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Genomics in the Journals: Jun 6, 2013

NEW YORK (GenomeWeb News) – In Genome Biology, researchers from the US Department of Agriculture-Agriculture Research Service, Mars, Indiana University, the Hudson Alpha Institute for Biotechnology, IBM, and elsewhere reported on a genome sequencing study of the cacao cultivar Theobroma cacao Matina 1-6, which represents an oft-cultivated Costa Rican cacao type with green pods.

The international team used a combination of Sanger and Roche 454 sequencing strategies to tackle the genome, predicted to be around 445 million base pairs in size. The resulting Matina 1-6 genome assembly — which came in at around 346 million bases — was subsequently compared with to the smaller genome of another sequenced cultivar, called Criolla.

Together with array-based SNP profiles and RNA sequence data for cacao plants from several populations, information gleaned from the Matina genome sequence helped investigators narrow in at least one variant that apparently alters the expression of a transcription factor gene with ties to pod color, a commercially relevant cacao trait.

An international team led by investigators at the University of Florida's pharmacotherapy and translational research department unearthed a new CYP2C gene variant that seems to influence appropriate dosing of the anticoagulant drug warfarin in African-American individuals.

For the discovery stage of their genome-wide association study, published in the Lancet, the researchers brought together data on 533 African-American individuals enrolled through the International Warfarin Pharmacogenetics Consortium or at the University of Alabama at Birmingham.

After accounting for known warfarin-related variants in the VKORC1 and CYP2C9 genes, the study's authors tracked down a new candidate SNP falling upstream of CYP2C18 in the CYP2C gene cluster — an association that they verified through validation testing on another 432 individuals.

Follow-up analysis included in the study suggests African-American individuals with one copy of the newly detected variant should probably get almost 7 milligrams less warfarin than usual each week, while those with two copies of the dose-related SNP may need a 9 milligram reduction in weekly warfarin dose.

"Adding this genetic marker to standard dosing algorithms could improve the predictability of warfarin dosing by 21 percent in [individuals who carry the variant], increasing the safety and effectiveness of this notoriously hard to administer drug," the University of Florida's Julie Johnson, senior author on the study, said in a statement.

Benign uterine tumors called uterine leiomyomas often harbor complex chromosomal rearrangements, a New England Journal of Medicine study suggests. The University of Helsinki's Lauri Aaltonen and colleagues performed whole-genome sequencing and array-based gene expression analyses on 38 uterine leiomyoma samples from 30 women.

Comparisons with profiles of matched normal myometrium tissue samples from each of the women revealed a range of apparent leiomyoma-related variants and expression features, including some genetic profiles shared across clonally related leiomyomas from the same women.

Along with specific rearrangements suspected of sparking leiomyoma development, the team found that, as a group, the benign uterine growths tend to contain complicated chromosomal rearrangements. Moreover, the pattern of these rearrangements hints that they stem from chromothripsis-like events involving several concurrent chromosome breaks and rearrangements.

"Chromosome shattering and reassembly resembling chromothripsis … is a major cause of chromosomal abnormalities in uterine leiomyomas," Aaltonen and company concluded. "[W]e propose that tumorigenesis occurs when tissue-specific tumor-promoting changes are formed through these events."

By adding protein structure data to a genomics-based, systems biology network model, a University of California, San Diego-led team has gained new clues to genome-wide metabolic patterns in Escherichia coli, particularly with respect to protein profiles that influence the bug's growth response to rising temperatures.

As they reported in Science, researchers incorporated experimentally verified and predicted protein structure information into a genome-wide computational model of E. coli metabolism to come up with a structural systems biology-based model dubbed GEM-PRO that represented almost 1,400 genes and their protein products.

The availability of this model subsequently helped them estimate proteins' relative sensitivity to higher-than-usual temperatures — information that's expected to prove useful for homing in on, and perhaps tweaking, temperature-vulnerable portions of E. coli's metabolic network.

"Evidence has accumulated over several decades that proteins are what limit the heat tolerance of cells," first author Roger Chang, a recent PhD graduate of UCSD's bioinformatics and systems biology program, said in a statement, "but pinpointing the weak points represented by specific proteins has never before been accomplished except when researchers have engineered certain proteins to be sensitive to temperature."

"Not only have we predicted some of these weak points in E. coli," added Chang, now a post-doctoral researcher at Harvard Medical School, "but we did so through an unprecedented integrative computational approach drawing from both three-dimensional protein structure analysis and genome-scale cellular network modeling."

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