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Genomics In The Journals: Sep 1, 2011

NEW YORK (GenomeWeb News) – American and Saudi Arabian researchers detected germline mutations in the BRCA1-associated protein-coding gene BAP1 that appear to predispose individuals to malignant mesothelioma, a cancer that's often associated with asbestos or erionite exposure. They first identified the mutations using array comparative genomic hybridization to test one tumor per family in two American families with high rates of mesothelioma and other cancers, but no known asbestos or erionite contact. During their subsequent linkage and targeted sequencing experiments, the researchers found examples of both germline and somatic BAP1 mutations in affected family members. They also tracked down somatic BAP1 mutations in unrelated individuals with no family history of mesothelioma.

Several individuals with familial or sporadic BAP1 mutations and mesothelioma had also been diagnosed with the eye cancer uveal melanoma, leading authors of the Nature Genetics study to speculate that the BAP1-associated cancer syndrome takes various forms depending on an individual's exposures.

"[W]e demonstrate the existence of a BAP1-related cancer syndrome characterized by mesothelioma, uveal melanoma, and possibly other cancer types," senior author Michele Carbone, a researcher at the University of Hawaii Cancer Center, and co-authors wrote. "We hypothesize that when individuals with BAP1 mutations are exposed to asbestos, mesothelioma predominates. Alternatively, BAP1 mutation alone may be sufficient to cause mesothelioma."

In another Nature Genetics paper, members of the Brassica rapa Genome Sequencing Project Consortium report in that they have sequenced, annotated, and analyzed the draft genome of a Chinese cabbage line known as Chiifu-401-42. The plant belongs to a group that split from the lineage leading to Arabidopsis thaliana some 13 to 17 million years ago and has since experienced genome triplication. Using Illumina GAII paired-end and BAC-end sequence data, the group sequenced and assembled the nearly 284 base pair genome, which contains an estimated 41,174 protein coding genes. Around 1,000 of these genes seem specific to the B. rapa lineage, they reported, while nearly 16,000 overlap with those in A. thaliana, and thousands more are shared with papaya and grape vine plants as well. By looking at gene loss and other patterns in the genome, the team is learning more about oilseed crop biology, the consequences of genome triplication, and plant evolution in general.

In Nature, an international team describes the genome-wide association approach that it used to look for genetic factors influencing metabolite characteristics and concentrations in the blood. The researchers assessed 1,768 individuals enrolled through the KORA F4 study in Germany and 1,052 participants from the British TwinsUK study who were genotyped at around 600,000 SNPs with Affymetrix or Illumina arrays. Using this genetic information — coupled with data on more than 250 metabolites in the individuals' fasting blood serum samples generated with Metabolon's metabolic profiling and analysis platform — the researchers identified 37 loci showing genome-wide significant associations with metabolite patterns.

From their findings so far, the team said these associations may be relevant for understanding past GWAS results on everything from heart disease and type 2 diabetes to cancer, kidney conditions, and Crohn's disease, since several metabolite-associated loci overlap with those found in disease studies.

"The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research," co-senior author Christian Gieger, a genetic epidemiology researcher at the German Research Centre for Environmental Health's Helmholtz Center Munich, and co-authors wrote.

Bacteria have had the genetic wherewithal to resist some antibiotics for 30,000 years or more, according to a Nature study by researchers in Canada and France. The team used Roche 454 GS FLX or Sanger sequencing to do metagenomic analyses on ancient bacterial DNA from permafrost samples collected near Dawson City in Canada's Yukon Territories.

After verifying the age of the samples by amplifying bits of plant and animal sequence, the team did deep 16S rRNA sequencing to identify bacteria in the samples, followed by assays to find sequences representing antibiotic resistance genes. Among them were genes contributing to vancomycin resistance that the team expressed and purified and found to be active in the lab setting. Those involved said the results hint that bacteria adapted to the presence of some antibiotic chemicals in the environment long before the compounds found favor in a therapeutic setting.

"Antibiotics are part of the natural ecology of the planet so when we think that we have developed some drug that won't be susceptible to resistance or some new thing to use in medicine, we are completely kidding ourselves," senior author Gerard Wright, scientific director of McMaster University's Michael G. DeGroote Institute for Infectious Disease Research, said in a statement. "Microorganisms have figured out a way of how to get around them well before we even figured out how to use them."

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

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