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Genomics in the Journals: Feb 20, 2014

NEW YORK (GenomeWeb News) – In BMC Genomics, researchers from the University of Edinburgh and elsewhere introduced a high-density SNP genotyping array developed for the Atlantic salmon, Salmo salar.

The team used a combination of reduced representation sequencing, restriction site-associated sequencing, and RNA sequencing to track down more than 400,000 candidate SNPs in samples from nearly 300 farmed and wild salmon.

From there, the researchers came up with a custom Affymetrix array that they went on to test in 96 more Atlantic salmon from farms and the wild, verifying 132,033 of the candidate SNPs as authentic polymorphisms with high call rates, appropriate cluster separation on the array, and so on.

The study's authors have already mapped tens of thousands of the array variants across salmon chromosomes and shown that the tool can discern fish from the same and different populations. They noted that the array should offer researchers an avenue for exploring the genetics behind salmon traits of interest — information that is expected to aid salmon breeding efforts.

"This new technology will allow the best breeding fish to be selected more efficiently and accurately," corresponding author Ross Houston, with the University of Edinburgh's Roslin Institute, said in a statement, "particularly those with characteristics that are difficult to measure such as resistance to disease."

A team from Canada, the US, and France used whole-genome sequencing and transcriptome sequencing to track down recurrent mutations in the PTPN1 gene in tumors from individuals with Hodgkin lymphoma or a related form of lymphoma called primary mediastinal B cell lymphoma (PMBCL).

As they reported in Nature Genetics, the researchers assessed samples from 30 individuals with Hodgkin lymphoma and 77 individuals with PMBCL, as well as nine cell lines derived from Hodgkin lymphoma samples and three PMBCL cell lines.

In the process, they detected PTPN1 mutations in 20 and 22 percent of the Hodgkin lymphoma and PMBCL cases, respectively. In the cell lines, mutations in the gene were even more common, turning up in 67 percent of Hodgkin lymphoma lines and around one-third of the cell lines derived from PMBCL samples.

All told, PTPN1 mutations occurred in around one-quarter of samples tested for the study. Through follow-up protein expression experiments on hundreds of fresh frozen or formalin-fixed, paraffin-embedded tissues samples from Hodgkin lymphoma and PMBCL patients, the investigators determined that such changes lead to a dip in expression by the protein tyrosine phosphatase encoded by PTPN1.

That appears to increase lymphoma risk by dialing down phosphatase enzyme activity and bumping up phosphorylation in the so-called JAK-STAT signaling pathway, the study's authors explained.

For another Nature Genetics study, members of an international team led by investigators in Belgium did whole-exome sequencing on 10 individuals with unexplained intellectual disability, facial dysmorphism, and autism spectrum disorder — an analysis that unearthed a de novo mutation in ADNP, a gene that codes for a transcription factor contributing to SWI-SNF chromatin remodeling complex function.

The researchers found more examples of ADNP mutation in ASD by doing molecular inversion probe or high-resolution melt curve analysis in thousands more individuals with ASD and digging into existing exome sequence data for 240 individuals with ASD. All told, they tracked down ADNP mutations in 10 of the 5,779 cases considered for the study.

"Mutations in ADNP may explain the etiology of 0.17 [percent] of patients with ASD," the study's authors wrote, "and thus constitute one of the most frequent known causes of autism."

A pair of studies in Nature outlined genetic alterations that can contribute to the development of childhood brain tumors known as ependymomas.

Through whole-genome sequencing experiments on matched tumor-normal samples from 41 individuals with ependymoma and RNA sequencing on 77 tumor-normal pairs, members of the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project detected recurrent fusions between a previously uncharacterized gene and a gene coding for an NF-kappaB signaling pathway effector.

The fusion, which links the chromosome 11 genes RELA and C11orf95, appears to stem from chromosome 11 chromothripsis and translocations, the team reported. Its initial analysis and follow-up experiments in formalin-fixed, paraffin-embedded findings indicate that the C11orf95-RELA fusion is particularly common in so-called "supratentorial" ependymomas found in the front part of the brain.

Researchers detected the fusion in some 70 percent of the supratentorial ependymoma cases, subsequently showing that the same translocation can spur ependymoma development and unusual signaling through the inflammation-related NF-kappaB pathway.

"This is an exciting finding, not only for understanding the biology of a rare and particularly devastating childhood brain cancer, but also for understanding how it might be effectively treated," Genome Institute at Washington University Director Richard Wilson, a co-author on the study, said in a statement.

Meanwhile, a German and Canadian-led team described epigenetic alterations in ependymoma cases occurring in the hindbrain that had particularly poor outcomes.

That group saw relatively few mutations when they did whole-genome sequencing on matched tumor-normal samples from five individuals with "posterior fossa" ependyomoma and whole-exome sequencing on 42 more cases.

On the other hand, the researchers' array-based look at methylation patterns in dozens more ependymoma cases uncovered posterior fossa ependymoma sub-types with distinct epigenetic patterns — findings supported by their subsequent bisulfite sequencing experiments.

One of these clusters contained tumors with so-called CIMP-positive hypermethylation profiles and poor prognostic patterns, authors of that study noted, pointing to possible epigenetics-based treatments for some forms of the disease. "We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland," they wrote.