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Genomics in the Journals: Arrays 2014.07.17

NEW YORK (GenomeWeb) – In Nature Genetics, a Cincinnati Children's Hospital Medical Center-led team described a tissue-specific genetic association behind a food sensitivity and chronic inflammatory condition called eosinophilic esophagitis.

Through a genome-wide association study involving 736 individuals with eosinophilic esophagitis (enrolled at Cincinnati Children's Hospital and elsewhere) and more than 9,200 unaffected controls, the researchers identified 20 SNPs at 17 loci with apparent ties to eosinophilic esophagitis.

Ten of those genomic sites were associated with eosinophilic esophagitis in an analysis of the Cincinnati Children's Hospital cases alone. That set of loci, which was validated using information on cases and controls from another cohort, included four loci with genome-wide significant associations with the disease.

Among them were loci in and around genes already implicated in eosinophilic esophagitis (such as the chromosome 5 gene TSLP) and a new eosinophilic esophagitis candidate gene on chromosome 2, called CAPN14, that's expressed exclusively in esophageal tissue that seems to show an uptick in expression during active eosinophilic esophagitis disease.

With the help of RNA sequencing and chromatin immunoprecipitation sequencing, the investigators demonstrated that at least some of the CAPN14-associated SNPs fall in regions regulated by an interleukin called IL-13. Their results also point to potential eosinophilic esophagitis associations involving hundreds more SNPs in sequences with enhanced esophageal expression.

In another Nature Genetics study, an international team led by investigators in Italy and the Netherlands used exome sequencing as part of their investigation of Primrose syndrome, a condition marked by exaggerated height and brain growth, intellectual delays, and autism-related behaviors.

The researchers did whole-exome sequencing on DNA isolated from blood samples for four unrelated individuals with Primrose syndrome. For two of the patients, they were able to do exome sequencing on unaffected parents as well.

By sifting through the resulting sequence data searching for de novo mutations that might explain the disease, the team tracked down functionally relevant alterations that were shared between all four cases but not found in the unaffected parental controls. Those missense mutations occurred in a portion of chromosome 3 containing the transcriptional repressor gene ZBTB20.

A closer look at the mutations, combined with cell line experiments, indicated that they contribute to an especially severe version of a known microdeletion syndrome involving chromosome 3, the study's authors explained, perhaps owing to a dominant-negative effect involving the ZBTB20 mutations identified.

A team from the UK, Italy, Norway, and France uncovered a Brucella melitensis strain that appears to have caused disease in a medieval man in Sardinia. As they reported in mBio, the researchers did shotgun metagenomics on a calcified protrusion found on the skeleton of a 50- to 60-year-old man who died in a medieval Sardinian village called Geridu in the 14th century.

By assessing sequences present in the ancient skeletal nodule with those found in matched human samples from the same historical period, the group found evidence that the long-deceased Sardinian may have suffered from brucellosis — a livestock infection that's sometimes passed to humans through unpasteurized dairy products, infected meat, or direct animal contact.

Within the Sardinian sample, investigators identified sequences matching an existing B. melitensis reference genome. After covering that reference to a depth of around 0.7-fold with the original medieval metagenomic sequences, they did further sequencing on the sample to flesh out a draft genome for the 700-year-old strain, ultimately establishing almost 7-fold coverage of the genome.

Using variants detected in the medieval bug, the team performed a phylogenetic analysis that indicated the B. melitensis strain belonged to a group that's most closely related to present-day B. melitensis isolates identified in Italy, indicating the bug may have persisted in that region over several centuries.

"Metagenomics stands ready to document past and present infections, shedding light on the emergence, evolution, and spread of microbial pathogens," Warwick Medical School microbial genomics researcher Mark Pallen, the study's co-senior author, said in a statement. "We're cranking through all of these samples and we're hopeful that we're going to find new things."

A study in BMC Evolutionary Biology suggests that the little known Spotted Green Pigeon, found in Liverpool in the late 1700s, belonged to a species distinct from the Nicobar pigeon, Caloenas nicobarica — a still-living bird species found on the Andaman and Solomon Islands.

Researchers from Australia and the UK did 12S-sequence focused DNA barcoding on feather samples from the last known Spotted Green Pigeon (C. maculata) specimen.

The team's comparisons with sequence data from hundreds of other bird species suggested the Spotted Green Pigeon was genetically distinct from the Nicobar pigeon. Moreover, its phylogenetic analysis pointed to relatively close genetic ties between the long-gone Spotted Green Pigeon and extinct birds from the Dodo and Rodrigues Solitaire sub-family.

Based on these and other results, the study's authors reasoned that the shared ancestor of these birds, the Spotted Green Pigeon, and Nicobar pigeon likely gravitated toward island living, was semi-terrestrial, and capable of flight.

"[T]he unexpected addition of another clade supports the idea of the stepping stone hypothesis [for movement of Dodo and Rodrigues Solitaire ancestors from one island to the next]," they concluded, "and contributes to our understanding of how the Dodo came to be such a remarkable example of distant isolation and subsequent morphological evolution."