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Helicos BioSciences, Leerink Swann, Invitrogen, Applied Biosystems, University of California Los Angeles, Translational Genomics Institute, NIH, Scripps Translational Science Institute, RainDance Technologies, National Science Foundation, Brigham Young Un

Leerink Swann Lowers Revenue Estimate, Cuts Price Target on Helicos' Stock
Investment bank Leerink Swann has cut its 12-month price target for Helicos BioSciences’ stock to $6 from $10 and has roughly halved its revenue estimates for the firm for fiscal years 2008-2010.
Leerink Swann analyst John Sullivan, in a research note, cited “execution problems” in the second quarter for Helicos, as well as limited “commercial visibility” in the near-term for the firm’s flagship product, the HeliScope single molecule sequencer.
Though Leerink Swann has maintained an “outperform” rating on the stock, Sullivan cut his revenue targets for Helicos through fiscal 2010. He now expects 2008 revenues to be around $4.6 million, compared to his previous estimate of $9.5 million. He also lowered his 2009 forecast to $32.2 million, from $60.1 million, and his 2010 estimate to $62.7 million, from $112.5 million.
“We’ve pushed out our HLCS commercialization ramp by a few quarters, over the slower-than-we-expected process of placing and bringing to full productivity the first few HeliScope instruments, the fewer orders to date than we had expected, and the ongoing productivity gains of competing [next-generation sequencing] platforms,” Sullivan wrote.
He is predicting Helicos will place 21 systems in 2009 and 35 in 2010, compared to earlier estimates of 39 instruments in 2009 and 66 in 2010.
Last month, Helicos reported a problem with unstable reagents that it said it has now solved. The company said it has not yet booked revenues from sales of its system and has had two orders for the instrument so far (see In Sequence 8/12/2008).

Invitrogen, ABI Shareholders to Vote on Merger in October
Invitrogen and Applied Biosystems announced separately last week that they each will hold a special meeting of shareholders on Oct. 16 to vote on the proposed $6.7 billion merger of the two firms.
Invitrogen and ABI each said that shareholders of record as of the close of business on Sept. 5 are entitled to vote at the meetings. The firms will mail a proxy statement and relevant materials to shareholders the week of Sept. 8, they said.
Shareholders of both firms must approve the transaction, and the merger requires the approval of the European Commission.
Under terms of the deal, ABI shareholders will receive $38 for each share they own in the form of Invitrogen stock and cash, with cash accounting for 45 percent of the split. The purchase price represents a 12-percent premium to ABI’s average closing price for the previous 30 trading days.

Study Finds European SNP Data Precisely Reflects Geography
In a paper appearing online this week in Nature, a team of American and Swiss researchers assessed SNPs in the genes of individuals from across Europe and used the data to construct two-dimensional genetic maps.
They found that genes were closely tied to geography. In fact, genetics pinpointed most individuals’ geographic origin within a few hundred miles. The results highlight the importance of accounting for geography in genetic studies and suggest precise genetic ancestry tests may not be far off.
“The surprise was just how well and clearly it relates to geography,” University of California at Los Angeles evolutionary biologist John Novembre, who recently completed his post-doctoral research in the University of Chicago’s department of human genetics and is lead author on the paper, told In Sequence’s sister publication GenomeWeb Daily News. “At the broadest level, it means that geography matters.”
The samples tested were collected as part of a larger study of about 6,000 individuals called the Population Reference Sample, or POPRES, project, Novembre explained. That study, led by GlaxoSmithKline and collaborators, was aimed at developing a reference sample for genetic and pharmacogenetic studies.
Novembre and his colleagues took advantage of this rich data set to ask questions about genetic history, genetic variation, and human population structures.
They initially genotyped 3,192 Europeans at 500,568 loci using Affymetrix 500K SNP arrays. After filtering out specific SNPs to minimize linkage disequilibrium patterns and limiting their analysis to individuals with well-defined ancestry, they were left with data on 197,146 loci in 1,387 individuals.
They then created two-dimensional maps revealing genetic patterns in the samples. Although the overall genetic variation across Europe was miniscule, Novembre explained, there were still enough differences to distinguish between geographic populations. Indeed, the two-dimensional genetic map closely resembled a map of Europe.
For half of the individuals tested, the researchers could place them within about 193 miles of their reported geographic origin. When they stretched that to about 435 miles, they could place 90 percent of the individuals.
Moreover, the team was able to distinguish incredibly subtle population effects, including genetic differences between French-, German-, and Italian-speaking individuals in Switzerland. As such, the results are providing new insights into the genetics associated with population structure.
That, in turn, brings a new level of information to genome-wide association studies, suggesting that there may be certain population-related traits that could create false-positive associations in these studies. Being aware of such population stratification effects should help researchers avoid such problems, Novembre said.
In the future, he predicted, whole-genome re-sequencing projects will likely add even greater resolution to this sort of gene-geography study. For the time being, though, Novembre and his colleagues are continuing to tap the POPRES data for more information about populations in other parts of the world, including South Asia, East Asia, and Latin America.
— By Andrea Anderson; originally published on GenomeWeb Daily News

TGen, UCLA Scientists Reveal Approach for Finding Needle in Genetic Haystack…
In a feat that may have implications for everything from forensics to securing the privacy of genome-wide association studies, a team of scientists from the Translational Genomics Institute (TGen) in Phoenix and the University of California at Los Angeles have developed a method for assessing complex DNA mixtures.
Their paper, appearing online last week in PLoS Genetics, describes how they designed and tested an algorithm for pinpointing one individual’s DNA in a complex genetic mixture using high-density SNP data. Based on their results, they concluded that it is possible to find an individual of interest in a mixture of hundreds or even thousands of people’s DNA — that, researchers say, could eventually open the door to a whole new way of gathering genetic evidence in law enforcement.
“Within the current forensics setting this is a new way of thinking,” senior author David Craig, associate director of TGen’s Neurogenomics Division, told In Sequence’s sister publication GenomeWeb Daily News. “It is a fundamental shift in how people approach a crime scene.”
In the past, Craig explained, crime scene investigators couldn’t easily analyze genetic samples containing DNA from multiple people. Although there are some techniques available for teasing apart one person’s DNA from another, once DNA from more than two or three people was mixed, the data become muddled.
“In large part, forensically identifying whether a person is contributing less than 10 percent of the total genomic DNA to a mixture is not easily done, is difficult to automate, and is highly confounded with the inclusion of more individuals,” the team noted in the paper.
So they came up with a new approach for looking at complicated genetic mixtures: integrating allele intensity measurement data for hundreds of thousands of SNPs to characterize shifts in allele probe intensities, comparing the individual of interest to both a reference population and to the mixture.
The researchers tested this approach using a series of simulations followed by experimental validation on a set of complex DNA mixtures. With just 10,000 to 25,000 SNPs it was possible to identify a person of interest even if his or her DNA comprised less than one percent of the total DNA.
Using even more SNPs, they added, it is possible to identify an individual’s DNA in a complex mixture even when that person’s DNA made up less than 0.1 percent of the total genomic DNA in the sample.
And, Craig said, the technique should work well in a variety of populations. Although there are SNPs that vary from one population to the next, he said, it is actually relatively simple to weed out the ancestrally-relevant SNPs and create an appropriate reference population.
In addition, the researchers found that both the Affymetrix and Illumina platforms produced very similar results when used for the application. “There really isn’t a huge advantage with either platform,” Craig said. “Both methods are surprisingly robust.”
Among the potential real-world applications, the researchers noted that this technique holds particular promise for forensics investigations, since it opens the door to analyzing contaminated DNA samples or sampling a large crime scene area.
“It opens up a whole new can of worms of what’s possible to do forensically,” co-author Stanley Nelson, a human genetics researcher who directs the National Institute of Health’s Neuroscience Microarray Consortium at the UCLA site, said in a statement.
But despite the potential benefits, Craig noted that it has been hard to convince the forensics and research communities that the approach really works as easily and effectively as his team claims. “The universal response is, ‘We don’t believe you,’” he said. Now that the paper has been peer-reviewed and published, Craig hopes that will change.
If the new technique is going to catch on in the forensics field, Craig predicted, it will probably be used in a few high-level cases and expanded from there if successful. If it proves valuable there, he added, the approach could become widespread within a few years.
The work also brings a new perspective to the question of whether it is possible to protect individuals’ identities and genetic privacy by pooling data from genome-wide association studies. “We show that you really can’t,” Craig said, adding that he has been pondering alternative methods for maintaining genetic privacy.
“Within GWA studies, there is a considerable push to make experimental data publicly available so that the data can be combined with other studies,” Craig and his colleagues wrote. “Our findings show that such an approach does not completely conceal identity since it is straightforward to assess the probability that a person or relative participated in a GWA study.”
— By Andrea Anderson; originally published on GenomeWeb Daily News

…As Forensic Breakthrough Stirs NIH to Close GWAS Data from Public View
Large amounts of aggregate human DNA data that the National Institutes of Health and other groups made open to researchers around the world is being locked up from public view due to privacy concerns that arose last week when a new forensic DNA method was announced that could conceivably leave people vulnerable to identification.
Until now, there was little concern that information from genome-wide association studies in large public databases could be used to identify individuals out of the thousands who gave samples.
But a study released last week by the Translational Genomics Research Institute and the University of California, Los Angeles, which is aimed at helping crime solvers identify one person from many potentially contaminated DNA samples at a crime scene, spurred NIH to close down their publicly available GWAS databases.
NIH said last week that on Aug. 25, it removed aggregate statistics files of individual GWAS studies, including the Database of Genotypes and Phenotypes (dbGaP), run by the National Center for Biotechnology Information, and the Caner Genetic Markers of Susceptibility database, run by the National Cancer Institute.
That data is still available for use by researchers who apply for access and agree to protect confidentiality, using the same approach that is used for individual-level study data.
NIH also confirmed that other groups, including the Wellcome Trust Case Control Consortium, and the Broad Institute of MIT and Harvard, that have been hosting such public datasets, also have removed the aggregate data from public view.
The TGen and UCLA research shows that it is possible to use an algorithm and Affymetrix or Illumina microarrays “to find an individual of interest in a mixture of hundreds or even thousands of people’s DNA.” Among the potential real-world applications, the researchers noted that this technique holds particular promise for forensics investigations, since it opens the door to analyzing contaminated DNA samples or sampling a large crime scene area.
“Similarly, it might provide closure to families of victims of mass disaster if individual DNA profiles could be identified from mixed samples,” Kathy Hudson, director of the Genetics and Public Policy Center at Johns Hopkins University, said in an e-mail. “Those are both two great contributions of genome science to society,” Hudson added.
This method also could potentially be used to identify individuals from a GWAS-style aggregate database, although, TGen researcher David Craig told In Sequence’s sister publication GenomeWeb Daily News, it is unlikely any information could have been compromised so far.
To dig out one specific profile from within a set, the inquirer would need to have a “highly dense genomic profile” of at least 10,000 specific genetic variations from an individual. That profile of single nucleotide polymorphisms then would be compared against the dataset to measure its uniqueness.
However complex, NIH admitted that this new analytical tool goes beyond prior expectations, which held that individual profiles would need to be compared one against another to confirm a match, and that it is now possible to detect a single profile even in pooled data.
When Craig alerted NIH to the methods that TGen and UCLA were developing, NIH tested it out and then began fashioning its policy response and then notified the Broad Institute and the Wellcome Trust about the vulnerability. Craig noted that he worked with NIH in advance of the release of this study, and that they were preparing for how to handle their public databases.
“We knew the implications, and we worked with [NIH] for a while,” Craig said. NIH “took all of this very seriously, even though it really sounds kind of farfetched,” he explained. “They went down a very pre-emptive path.”
NIH and other groups conducting GWA studies know that one of the core ethical components of their work, and a critical element of convincing people to participate in these studies, is offering the closest guarantee possible that their personal medical and genomic information will not be compromised. As genomics researchers launch major pushes to try to recruit new people to join GWA studies, they will want assurances that no one will pinpoint them and misuse their information in unethical or harmful ways.
GPPC’s Kathy Hudson described one of the ethical concerns in her e-mail: “So, the unlikely but concerning scenario is that law enforcement has a DNA sample from a crime scene, searches an NIH database, finds a match and gets a subpoena to identify what researcher provided the cohort data.
“While a fairly remote concern, and there are some protections even against subpoena, NIH did the right thing in acting to protect research participants,” she wrote.
NIH said today that it is “unaware that [this technique] has been used to compromise any information within NIH GWAS datasets,” and added that the genomics tools required are “not commonly used outside of the research community.”
Further, NIH said, “even if an individual’s SNP profile was found within a pooled dataset, all that would be learned is that this profile was contained in the dataset and, thus, it could then be associated with the characteristics of that dataset (e.g., disease or control population).”
That is not a concern because the NIH’s GWAS databases do not contain names or other such identifiable information about participants.
“The confidence level in the system is very high,” said Laura Rodriguez, who is acting director of the National Human Genome Research Institute’s Office of Policy Communications and Education.
Under a new policy adopted earlier this year, which now will cover the aggregate data from GWA studies, “Access is granted for a specific research purpose, for a specific data set, for a specific period of time.”
When the news came up that this new method was possible, Rodriguez said, NIH wanted to respond very prudently. “Our goal is to protect confidentiality of the data, and that’s why we took the cautious step,” she said.
Rodriguez expects that in the long run, this new research will not steer individuals away from participating in GWA studies, and she said that NIH expects to continue to provide access to this data, if through a more secure process.
She added that NIH is still considering how it will handle these types of databases in the future, and she admitted “this issue is broader than dbGaP now,” and that NIH is “aware of the bigger picture.”
— By Matt Jones; originally published on GenomeWeb Daily News

Scripps to use RainDance Technology in 'Wellderly' Study
The Scripps Translational Science Institute will use RainDance Technologies’ sequence enrichment application as part of its ongoing research into the genetics of healthy elderly Americans.
Scripps’ “Wellderly” Study is collecting DNA from volunteers for a gene bank. The samples will be studied by Scripps researchers to identify protective elements of the human genetic code.
Lexington, Mass.-based RainDance said that its technology will be used in a proof-of-principle study to show the effectiveness of its RainStorm technology in amplifying a large number of genomic loci across a diverse set of samples. The firms said that the technology will enable researchers to perform millions of individual PCR reactions per day using conventional thermocyclers.
“We believe our collaboration will accelerate the completion of the program’s research objectives by using RainDance’s sequence enrichment application to enhance the efficiency of STSI’s next-generation sequencing technology,” RainDance President and CEO Chris McNary said in a statement.

NSF Grants $1.3M to Study Oklahoma Sulfur Spring Microbes
The National Science Foundation has granted $1.3 million to Oklahoma scientists to use genomics and other approaches to study microbes living at a sulfur spring in the state’s southwestern region.
Under the five year program, the NSF will give $800,000 to Oklahoma State University and $500,000 to Oklahoma University to study microorganisms at the Zodletone Spring, OSU said last week.
“The spring has high sulfide and sulfur concentrations, high levels of gaseous hydrocarbons, and an absence of oxygen that makes it ideal to study and hunt for many of these unique bacteria,” OSU assistant professor of microbiology and molecular genetics, Mostafa Elshahed, said in a statement.
Scientists will use this unusual natural location as “a microbial observatory” for studying four groups of bacteria and the ecological role they play in the spring, according to Elshahed.
Along with the genomics studies, OSU said, researchers will cultivate and study these bacteria in the laboratory.
“Because these bacteria come from an environment in which oxygen is rare, some sophisticated isolation strategies will be used in the laboratory as we verify their environmental role and avoid the presence of oxygen which can kill them,” Elshahed added.
The grant also will support an educational outreach program that will allow high school students to study in a lab, conduct research, and present findings at the Junior Science and Humanities Symposia at OSU.

Research Raises Questions about DNA Barcoding Methodology
In a paper that appeared in the Proceedings of the National Academy of Sciences last week, a team of researchers from Brigham Young University suggest that DNA barcoding may inadvertently overestimate species diversity by amplifying pseudogenes in the nucleus.
The researchers warned that nuclear mitochondrial pseudogenes, which were rife in the four grasshopper and four cave crayfish species they tested, could lead to species misidentification or overestimates during DNA barcoding. Those involved in the International Barcode of Life, or iBOL, project counter that pseudogenes are well-known and are already being addressed.
“We think it’s a pretty reasonable idea to be able to identify species with genetic tags,” senior author Keith Crandall, a biologist at BYU, told In Sequence’s sister publication GenomeWeb Daily News. But, he said, pseudogenes could wreak havoc with barcoding efforts if researchers do not take adequate steps to account for them. “If you weren’t watching for such things, [pseudogenes] would pose some problems for DNA barcoding.”
“Sadly, the authors of this paper do not understand barcoding protocols,” Paul Hebert, director of the Biodiversity Institute of Ontario at the University of Guelph, told GWDN. Calling the title of the paper misleading, he said barcoders have been aware of nuclear pseudogenes for years and have already designed strategies for dealing with the problems described in the paper.
DNA barcoding, in which a standard genetic sequence is determined to catalog and identify species, has been touted as a tool for everything from exploring biodiversity to tracking poachers to ensuring food safety.
But because barcoding relies on mitochondrial sequence, it may be confounded by nuclear mitochondrial pseudogenes or “numts” — chunks of mitochondrial DNA that are inserted into the nuclear genome, Crandall explained. The function of the numts, if any, is unknown.
Crandall and his team encountered numts during a phylogeography project on cave crayfish, during which they sequenced small stretches of DNA using primers designed to anneal to mitochondrial DNA. They came up with a large number of numts — as did another research team working on grasshoppers.
The two groups decided to collaborate, characterizing the numts in the species. They found that many of the grasshopper and crayfish species contained one or several numts that could be amplified with mitochondrial DNA. Most, but not all, contained numt signals such as indels, in-frame stop codons, and certain nucleotides.
The paper went on to explore the potential pitfalls of numts for DNA barcoding and described approaches for minimizing these problems — for example, focusing on mitochondria-rich tissues, amplifying longer sequences, or looking at additional markers that could decrease the risk of barcoding numts.
“Whereas DNA barcoding strives for rapid and inexpensive generation of molecular tags, we demonstrate that the presence of [cytochrome c oxidase I] numts makes this goal difficult to achieve when numts are prevalent and can introduce serious ambiguity into DNA barcoding,” the authors wrote.
“Given that pseudogenes were reported 25 years ago, it’s not new news to us,” Hebert said. He said the team focused on species in which numts are particularly common and drew conclusions based on these eight species. Barcoding projects such as iBOL, he said, include data from thousands of species and are carried out using methods that differ from those described in the paper.
Hebert emphasized that the Barcoding of Life Data Systems, or BOLD, database scours sequences for indels, stop codons, and other tell-tale pseudogene signs. Barcoding sequences are also screened against a pool of sequences representing known contaminants, he said. Sequences that raise red flags are then set aside for further assessment, including longer sequence analysis or RT-PCR.
And, he noted, large barcoding studies typically amalgamate DNA barcode data with information provided by taxonomy, morphology, ecology, and other biological measures. “We’ve never advocated that sequence information alone is declarative for species boundaries,” he said.
“In certain taxonomic groups we need to do better in adding to the standard barcoding,” Hebert admitted. He said barcoders are working to come up with new solutions for analyzing pseudogene-prone groups. Some options include weeding out pseudogenes by using nuclear histones as a marker for nuclear DNA or developing new primer sets for pseudogene-rich species. Alternatively, he said, it may eventually be simpler to tease nuclear and mitochondrial DNA apart with commercial kits.
But, Hebert emphasized, pseudogenes are not usually a concern in the majority of species — especially those in the most diverse species groups.
While he is confident that iBOL is taking adequate steps to address numts, Hebert is concerned that individuals who naively read the PNAS paper might mischaracterize iBOL’s work plan. He and others are currently preparing a response to the paper.
Overall, though, Hebert said such criticisms will ultimately serve to make the program stronger. “Barcoding has weathered many, many other assaults,” he said. “We’re ready to weather this storm, too.”
For his part, Crandall conceded that large barcoding projects such as iBOL “have excellent strategies for quality control of data” and are already applying many of the steps he and his colleagues recommended. Still, he said, even though some people are already worrying about numts does not mean everyone in the field is addressing the problems appropriately.
“The message is relevant for everybody doing barcoding,” Crandall emphasized. In particular, he noted, the paper should be a wake-up call for those who are attempting to do DNA barcoding projects that rely on databases such as GenBank that do not use the same sort of pseudogene screening methods employed by BOLD.
— By Andrea Anderson; originally published on GenomeWeb Daily News

NHGRI Offering $12.5M for GWAS of Treatment Response and Coordinating Center
The National Human Genome Research Institute plans to spend $8.8 million to fund three to five genome-wide association studies of treatment response in randomized clinical trials over the next three years, and will use another $3.7 million for a coordinating center to support those programs.
The National Institutes of Health, in two requests for applications last month, said it wants NHGRI to use the coordinating center, and community resources such as the Database of Genotype and Phenotype at the National Center for Biotechnology Information, to support “rapid and widespread sharing” of the genotype data that these studies generate. For the purposes of this program, “rapid” means that data and samples must be ready for submission within nine months of the award, and for unmasked analysis within 12 months of the award.
NIH stipulates that applicants should not include the costs for genome-wide genotyping in their applications, as these will be supported separately by NHGRI.
NHGRI is encouraging population-based studies, and does not require applicants to propose hospital or clinic-based research programs. For this research program, NHGRI is defining a treatment as “an intervention, whether involving drug, dietary, and/or lifestyle modification, that aims to reduce morbidity and/or prevent disease.”
NHGRI has set three goals for the program. Researchers should seek to identify genetic variants that influence individual treatment response; determine whether specific treatments are more or less effective in groups that are defined by genotype; and develop and disseminate methods for adding genome-wide technologies to randomized clinical trials and interpreting the results in a randomized treatment context.
For this grant program, the budget period covers three years, and direct costs are limited to $375,000 in fiscal 2009, $600,000 in fiscal 2010, and $610,000 in fiscal 2011.
Over the same period, the Coordinating Center program will provide one grantee with direct costs of around $1.2 million per year.

Applied Biosystems Declares Dividend
Applied Biosystems said last month that its board of directors has declared a quarterly dividend of $.0425 per share of ABI common stock.
The dividend is payable on Oct. 1 to shareholders of record as of the close of business on Sept. 2. ABI had nearly 169 million shares outstanding as of the end of June.

California Grants Navigenics, 23andMe Licenses to Offer Services in State
California will allow two of the fourteen consumer genomics companies it slapped with cease-and-desist letters several months ago to again market their genotyping services in the state, the state’s Department of Public Health confirmed last month.
The CDPH inspected both companies, and on Aug. 7 granted a license to operate in the state to Navigenics, and a week later to 23andMe. Both companies were among the group that CDPH in June said were operating outside of state regulations.
“State law requires these laboratories to have a license, obtain a physician's order from the consumer, and demonstrate how they validate the results of their tests,” CDPH spokesperson Lea Brooks told In Sequence’s sister publication GenomeWeb Daily News in an e-mail.
Brooks also said that “several” of the other companies that received the cease-and-desist notification have now applied for licenses in the state, but noted that the state is not currently disclosing further information about how it is investigating the other laboratories.
Navigenics and 23andMe are both headquartered in California.
Rachel Cohen, a spokesperson for 23andMe, told GWDN that the company has been involved in discussions with the state for “a few weeks” and that the firm is “happy” that the state was satisfied with the company’s processes.
The firm is not commenting on the discussions it continues to have with the state, Cohen said, but she confirmed that 23andMe has satisfied the state’s regulation for physician oversight.
California may have had a breakthrough over how to gauge the validity of consumer genomics when it opted to review Navigenics’ analytical service as a lab, company CEO Mari Baker told GWDN today.
She said that the state quelled its concerns over the validity of the service when it focused on how the company performs its analysis, “and they were satisfied with what they saw, with our appropriate quality controls.”
The company’s genotyping function, the chemical end of the service, is provided by Affymetrix, which has a licensed lab in California.
“This is all a new area, and the state was incredibly responsive in dealing with us and others,” Baker added, saying the state “tried to really dive in and understand how we do what we do and if it’s reliable and replicable for consumers.”
Baker explained that CDPH reviewed the company’s “processes and procedures to ensure that consumers have some degree of quality and confidence in what they’re getting.”
Navigenics also has been involved in discussions with the Centers for Medicare and Medicaid Services, which Baker suggested may offer a solution in the future for the consumer genomics field by adopting a federal framework.
In addition, the firm is opening communication lines with the states “one at a time,” she said. The company also recently has been licensed by the state of Maryland, and has been working with the Personalized Medicine Coalition to develop an approach for federal and state regulators, she added.
“I hope this [California approach] could be a benefit to help give people confidence in the quality and allow us to keep moving forward, to educate physicians, and to educate consumers,” Baker said.
— By Matt Jones; originally published on GenomeWeb Daily News

Comparative Genomics Yields Clues to African Crop Virus
In a paper scheduled to appear in the September issue of the Journal of General Virology, an international team of researchers sequenced more than 80 maize streak viruses in an effort to understand the evolution of MSV-A — a strain that damages maize crops in sub-Saharan Africa. The research uncovered a handful of new grass-adapted MSV strains and provided new insights into the emergence of the disease-causing strain. Now, researchers say, this information is being applied to develop maize resistance strategies.
“Given the frailty of African agriculture and perpetual famine risks with millions of lives at stake, MSV is actually one of the most important plant pathogens worldwide,” senior author Darren Martin, an infectious disease researcher at the University of Cape Town, said in a statement. “We wanted to learn more about how the virus emerged and spread so we can develop new ways to fight the diseases it causes.”
Maize streak disease, caused by the MSV-A strain, is transmitted by leafhoppers and leads to yellowing and severe disease in African maize crops. In contrast, four grass-adapted MSV strains — MSV -B to -E — mainly infect crops such as wheat, rye, barley, and oats, causing only mild damage in maize.
The researchers suspected that understanding the genetics of these grass-adapted strains could improve their understanding of MSV-A’s biology and evolution as well. They sequenced the genomes of 83 MSVs from African grasses in South Africa, Zimbabwe, Mozambique, Nigeria, Uganda, Burundi, Rwanda, Mali, and La Reunion. In the process, they uncovered six new strains, dubbed MSV-F to –K.
By combining their own data along with publicly available sequence data for MSV and non-MSV streak viruses, the team began pinpointing recombination hotspots in the MSV genome. They found that more than 90 percent of the MSVs appear to be recombinant, with the most pathogenic MSV-A strain representing a combination of two apparently harmless grass-adapted strains.
“[E]very MSV that causes severe disease in maize has descended from an ancestral virus that was the recombinant offspring of two relatively harmless wild grass infecting viruses,” Martin noted in a statement. “This chance recombination event could be the reason MSV has become such a serious problem.”
Even so, Martin told In Sequence’s sister publication GenomeWeb Daily News, there are limitations to MSV recombination, with MSV strains apparently undergoing conserved gene swapping events. “The patterns are evolutionarily constrained,” Martin said. “In the design of resistance strategies, we are specifically taking that into account.”
The patterns of MSV infection were also telling. Overall, the researchers found significant MSV strain differences in southern Africa, East Africa, West Africa, and La Reunion. In contrast, the MSV-A strains were relatively similar in each of these regions. The team’s conclusion: the MSV-A strain may be moving across Africa more quickly than other, less damaging MSV strains.
That, in turn, may be due to the strain’s ability to infect numerous plant species. Indeed, based on their data, the researchers speculated that MSV-A might be more promiscuous than anticipated, infecting a greater variety of grasses than any of the other MSV strains.
Together, that convergence of recombination events, broad host range, and increased transmission speed appear to have contributed to the emergence of increasingly pathogenic MSV-A viruses, Martin said.
By collecting and sequencing MSVs from additional parts of Africa, the researchers hope to learn even more about the nature of MSV recombination, evolution, and the emergence of pathogenic strains such as MSV-A.
In addition, using their knowledge of MSV recombination traits and host resistance factors, the researchers are developing new tactics to combat maize streak disease and curb its spread. “There’s very little you can do to stop a virus from emerging,” Martin said. “You can just prepare for it to emerge.”
For instance, Martin said, co-author Dionne Shepherd, a virologist and plant biotechnologist at the University of Cape Town, is spearheading an effort to create transgenic maize lines with MSV resistance strategies. Those lines, which are being developed in conjunction with the South African company Pannar Seed, are currently being tested and are predicted to be on the market within three years or so, Martin said.
And although there are regulatory hurdles, he added, genetically modified crops generally face less opposition in Africa than in other parts of the world. “Starvation and malnutrition are by far the biggest killer in Africa,” Martin said. “Being a bit squeamish about GM plants and things is not something that African governments are going to do.”
— By Andrea Anderson; originally published on GenomeWeb Daily News

Johns Hopkins Center Launches Genetic Rights Educational Effort
Johns Hopkins University’s Genetics and Public Policy Center has launched an educational effort aimed at informing the public of how their genetic data can and cannot be used under the recently enacted Genetic Information Nondiscrimination Act.
As part of its so-called “Project GINA,” the GPPC plans “to disseminate information” about the legislation to healthcare stakeholders and the general public, GPPC Law and Policy Director Susannah Baruch told In Sequence’s sister publication Pharmacogenomics Reporter last month.
As part of its plan, the GPPC will launch a website describing and explaining the federal law that bars health insurers and employers from discriminating based on genetic data. The website, slated to launch this month, will outline what protections are provided under the law, contain a FAQ page, and will provide updates describing how federal and state regulators are implementing the law.
Until the launch of the site, however, GPPC is providing information on GINA under the “What’s Happening” heading on its homepage.
Since GINA became law in May, GPPC Director Kathy Hudson has said that the center intends to spearhead a “major education campaign” to inform “doctors and patients … of these new protections, so that fear of discrimination never again stands in the way of a decision to take a genetic test that could save a life."
Ahead of the website’s launch, GPPC has made preliminary efforts to educate the public and stakeholders about the law through peer-reviewed publications, webinars, and fact sheets. GPPC recently hosted a series of webinars with the Bureau of National Affairs and has disseminated informational fact sheets describing GINA’s provisions.
Additionally, Hudson co-authored an article in June in the New England Journal of Medicine with Francis Collins, former director of the National Human Genome Research Institute, and M.K. Holohan, an NHGRI senior health-policy analyst, asserting that “it will take much more than sound regulations to ensure that we reap the full benefits” of GINA.
GPPC said it plans to work with Jeremy Gruber of the National Workrights Institute and Karen Pollitz of Georgetown Health Policy Institute to specifically target information to clinicians, health insurers, employers, researchers, ethics boards, and state legislatures. The center will also assist agencies charged with implementing provisions for GINA, Baruch noted.
— By Turna Ray, editor of Pharmacogenomics Reporter

UC Berkeley, JGI Collaboration Sequences Trichoplax Genome
An international research team led by scientists at the University of California at Berkeley and the US Department of Energy’s Joint Genome Institute has completed the draft genome of an organism representing one of the earliest forms of animal life.
The Trichoplax adhaerens genome, published last month in Nature, reveals the genetics behind a group of animals called placozoans — tiny, disc-shaped creatures with just four or five documented cell types. The work is helping to clarify the phylogeny of placozoans and also revealing the surprising complexity housed in the compact Trichoplax genome — information that is expected to shed light on early stages in animal evolution.
“With the genome in hand, renewed interest in this ‘simple’ animal with a complex genome will add to our appreciation of animal diversity and perhaps yield fundamental insights into early animal evolution,” the authors concluded.
“People are really interested in how Trichoplax relates to other animals,” lead author Mansi Srivastava, a graduate student in Daniel Rokhsar’s lab at the University of California at Berkeley, told In Sequence’s sister publication GenomeWeb Daily News.
Trichoplax is composed of two epithelial layers flanking core fiber cells that contain more than one nucleus. Although Trichoplax is a “simple critter with just a few different cell types,” Srivastava said, many have hypothesized that it actually represents the earliest form of animal life. Even so, Trichoplax’s phylogenetic placement with respect to other animals has been hotly debated.
In an effort to get to the bottom of Trichoplax biology and evolution, the researchers used whole-genome shotgun sequencing to determine the roughly 98 million base pairs of the Trichoplax genome to about eight-fold coverage. They then assembled and analyzed this sequence data to get a handle on Trichoplax function and phylogeny.
By comparing about a hundred nuclear genes between Trichoplax and other animals, Srivastava explained, the researchers were able to shift placozoan placement in the animal tree. In contrast to mitochondrial DNA sequence analyses that put placozoans at the base of this tree, branching before other animals, the latest data suggests placozoans diverged in the Precambrian period before both cnidarians, such as anemones and jellyfish, and animals with bilateral symmetry, but after some sponges.
The researchers also gained a better appreciation for the genetic complexity of this seemingly straightforward organism. “It is a really simple-looking organism,” Srivastava said.
Still, she emphasized, the small Trichoplax genome contains sequences coding for many of the major transcription factors, signaling proteins, and pathways found in humans and other animals, including some involved in neuron development. “Even though Trichoplax doesn’t have a neuron, it has many of the genes that we use to make a neuron,” she said.
The organism’s genome also retained some conserved introns that are found in the human genome but which have been lost from the genomes of fruit flies, sea squirts, and other animals. “The observation of blocks of conserved synteny is consistent with a relatively low rate of local rearrangement in Trichoplax,” the authors wrote.
That, in turn, suggests that these genes were present in the last shared common ancestor between humans and Trichoplax, some 600 million years ago. “We still retain some of the signatures of how genes were organized in the common ancestor,” Srivastava explained.
Overall, the research provides new information about basal animal relationships. Still, Srivastava noted, only by sequencing additional genomes will researchers be able to resolve the details of these relationships. To that end, she said that the team is currently unraveling the genome of a sponge called Amphimedon queenslandica.
— By Andrea Anderson; originally published on GenomeWeb Daily News

Myriad Mulls Split of Molecular Dx, Pharma Businesses
Myriad Genetics said last month that it will conduct a review of its business and consider the possibility of splitting up its molecular diagnostic business and pharmaceutical business as independent operating entities.
The Salt Lake City-based firm noted the possibility of the split or other corporate restructuring in a statement announcing its fourth-quarter and fiscal-year 2008 results.
It reported fourth-quarter molecular diagnostic revenues of $64.7 million, up 53 percent from $42.3 million in the fourth quarter of fiscal 2007. Overall, revenues for the quarter were $166.9 million, compared to $45.5 million in revenues for Q4 of 2007, with $100 million coming from pharmaceutical sales, due entirely to an up-front license payment from Lundbeck for European marketing rights to Flurizan.
Myriad also reported that it was profitable for both the fourth quarter and fiscal 2008. The firm’s Q4 net income was $65.5 million, or $1.40 per share, compared to a net loss of $7.8 million, or $.18 per share, in the comparable period a year ago. Its FY2008 profit was $47.8 million, or $1.02 per share, compared to a loss of $35 million, or $.85 per share, for fiscal 2007.
Myriad’s R&D expenses for the fourth quarter more than doubled to $55.2 million, compared to $24.8 million for the same period in 2007. Its SG&A costs rose to $36.4 million, from $30.2 million year over year.
As of June 30, Myriad had $420.1 million in cash, cash equivalents and marketable investment securities. The firm also noted that it has no debt and no convertible securities. 
Myriad’s strategy up to this point has been to use its cash flow from the profitable molecular diagnostics business to invest in drug development activities. The firm said that now that it has become profitable, it will be viewed differently by Wall Street.
“The company's goal will be to develop a strategy that maximizes both the potential of our molecular diagnostic business, and the opportunity associated with our pharmaceutical research and development programs — thereby maximizing shareholder value,” Myriad said in a statement.
It said that such a strategy could mean a split of the two businesses. Myriad noted that it has retained investment banking firm JP Morgan to assist it in a review of its business and an evaluation of its strategic alternatives. The firm expects JP Morgan and Myriad’s management to present their analysis to the board of directors in the fall.

The Scan

Self-Reported Hearing Loss in Older Adults Begins Very Early in Life, Study Says

A JAMA Otolaryngology — Head & Neck Surgery study says polygenic risk scores associated with hearing loss in older adults is also associated with hearing decline in younger groups.

Genome-Wide Analysis Sheds Light on Genetics of ADHD

A genome-wide association study meta-analysis of attention-deficit hyperactivity disorder appearing in Nature Genetics links 76 genes to risk of having the disorder.

MicroRNA Cotargeting Linked to Lupus

A mouse-based study appearing in BMC Biology implicates two microRNAs with overlapping target sites in lupus.

Enzyme Involved in Lipid Metabolism Linked to Mutational Signatures

In Nature Genetics, a Wellcome Sanger Institute-led team found that APOBEC1 may contribute to the development of the SBS2 and SBS13 mutational signatures in the small intestine.