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Genomics in the Journals : Feb 7, 2013

NEW YORK (GenomeWeb News) – In PLOS One, researchers from the US and Iceland offered evidence for previously unappreciated ties between copy number variants and lifespan length.

As part of its search for rare variants related to lifespan, the team used SNP arrays to assess CNV patterns in 7,313 pediatric patients believed to be at risk of shorter-than-usual lifespans and in 2,701 individuals from Iceland over the age of 67 years. After testing candidate CNVs from the discovery group in 2,079 American children and 4,692 older controls from the same population, investigators were left with eight deletions and 10 duplications that were over-represented in the pediatric patients. Five of these deletions and three duplications remained statistically significant following the team's additional analyses. Moreover, several of the CNVs found affected genes from alternative splicing pathways, study authors said, hinting that changes to RNA slicing and dicing might be linked to lifespan.

"Our results suggest that CNVs and other genetic variants may exert their effects through gene networks and pathways that regulate biological functions through mechanisms such as alternative splicing," senior author Hakon Hakonarson, a University of Pennsylvania researcher and director of the Children's Hospital of Philadelphia's Center for Applied Genomics, said in a statement.

"Possibly in a more global way than previously thought, some of these CNVs may have favorable effects, whereas others are bad for you and predispose you to diseases," he added.


Studies by two independent research groups have identified relapse-related mutations in the same gene in children with acute lymphoblastic leukemia.

Reporting in Nature Genetics, New York University's William Carroll and colleagues used RNA sequencing to profile samples taken at the time of diagnosis and after relapse for 10 children with the B-lymphoblastic leukemia subtype of ALL. Among the 20 relapse-associated mutations they detected were alterations affecting the 5'-nucleotidase enzyme-coding gene NT5C2. Mutations in the gene appeared in two of the 10 relapse cases tested initially, the researchers reported, and in five of the 61 relapsed pediatric ALL cases subsequently screened by targeted gene sequencing. As a set, the relapse-linked mutations in NT5C2 appeared to boost the activity of the resulting enzyme, they said, prompting resistance to treatments based around nucleoside analogs. If such patterns hold, those involved in the study added, it's possible that NT5C2 mutation status may prove useful for guiding ALL therapy in a clinical setting.

"We plan to test the feasibility of screening patients during therapy using sophisticated sequencing technology to pick up low-level mutations in NT5C2 and other genes indicating that a mutant clone is growing," said Carroll, director of the NYU Langone Medical Center Cancer Institute, in a statement.

Over at Nature Medicine, meanwhile, an international team led by investigators at Columbia University described activating mutations in NT5C2 corresponded with treatment resistance and relapse in both B-cell precursor and T-cell precursor forms of ALL.

For that study, researchers performed whole-exome sequencing on samples taken from five pediatric T-ALL patients at the time of diagnosis, remission, and relapse. Within the set of suspicious mutations found at relapse were changes to NT5C2, which also showed up in other T-ALL and B-ALL samples assessed in the group's follow-up experiments. All told, that team tallied up NT5C2 mutations in 19 percent of relapse T-ALL cases and 3 percent of B-ALL relapses. Again, these mutations seemed to enhance the activity of the resulting nucleotidase enzyme, fueling metabolism of the nucleoside analogs used to treat ALL, authors of that study said.


Researchers from the University of Hawaii, the University of Science, Malaysia, and other centers around the world have reported on efforts to sequence the genome of the rubber tree, Hevea brasiliensis, in BMC Genomics.

The team used a combination of Roche 454, Illumina, and SOLiD sequencing to sequence genomic DNA from a Malaysian rubber tree clone. Using this sequence, the researchers put together a 1.1 billion base draft genome sequence for the plant, which is commonly used as a natural rubber source. That repeat element-rich sequence assembly covers more than half of the rubber tree's total genome, estimated at around 2.15 billion bases in total.

In their analyses so far, investigators have identified 68,955 predicted protein-coding genes, including thousands of genes not found in the genomes of more than a dozen other previously sequenced plants. In addition to the candidate trait genes already found in the genome, authors of the study said the sequence should serve as a resource for finding molecular markers to improve natural rubber production from the plant.

"The knowledge gained from this genome sequence will aid in the future development of high-yielding clones to keep up with the ever-increasing need for natural rubber," they argued.


By folding morphological data into phylogenetic analyses, an international group headed by researchers at Stony Brook University and the American Museum of Natural History has refined the divergence time for the shared ancestor of placental mammals. As they reported in Science, the investigators considered not only genomic clues, but also information on more than 4,500 phenomic traits — described in a database called MorphoBank — for dozens of existing and fossilized species.

Their analyses, which were done as part of the Assembling the Tree of Life project, indicated that placental mammals began to emerge and diversify within the past 65 million years or less — more recently than estimates produced in the past using genetic data alone indicated. In particular, the team's so-called "phenomic character matrix," suggested placental mammals originated after a Cretaceous-Paleogene transition period that's been linked to the disappearance of many species, including non-avian dinosaurs.

"Species like rodents and primates did not share the Earth with non-avian dinosaurs but arose from a common ancestor — a small, insect-eating, scampering animal — shortly after the dinosaurs' demise," first author Maureen O'Leary, an anatomical sciences researcher affiliated with Stony Brook University and the American Museum of Natural History, said in a statement.


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

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