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Genomics In The Journals: Jun 28, 2012

NEW YORK (GenomeWeb News) – Using exome sequencing, a University of California-led team has tracked down somatic mutations involved in a brain overgrowth condition known as hemimegalencephaly.

As they report in Nature Genetics, the researchers sequenced coding sequences in surgically resected brain tissues and matched normal blood samples from 20 individuals with the condition, identifying suspicious somatic de novo somatic mutations in six of the cases. Consistent with findings from a study published by another research group in Neuron recently, one of the cases involved an alteration in the AKT3 gene. The current study also uncovered disease-associated mutations in genes coding for other components of an AKT3-containing pathway, including MTOR and PIK3CA. In particular, researchers noted, four cases involved the same PIK3CA point mutation.

A second exome sequencing study in Nature Genetics by a large international team implicates de novo germline and post-zygotic mutations in AKT3, PIK3CA, and PIK3R2 in other brain overgrowth conditions called megalencephaly-capillary malformation, or MCAP, and megalencephaly-polymicrogyria-polydactyly-hydrocephalus, or MPPH. Meanwhile a third Nature Genetics study by investigators in the UK, US, and elsewhere demonstrates that mosaic activating PIK3CA mutations can also lead to a syndrome that involves the overgrowth of fibrous tissue, adipose tissue, and bone.

"Our data highlight the central role of PI3K-AKT signaling in vascular, limb, and brain development," University of Washington researcher William Dobyns, senior author on the megalencephaly study, and his colleagues wrote, "and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism."

In the New England Journal of Medicine, researchers from Brigham and Women's Hospital, the San Francisco-based molecular cytology company Veracyte, and elsewhere report on findings from a prospective validation study of a diagnostic test based on the expression of 167 genes for distinguishing between benign and cancerous thyroid nodules in fine-needle aspiration biopsy samples with indeterminate cytology.

Of the almost 5,000 fine needle aspirate samples collected from around 3,800 individuals at dozens of clinical sites over 19 months of the study, which was funded by Veracyte, investigators identified 265 samples with intermediate cytology that met the study's inclusion criteria. In these samples, the gene expression-based classifier showed 52 percent specificity and 92 percent sensitivity, correctly identifying 78 of the 85 malignant thyroid nodules. It also had between 85 percent and 95 percent negative predictive value for non-cancerous cases.

"[T]his study shows that a gene-expression classifier can be used to identify a sub-population of patients with a low likelihood of cancer in a population of patients for whom diagnostic surgery is otherwise recommended," the study's authors wrote.

"Though each clinical decision must be individualized," they added, "these data suggest consideration of a more conservative clinical approach for patients who have nodules with indeterminate cytologic features on fine-needle aspiration and a benign result on gene-expression classifier testing."

A Nature study outlines an international team's approach for testing the notion that de novo gene birth can occur through transitional proto-genes. The researchers, who were from the US, France, and Belgium, tested this evolutionary model using RNA-sequencing, ribosomal footprint information, and more in Saccaromyces cerevisiae. In the process, they uncovered evidence for translation of hundreds of non-protein coding open reading frames and tracked down a set of roughly 1,900 potential proto-genes in the budding yeast.

"[D]e novo gene birth seems to be more prevalent than previously supposed," Dana-Farber Cancer Institute and Harvard Medical School researcher Marc Vidal, the study's corresponding author, and colleagues wrote. "The involvement of proto-genes in de novo emergence of protein-coding genes in S. cerevisiae probably holds for other species and may extend to RNA genes and regulatory elements."

A University of Cambridge-led team describes a previously undetected influenza A gene dubbed X-ORF in Science. Investigators found the open reading frame, which overlaps with segment 3 of the influenza A virus genome, during a study looking at synonymous codon usage and RNA packaging in the virus. The resulting polypeptide, known as PA-X, is produced through ribosomal frameshifting, the researchers reported. And their subsequent experiments in human cell lines and in mice hint that the product of the newly identified gene contributes to a process that affect host cell function and gene expression, influencing viral pathogenicity.

Researchers from the US, Spain, and Argentina have found that the selection for one commercially appealing trait in tomato — even fruit ripening — has diminished another important attribute: the fruit's flavor.

With access to tomato plants from populations with or without the even ripening trait and the help of tomato sequences provided by members of the Tomato Genome Consortium and SOL Genomics Network, the team tracked down two transcription factors involved in ripening-related processes. Their findings, appearing online in Science, suggest that breeding efforts over several decades have introduced a truncating, loss-of-function frame shift mutation into one of these, the chromosome 10 transcription factor SlGLK2 that normally regulates chlorophyll accumulation and distribution as well as carbohydrate and carotenoid levels. Without it, researchers found, tomatoes have lower sugar content and less lycopene, indicating that systematic breeding for even ripening has "inadvertently compromised ripe fruit quality in exchange for desirable production traits."

"This information about the gene responsible for the trait in wild and traditional varieties provides a strategy to recapture quality characteristics that had been unknowingly bred out of modern cultivated tomatoes," University of California at Davis plant sciences researcher Ann Powell, the study's co-first author, said in a statement.

"Now that we know that some of the qualities that people value in heirloom tomatoes can be made available in other types of tomatoes," she added, "farmers can have access to more varieties of tomatoes that produce well and also have desirable color and flavor traits."

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

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