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Genomics in the Journals: Aug 8, 2013

NEW YORK (GenomeWeb News) – In Nature Genetics, an international team led by investigators at Columbia University presented findings from an integrated analysis of glioblastoma. The search for driver mutations in the brain cancer centered on a computational pipeline called MutComFocal, which considers the site and size of copy number changes and their relationship to other somatic mutations in a tumor genome.

Based on somatic mutation profiles identified using exome sequence data on 139 matched tumor-normal samples from individuals with glioblastoma and array-based copy number profiles of 469 glioblastomas, for instance, the researchers narrowed in on 67 genes that were either recurrently mutated in glioblastoma, but not prone to copy number changes or recurrently mutated and falling in frequently amplified or deleted parts of glioblastoma genomes.

Targeted sequencing on two dozen of the candidate genes in another 83 tumor-normal pairs led to 18 apparent new players in glioblastoma development, including the ligase complex adapter gene LZTR1 and the delta-catenin gene CTNND2, both of which the team went on to characterize in more detail.

Meanwhile, the researchers' analysis of RNA sequence data from 161 primary glioblastomas and 24 glioma sphere cultures led to previously undetected translocations in glioblastoma. Among them were recurrent, EGFR-containing fusions that seem to ramp up the activity of a STAT3 signaling pathway and render tumors susceptible to EGFR-inhibiting drugs.

"We think patients with this fusion might benefit from EGFR inhibitors that are already on the market," Columbia cancer geneticist Antonio Iavarone, one of the study's co-corresponding authors, said in a statement. "In our study, when we gave the inhibitors to mice with these human glioblastomas, tumor growth was strongly inhibited."

A meta-analysis of two prior genome-wide association studies suggests Alzheimer's disease and Parkinson's disease do not typically share genetic risk variants. As they reported in JAMA Neurology, members of the International Parkinson's Disease Genomics Consortium and the Genetic and Environmental Risk in Alzheimer's Disease Consortium pulled together genotyping data for tens of thousands of cases and controls sampled in the UK, Germany, France, and the US for past GWAS.

Using Alzheimer's study data for 3,177 cases and 7,277 controls and Parkinson's GWAS data for 5,333 cases and 12,298 controls, the researchers did not see significant overlap between SNPs implicated in each of the conditions. Nor did they unearth a pronounced polygenic signal associated with both Alzheimer's disease and Parkinson's disease.

Likewise, the team's gene-centered analysis — focused on more than 27,000 genes covered by variants assessed in available GWAS data — didn't lead to coding sequences that contained a substantial number of variants linked to both diseases.

"Our findings … imply that loci that increase the risk of both [Parkinson's disease] and [Alzheimer's disease] are not widespread and that the pathological overlap could instead be 'downstream' of the primary susceptibility genes that increase the risk of each disease," corresponding author Valentina Moskvina, a researchers with Cardiff University's Institute of Psychological Medicine and Clinical Neurosciences, and colleagues noted.

Still, they cautioned that "future application of more refined analyses of larger [Alzheimer's disease] and [Parkinson's disease] studies … could identify genetic variants that confer an increased risk of both [Parkinson's disease] and [Alzheimer's disease]."

A New England Journal of Medicine study by researchers based at the Dana-Farber Cancer Institute and elsewhere described the sequencing scheme used to implicate a new bacterial species in a cord blood stem cell transplant complication called cord colitis syndrome.

The team used shotgun DNA sequencing, together with PCR assays and fluorescence in situ hybridization, to search for infectious agents that might explain the onset of colitis symptoms in some individuals receiving transplants of hematopoietic stem cells from umbilical cord blood.

After sequencing paraffin-embedded colon biopsy samples from two individuals with cord colitis from the Brigham and Women's Hospital, the researchers narrowed in on millions of non-human sequence reads that didn't correspond to known microbes. From such reads, they put together a 7.65 million base draft genome sequence representing a heretofore-unrecognized bacterial species dubbed Bradyrhizobium enterica.

Sequences from B. enterica turned up in a PCR-based analysis of samples from three more cord colitis patients, too, the study's authors noted, but were not found in samples from healthy controls or from individuals with other forms of colon- or transplant-related disease.

"Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic pathogen," they wrote, noting that more research is needed to determine whether the microbe actually causes cord colitis and, if so, whether it is linked to cases at other health care centers as well.

The Broad Institute's Steven McCarroll and colleagues mapped nearly 20 million bases of missing sequence to the human reference genome using existing genome sequence data for hundreds of admixed Latino individuals — work that they outlined in the American Journal of Human Genetics.

The team came up with a statistical strategy for looking at local ancestry patterns in the Latino individuals' genomes, which often contain sequences that can be traced back to European, Native American, and West African ancestors.

Through an admixture mapping analysis that hinged on genome sequence data for 242 Latinos tested for the first phase of the 1000 Genomes Project, the investigators found informative variants falling in previously un-mapped portions of the human genome.

Using almost 3,900 such SNPs, they were able to map more than 19 million bases of sequence that were missed and/or un-mapped in the reference genome, with much of the newly placed sequence landing in repetitive regions in and around chromosomes' centromeres.

Optical mapping on a subset of newly localized BAC clones verified the veracity of the admixture approach, prompting the study's authors to propose that such mapping methods "will complement current, clone-based efforts to finish the human genome assembly."