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Genomics in the Journals: Jul 11, 2013

NEW YORK (GenomeWeb News) - An international team led by investigators at the Salk Institute for Biological Studies tracked methylation dynamics across the genome in developing and differentiated mammalian brain cells from the frontal cortex.

As they reported in Science, the researchers used bisulfite sequencing to get single-base resolution of DNA methylation marks genome-wide in frontal cortex samples from mouse and/or human brains during fetal development, after birth, and into adulthood.

By folding in transcriptome and 5-hydroxymethylation data from RNA sequencing and Tet-assisted bisulfite sequencing, or TAB-seq, experiments, respectively, the team was able to trace development-related epigenetic shifts in multiple cell types within the brain region, known for its role in behavior and higher thinking processes.

During synaptic development, for instance, researchers saw dramatic rearrangements in the cytosine methylation patterns, including a jump in methylation at cytosine bases falling outside of cytosine and guanine-rich sequences in neurons but not in glial cells. They also characterized hydroxymethylcytosine profiles in the frontal cortex during fetal development, unearthing ties to potential regulatory regions active during later stages of development.

"These results extend our knowledge of the unique role of DNA methylation in brain development and function," Salk researcher Joseph Ecker, a co-corresponding author on the study, said in a statement. "They offer a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits."

A Japanese-led team did viral genome sequencing as part of its effort to characterize an avian influenza A virus called H7N9 that has caused sporadic infections and dozens of human deaths in China — an analysis described in Nature.

The researchers focused on two H7N9 isolates collected from humans in China, called A/Anhui/1/2013 and A/Shanghai/1/2013, for their study of H7N9 characteristics, pathogenicity, and transmissibility.

In addition to demonstrating that H7N9 is capable of infecting — and replicating in — mammals such as ferrets and monkeys, the team determined that at least one of the new isolates can occasionally pass between ferrets, an oft-used animal model for flu studies. The group also considered the genetics of the Anhui and Shanghai isolates and their relationship to other flu strains.

"[O]n the basis of their sequences and phylogenetic relationships, [A/Anhui/1/2013] and [A/Shanghai/1/2013] originated from an avian host," senior author Yoshihiro Kawaoka, a researcher affiliated with the Japan Science and Technology Agency, the University of Wisconsin at Madison, the University of Tokyo, and Kyoto University, and his colleagues wrote, "but possess several characteristic features of human influenza viruses, such as efficient binding to human-type receptors, efficient replication in mammalian cells … and respiratory droplet transmission in ferrets [in the case of Anhui/1]."

"If H7N9 viruses acquire the ability to transmit efficiently from person to person," Kawaoka said in a statement, "a worldwide outbreak is almost certain, since humans lack protective immune responses to these types of viruses."

In a related Nature paper, an independent team from the US Centers for Disease Control and Prevention reported on findings from its own analysis of A/Anhui/1/2013 and A/Shanghai/1/2013 isolates of H7N9 from China.

Using phylogenetics, the researchers determined that the virus is made up of hemagglutinin sequences that resemble those in the H7N3 influenza virus, neuraminidase sequences similar to those in other H7N9 strains, and additional gene sequences that are reminiscent of those in the H9N2 flu virus.

Based on their own ferret experiments, which showed infrequent H7N9 transmission, the authors of that study concluded that "additional [H7N9] virus adaptation in mammals would be required to reach the high-transmissible phenotypes observed by the respiratory droplet route with pandemic and seasonal influenza A viruses."

Still, authors of that study cautioned that "[o]ur results indicate that H7N9 viruses have the capability for efficient replication in mammals and human airway cells and highlight the need for continued public health surveillance of this emerging virus."

In the American Journal of Human Genetics, a large international team touched on the feasibility of using whole-genome sequencing to root out de novo and rare inherited mutations involved in autism spectrum disorder.

Using genome sequence data for members of 32 unrelated ASD affected parent-child trios from Canada, the researchers found potential ASD culprit mutations in half of the cases. In six of the families — or 19 percent of those tested — those alterations were de novo mutations not present in either parent. For affected children from 10 other families, the presence of ASD appeared to coincide with rare, inherited mutations on the X chromosome and/or on autosomal chromosomes.

As a group, these mutations affected nine genes with past ties to autism as well as four previously unrecognized gene players in the condition and several more candidate contributors to ASD, study authors noted. "Taken together," they wrote, "these results suggest that [whole-genome sequencing] and thorough bioinformatics analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms."

Using in vitro competition binding experiments, a University of Toronto-led team systematically sized up the RNA motifs that are recognized by hundreds of eukaryotic RNA binding proteins. As noted in Nature, the researchers relied on a so-called RNAcompete method to tally up the sequences that were bound by more than 200 eukaryotic RNA binding proteins.

From the set of motif sequences found in those experiments, the group went on to characterize everything from the evolutionary conservation of RNA binding patterns to inter-relationships between the binding motifs and post-translational RNA regulation.

Amongst the messenger RNAs carrying binding motifs that match up with an RNA binding protein called RBFOX1, for instance, investigators saw an over-representation of transcripts corresponding to ion channel and/or nervous system-related genes. Their data also suggest that RBFOX1, an alternative splicing factor, may stabilize such transcripts. That's intriguing, study authors noted, since RBFOX1 has previously been found at lower-than-usual levels in brain tissue from some individuals with autism spectrum disorder.

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