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Oxford Nanopore Technologies, University of California-Santa Cruz, Translational Genomics Research Institute, Febit, Roche, Illumina, US Department of Energy-Joint Genome Institute, University of Washington, IBM Thomas J. Watson Research Center, Lawrence

Oxford Nanopore Licenses UCSC Technology
Oxford Nanopore Technologies this week said it has signed an exclusive license agreement for nanopore technology developed at the University of California, Santa Cruz.
Under the terms of the agreement, the company will fund research in the laboratories of UCSC professors David Deamer and Mark Akeson, who have developed methods for using protein nanopores to analyze DNA.
Oxford Nanopore said that applications of the UCSC technology include single-molecule DNA sequencing and molecular sensing.
The agreement follows a deal that the company announced earlier this month in which it licensed approximately 60 to 70 patents and patent applications related to nanopore technology from Harvard University [In Sequence 08-12-08].  
The Harvard agreement included “some discoveries” from UCSC, Oxford Nanopore said.
In addition to the UCSC and Harvard agreements, the company said it has also signed licensing deals related to nanopore science with the University of Oxford, Texas A&M, the University of Massachusetts Medical School, and the National Institute of Standards and Technology.
Financial terms of the UCSC agreement were not disclosed.

TGen to Evaluate Febit's DNA-Capture Arrays for Next-Gen Sequencing
Febit said last week that it will collaborate with the Translational Genomics Research Institute to evaluate the use of Febit’s Geniom microarray technology in capturing DNA for next-generation sequencers.
TGen is Febit’s first US pilot user for the HybSelect technology, which the company said enables selective DNA capture and elution in order to pre-select sequences for next-generation platforms.
Febit President Cord Staehler in a statement said the TGen study will provide “important data” that will help the company prepare to launch the HybSelect in early 2009.
HybSelect is based on Febit's Geniom technology and uses arrays within microfludic biochips to select targeted regions of DNA for sequencing. The company said that the Geniom biochips are “programmable” and can contain “any desired set of capture probes.”

454 Sequencing, Phylogenetics Reveal Cancer Cell Evolution
Second-generation sequencing techniques can help researchers organize cancer cells into phylogenetic groups that provide insights into the progression of cancer, according to new research.
In a paper appearing online last week in the Proceedings of the National Academy of Sciences, researchers from the UK used the Roche/454 FLX sequencer to look at the evolution of B-cell chronic lymphocytic leukemia (CLL) cells. In the process, the team came up with a new algorithm to weed out real mutations from sequencing errors. Their results suggest that it’s possible to combine sequencing with principles from evolutionary biology to understand the transition from early mutations to dominant tumor cells.
Because abnormal masses of tissues that develop during cancer sometimes contain cells with more than one cellular genotype, the researchers reasoned that these cells may display some traits and relationships normally associated with evolutionary biology. As these competing genotypes develop and evolve, they noted, some subclones will be more evolutionarily fit than others and will eventually take over the population. Understanding this evolution, in turn, could help expose the mutations driving cancer.
“Cancer encapsulates many of the tenets underpinning evolutionary biology,” the authors argued. “[D]irect demonstration of multiple genetically related subclones within a tumor and their phylogenetic relationships has been hampered by the lack of tools for the detection of rare genetic variants.”
To address this, the team used Roche/454 sequencing to identify genetic variants — including rare variants — present in 24 human B-cell CLL tumors from 22 patients. Using nested PCR, they amplified the Ig heavy chain, or IGH, locus of tumor cells, a region of the genome that’s often dramatically rearranged during B-cell CLL.
In order to discern real variants from sequencing artifacts, the researchers developed a bioinformatic algorithm to weed out common sequencing errors. Once these artifactual insertions, deletions, and substitutions were accounted for, the researchers were able to identify genuine somatic mutations that were present in as few as one in every 5,000 cells. 
Indeed, the samples tested contained anywhere from one dominant mutation to up to 18 different clonal populations with distinct somatic mutations. A quarter of the samples tested contained a dominant clone as well as one or more of these subclones. The sequences of these subclones differed from the dominant clone by as many as 18 bases.
Based on their subsequent experiments and analyses, the team speculated that these subclones “represent genuine stages in the clonal evolution of CLL in these patients.” For instance, they noted, the dominant clone often contains mutated bases that are absent in other subclones, suggesting some subclones may represent steps on an evolutionary path toward the dominant mutation.
Next, they looked at the evolutionary relationships between dominant clones and subclones, generating phylogenetic trees to compare two samples that contained many subclones. Intriguingly, they found three kinds of subclones in these samples. One group of subclones seemed to be intermediates en route to the dominant clones. Another appeared to have diverged on the road to becoming the dominant clone and a third group contained cells that were apparently evolving from dominant clones.
That indicates that some of the earliest cellular mutations contain driver mutations that push cells toward the dominant clonal form, the authors hypothesized. Once a dominant clone — with a selective advantage — establishes itself in the tumor, meanwhile, subsequent mutations are under negative selection pressure and may be less common.
“[F]or the dominant clone to become numerically predominant, it must have a selective advantage over its direct predecessors, suggesting the existence of at least one or more driver mutation in that clone, whether it be in the IGH locus or elsewhere,” the authors wrote. “[T]his finding would be consistent with the hypothesis that somatic hypermutation of the antigen receptor plays an early role in leukemia development.”
Although they noted that the results need to be verified in larger studies, the researchers expressed enthusiasm about the possibility of applying sequencing technology and phylogenetic trees to answer questions about the cellular evolution of cells in other types of cancer as well.

Illumina Nets $340M in Public Offering
Illumina said last week that it raised $342.6 million in net proceeds from a previously disclosed public stock offering.
Goldman, Sachs was the sole manager of the offering, which sold 4,025,000 shares at $87.50 apiece.
Illumina had said that it plans to use the capital to fund R&D efforts, expand its manufacturing capacity, and for working capital needs. The company said that it may also use the financing to acquire, license, or invest in other businesses, technologies, or products.

JGI's Rubin Predicts Genomics Will Spur Biofuel Development
Genomics will play a key role in helping to shift energy production away from fossil fuels and toward biofuels, according to Eddy Rubin, director of the US Department of Energy’s Joint Genome Institute.
In a review article appearing online this week in Nature, Rubin called the development of alternative energy sources an “urgent global priority” and said genomics research and technologies will enable researchers to create biofuels, particularly those based on cellulosic biomass. Rubin also highlighted the impact that current genomics projects could have on biofuel production and pointed to areas that are ripe for exploration.  
Rubin said he thinks that “in the future biology is clearly going to impact on energy,” Rubin told In Sequence sister publication GenomeWeb Daily News last week. “Due to the dramatic demand for liquid fuels, we are going to use biology — either inefficient or efficient biology — to meet that demand.”
The energy in biofuels ultimately relies on the ability of plants to store the sun’s energy as plant material — particularly cell wall compounds such as cellulose, hemicellulose, and lignin. Harnessing and releasing that energy can be done in several different ways. For instance, Rubin noted, ethanol production from corn is currently a common method of biofuel production.
But, he noted in the article, cellulosic biofuels — those based on breaken-down cell-wall polymers that ferment into biofuels — are considered by many to be the most scaleable and high-energy biofuel source. Because they aren’t based on food crops and can grow in areas that don’t produce these crops, cellulosic biofuels are also less likely to create a “food-versus-fuel” conflict, Rubin said.
With sufficient investment in science, biology, and genomics, Rubin said it should also be possible to come up with strategies to make biofuel production more cost-effective and efficient, while simultaneously minimizing the impact of biofuel production on land and resources.
A better understanding of other microorganisms, such as the recently sequenced yeast Pichia stipitis, which ferments specific plant sugars, may provide insights into the most efficient way of converting the plant biomass to the sugars that form the foundation of biofuels.
In addition, metagenomic surveys looking at the collection of organisms in certain environment may prove very useful, Rubin emphasized. “Using this prospecting technique, we can survey the vast microbial biodiversity to gain a better picture of the metabolic potential of genes and how they can be enlisted for the enzymatic deconstruction of biomass and subsequent conversion to high energy value fuels,” Rubin said in a statement.
Genomics and metagenomics can also inform studies of other, non-cellulosic energy sources, including algae and microbes. Synthetic biology may also help spur biofuel production programs that are cheaper and more efficient than the naturally occuring alternative, Rubin pointed out.
“The strategies that were pioneered in sequencing the human genome for the improvement of human health are now poised to be an important contributing technology in the challenge to develop environmentally and socially acceptable alternatives to fossil fuels,” he wrote.
— Andrea Anderson

Functional Metagenomics Uncovers New Microbe Genome
A team of US researchers have unocovered a new microbial genome after using DNA labeling to target methylotrophs in sediment samples pulled from the floor of Seattle’s Lake Washington that contained thousands of microbes, according to a published study.
“Our approach was simply to define our community before sequencing,” senior author Ludmila Chistoserdova, a microbiologist at the University of Washington, told In Sequence sister publication GenomeWeb Daily News last week.
From the sequence they garnered, the team was able to stitch together a nearly complete genome for a previously unknown microbe called Methylotenera mobilis and begin analyzing its function. The researchers noted that such functional metagenomics techniques will likely prove useful in other environments as well.
Although metagenomic sampling offers the potential to capture all of the DNA in a particular environment, it also has drawbacks, Chistoserdova explained. For instance, because environmental samples usually contain complex communities, metagenomic sequencing frequently turns up bits and pieces of DNA that don’t quite fit together. That makes it difficult to determine what sorts of organisms are in a sample, what they’re doing in the environment, how they fit together, and how they’re related to one another.
By linking sequence to function, Chistoserdova and her colleagues were able to start honing in on relationships between certain community members and understanding the functions and interactions of these players.
The research, which appears in Nature Biotechnology’s advanced, online publication this week, included collaborators from the University of Washington, US Department of Energy’s Joint Genome Institute, the IBM Thomas J. Watson Research Center, Lawrence Berkeley National Laboratory, Combimatrix, and the Los Alamos National Laboratory.
It focused on methylotrophs, microorganisms that break down one-carbon compounds such as methane and that a role in carbon cycling. “They consume C1 compounds and some of these are very potent greenhouses gases, such as methane,” Chistoserdova said.
After collecting mud samples from more than 200 feet below the surface of Lake Washington, Chistoserdova and her team mixed them with five 13C-labeled C1 compounds: methane, methanol, methylamine, formaldehyde, and formate. They then separated the DNA by weight using density gradient ultracentrifugation, constructed a shotgun library for each substrate, and sequenced each using ABI PRISM 3730 sequencers.
“It took a lot of mud,” Chistoserdova said. But in the process, the researchers managed to score an unexpected find: sequence covering almost the entire genome of M. mobilis, a previously unknown and uncultured organism.
Based on information gleaned from its genome, the researchers speculated that M. mobilis probably prefers a microanaerobic environment and acts as a denitrifier. Chistoserdova and her team are currently doing follow up experiments to test these and other hypotheses about M. mobilis. They are also studying another bug from the lake mud sample, an organism called Methylobacter tundripaludum, for which they have put together a partial genome.
The team also compared the M. mobilis genome with that of another methylotroph called Methylobacillus flagellatus. That analysis suggested that the two microbes share genes involved in some central functions and in methylotrophy but diverge in those other biochemical functions. “We learned that they are quite different even though there are a core set of genes that are similar,” Chistoserdova said.
Although the researchers focused on lake sediments for this study, Chistoserdova noted that functional metagenomics should work in other environments, too, as long as there is sufficient DNA available and appropriate enrichment conditions are selected. “If you are interested in a certain function,” she explained, “you just need to pick a substrate that will work.”
For her part, Chistoserdova said that she is interested in pursuing additional functional metagenomic studies, including some aimed at assessing methylotroph transcriptomes. That should be possible using techniques similar to those described in this study by sequencing RNA rather than DNA, she said.
— Andrea Anderson

The Scan

Germline-Targeting HIV Vaccine Shows Promise in Phase I Trial

A National Institutes of Health-led team reports in Science that a broadly neutralizing antibody HIV vaccine induced bnAb precursors in 97 percent of those given the vaccine.

Study Uncovers Genetic Mutation in Childhood Glaucoma

A study in the Journal of Clinical Investigation ties a heterozygous missense variant in thrombospondin 1 to childhood glaucoma.

Gene Co-Expression Database for Humans, Model Organisms Gets Update

GeneFriends has been updated to include gene and transcript co-expression networks based on RNA-seq data from 46,475 human and 34,322 mouse samples, a new paper in Nucleic Acids Research says.

New Study Investigates Genomics of Fanconi Anemia Repair Pathway in Cancer

A Rockefeller University team reports in Nature that FA repair deficiency leads to structural variants that can contribute to genomic instability.