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Genomics in the Journals: Dec 12, 2013

NEW YORK (GenomeWeb News) – A team from the US and Israel has characterized the genetic variation present in Burkholderia dolosa pathogens from cystic fibrosis patients with chronic B. dolosa infections that can be traced back to an outbreak that began in Boston in the 1990s — an analysis that offered a peek at the effects of adaptive mutations and selective pressures on such pathogen populations.

As they reported in Nature Genetics, the researchers used Illumina's HiSeq 2000 instrument to do single colony genome sequencing and/or deep sequencing on populations of B. dolosa from the sputum samples of five individuals with cystic fibrosis who have been infected with the bug for roughly a decade.

The team's sequence data and comparisons with B. dolosa reference genome pointed to extensive allelic diversity within B. dolosa bugs from each patient. That observation — coupled with the identification of multiple mutations that seem to stem from past selective events — indicated that adaptive mutations arising in B. dolosa aren't prone to fixation in populations.

Instead, such changes seem to stick around over time, leading to co-existing B. dolosa lineages that make it possible to retrace past exposures and selective pressures faced by the B. dolosa pathogens in a cystic fibrosis patient's samples.

"We find extensive intra-sample diversity," co-senior author Roy Kishony, a systems biology researcher affiliated with Harvard Medical School and the Israel Institute of Technology, and colleagues wrote, "suggesting that mutations rarely fix in a patient's pathogen population — instead, diversifying lineages coexist for many years."

Researchers from China, Denmark, and Saudi Arabia used exome sequencing to find a recurrent mutation in the transcription factor-coding gene YY1 in tumors from a form of pancreatic neuroendocrine cancer called insulinoma — work that they described in Nature Communications.

The team started by screening for glitches in known pancreatic neuroendocrine tumor-related genes using matched tumor and normal samples from more than three-dozen individuals with insulinoma. The condition is marked by tumors that cause low blood sugar by releasing the insulin hormone in the absence of a glucose trigger.

Mutations in genes known for contributing to other, non-functional forms of pancreatic neuroendocrine tumors were scarce in the insulinoma, researchers found, prompting them to do exome sequencing on tumor and normal pairs from 10 of the insulinoma patients.

They found nearly 80 somatic mutations in insulinoma tumors when they sorted through the protein-coding sequence data, including a recurrent missense mutation in YY1 that swaps the amino acid at position 372 in the resulting transcription factor protein.

Mutations at that hotspot occurred in nearly a third of the sporadic insulinomas overall, based on follow-up assessments of another 103 insulinoma tumors, and appeared to be especially common in tumors arising somewhat later in life. Moreover, the study's authors noted that YY1 alterations may be susceptible to treatment with so-called mTOR inhibitors, suggesting that it could eventually be clinically useful to genotype and/or target the newly detected glitch in the gene.

In Science, members of the Encyclopedia of DNA Elements (ENCODE) consortium described epigenetic regulatory features tucked away in protein-coding sequences. The researchers detected these dual-use codons — dubbed duons for their ability to encode amino acid information as well as transcription factor recognition sites — with the help of enzyme-based transcription factor occupancy mapping and experiments that used targeted sequencing to focus in on specific transcription factor footprints.

Based on findings from 81 human cell types, the investigators estimated that roughly 15 percent of codons in exonic parts of the human genome act as duons. Such interactions appear to influence everything from codon use biases and protein evolution patterns to the protein and regulatory effects that a given mutation may produce.

"The fact that the genetic code can simultaneously write two kinds of information means that many DNA changes that appear to alter protein sequences may actually cause disease by disrupting gene control programs or even both mechanisms simultaneously," the University of Washington's John Stamatoyannopoulos, senior author on the study, said in a statement.

An international team led by investigators at the University of California at San Francisco did exome sequencing on tumors from nearly two-dozen individuals with glioma as part of its effort to tally up mutations contributing to post-treatment recurrence by the brain tumors.

As they reported in another Science study, the researchers used exome sequencing to profile low-grade glioma tumors resected from 23 individuals with the disease at the time of diagnosis.

By comparing those protein-coding sequences to exome sequences for recurrent tumors taken from the same individuals as much as 11 years later, the team saw that many mutations in the initial sample were missing in tumors that reappeared later in life. For 43 percent of the individuals tested, for example, at least half of the mutations characterized in tumors at the time of diagnosis did not turn up at recurrence, hinting that very early-stage tumor cells often spawn recurrent forms of the brain cancer.

The analysis also revealed rampant mutations in a subset of tumors taken from the 10 glioma patients who had received temozolomide chemotherapy for their tumors, including mutation signatures that appear to reflect DNA damage caused by the treatment itself.

Based on their findings, the study authors argued that "[f]uture basic and clinical studies must weigh the anti-tumor effects of [temozolomide] against the potential risk of inducing new driver mutations and malignant progression."

"Ultimately, a better understanding of the invading cells that give rise to recurrent tumors and the effect of adjuvant therapeutics on their evolution will facilitate the development of new strategies to delay or prevent recurrence and malignant progression," they concluded.