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Genomics in the Journals: 2014.03.06

NEW YORK (GenomeWeb News) – In BMC Genomics, Swiss researchers described efforts to sequence and characterize the genome of a previously unknown Gram-negative bacterial species from a family called Alcaligenaceae.

The team performed targeted 16S ribosomal RNA gene sequencing, whole-genome sequencing, and biochemical analyses on the bug, which had been isolated from the lungs of a deceased parakeet in a Swiss pet store.

Through 16S sequence-based phylogeny and comparisons with bacteria strains sequenced in the past, the researchers determined that the bacterial isolate belongs to the Alcaligenaceae family and shares similarities to a species called Pelistega europaea and to species from the Bordetella and Taylorella genera.

Information in the bug's 2-million-base genome indicated that it is taxonomically distinct from Alcaligenaceae species and genera described in the past, prompting the study's authors to dub the newly detected parakeet respiratory pathogen Basilea psittacipulmonis. Their survey of healthy parakeet housing, both in pet stores and private domiciles, suggests the bug is not ubiquitous in captive birds' cages.

A large international collaboration led by the Broad Institute's David Altshuler and Decode Genetics' CEO Kari Stefansson used targeted sequencing and genotyping data from roughly 150,000 individuals to track down mutations that appear to protect against type 2 diabetes. As they reported in Nature Genetics, the researchers began by sequencing the exons of more than 100 genes found in the vicinity of diabetes-associated signals from past genome-wide association studies.

Starting with exon sequence data for more than 750 individuals from Finland and Sweden — including young, lean individuals with type 2 diabetes and elderly, obese individuals without — the team tracked down almost 1,500 non-synonymous variants found in fewer than 1 percent of participants.

When they took 71 of those SNPs forward for genotyping in 6,388 individuals with diabetes and 7,496 without, the researchers did not see significant type 2 diabetes associations, though they noticed a mutation in an islet cell zinc transporter-coding SLC30A8 gene with subtle protective effects.

Indeed, genotyping assessment of the nonsense mutation in tens of thousands more cases and controls indicated that the alteration, which lops off part of the resulting ZnT8 protein, offers some protection against developing diabetes. Because the protective allele is very rare outside of Finland, investigators searched for other SLC30A8 variants showing similar effects.

Using genome sequencing data from Icelandic individuals (provided by Decode Genetics) and new sequence data on another 13,000 individuals from other populations, they found additional protective variants in SLC30A8, ultimately showing that such alterations can diminish type 2 diabetes risk by up to around 65 percent. Based on such preliminary findings, the study's authors argued that there may be a benefit to pursuing potential treatments that inhibit activity of the ZnT8 protein encoded by SLC30A8.

Researchers from the UK and the US scrutinized the protein and gene expression profiles present in human myeloid leukemia cells during different stages of the cell cycle — work they described in eLife.

The group used a combination of RNA sequencing and mass spectrometry to follow transcriptome and protein patterns in cells that had been fractionated using a centrifugation-based approach.

The resulting data — which included information on myeloid gene expression, isoform profiles, protein levels, and phosphorylation patterns from various stages of the cell cycle — has been deposited into the Encyclopedia of Proteome Dynamics, the study authors noted.

Datasets in that online resource "show the importance of moving beyond simple protein identification to a more detailed analysis of complex proteome dynamics," they wrote, "including the selective regulation of distinct protein isoforms and post-translational modifications for deciphering cellular regulation mechanisms."

A New England Journal of Medicine paper presented data from a successful gene editing study done in individuals infected with HIV.

Researchers from the University of Pennsylvania, Albert Einstein College of Medicine, and Sangamo BioSciences performed an open-label, non-randomized trial on a dozen individuals with chronic HIV infection who were being treated with highly active anti-retroviral therapy (ART).

For the study, individuals were infused with billions of their own CD4 T immune cells. A fraction of CD4 T-cells in each infusion contained altered versions of an HIV entry co-receptor-coding gene called CCR5, which had been modified with Sangamo's proprietary zinc-finger nuclease (ZFN)-based genome editing approach. The team took half of the study participants off of ART for four weeks following the infusion, while half continued receiving the treatment.

The treatment led to a significant jump in individuals' CD4 T-cell counts, researchers reported, with cells containing the modified version of CCR5 making up an average of almost 14 percent of total CD4 T-cells in circulation after one week. One patient experienced a serious adverse event that appeared to reflect a reaction to the transfusion process.

Most of the individuals treated with the infusion technique ultimately saw a dip in viral load, with four showing undetectable HIV RNA levels over the following few months. Based on those findings, the study's authors expressed enthusiasm about the prospect of using gene editing to control HIV infection without relying on ongoing ART.

"Our experience reinforces our belief that an immunological approach is a promising approach to enable functional control of HIV infection and eliminate the need for lifelong ART," the study's senior author Carl June, a pathology and laboratory medicine researcher at the University of Pennsylvania's Perelman School of Medicine, said in a statement.

In an accompanying NEJM editorial, Stanford University pediatrics and genetics researcher Mark Kay and the Ragon Institute's Bruce Walker noted that the "proof-of-principle study is an important first step, not just in the treatment of those infected with HIV but also for genome editing in a broader sense."