collaborators at three centers in the UK prepared the S. bongori samples for sequencing using different batches of a soil DNA sample preparation kit before sending 16S amplicons back to the Sanger Institute to be sequenced with Illumina's MiSeq instrument.

Although sequences from the starting culture confirmed that it was comprised solely of S. bongori, the team saw significant contamination in the subsequent samples, particularly in samples that had undergone several serial dilutions.

The researchers saw signs of contamination in S. bongori samples sequenced using metagenomics strategies, too. When they performed metagenomic sequencing on S. bongori dilution samples using four different DNA extraction kits in the same lab, they detected distinct contamination patterns that appeared to coincide with each of the sample prep kits.

Based on their findings, the authors of the study went on to share a set of recommendations aimed at mitigating misleading results due to contamination when doing microbiome studies, which included quantification of the negative controls, maximizing the sample material used in an experiment, and so on.

Genetic variability appears to influence the timing with which the DNA in an individual's cells replicates, according to a new Cell study.

Building from DNA replication timing assessments that relied on cell sorting and synchronization, American and Croatian researchers developed an analytical method that harnessed read-depth data from the 1000 Genomes Project to discern replication timing.

Using this approach, they then estimated replication timing in 161 1000 Genomes Project participants, using the individuals' genotyping profiles to perform a genome-wide association study for variants linked to this process.

The search led to 16 replication timing-associated sites in the genome, dubbed replication timing quantitative loci, or rtQTLs. Follow-up experiments, including an analysis of RNA sequence data on 462 1000 Genomes Project samples, suggest that the timing of DNA replication may impact everything from gene expression patterns to mutation rates.

"It's a new form of variation in people no one had expected," first author Amnon Koren, a post-doctoral researcher affiliated with the Broad Institute and Harvard Medical School, said in a statement.

A team from France and Turkey found loss of function mutations in the WDR73 gene when it did autozygosity mapping, whole-exome sequencing, and/or targeted gene sequencing on members of unrelated families with a rare, autosomal recessive condition called Galloway-Mowat syndrome (GMS), which is characterized by kidney problems, brain abnormalities, and neurological impairment.

As they reported in the American Journal of Human Genetics, the researchers began by doing autozygosity mapping and exome sequencing on samples from two children with GMS from the same Moroccan family. The data revealed a shared run of homozygosity on chromosome 15 in both children, which contained a nonsense mutation affecting the poorly characterized WDR73 gene.

Through screening on another 30 unrelated individuals with similar kidney and brain features, the team tracked down another Turkish child with a frameshift mutation in WDR73. On the other hand, that gene was not altered in samples from 26 individuals who had comparable brain and neurological symptoms as those with GMS, but lacked kidney-related symptoms.

In their follow-up experiments, the investigators used immunochemical staining to trace WDR73's localization and expression in various tissue types, demonstrating that it is present in human fetal kidney and infant brain samples. They also saw clues of a microtubule-related role for the gene in ensuring typical development and function of the nervous system and kidney filtering system.