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Pacific Biosciences, Beijing Genomics Institute Shenzhen, Fluidigm, Stanford University, Sequenom, Chinese University of Hong Kong, Applied Biosystems, Invitrogen, Life Technologies, International Cancer Genome Consortium, Transgenomic, Geospiza, VizX, My

Pacific Biosciences Raises $20M
Menlo Park, Calif.-based Pacific Biosciences said two weeks ago that it recently received $20 million in funding from new investor Blackstone Cleantech Venture Partners.
Including the new funds, Pac Bio has raised $120 million in its latest financing round. It plans to use the resources to support its efforts to bring its single-molecule, real-time DNA sequencing platform to market by the second half of 2010. The company said it has raised $193 million since it was founded in 2004.
Pac Bio also announced that Elaine Mardis, co-director of the Washington University School of Medicine Genome Sequencing Center, has joined its scientific advisory board (see Paired Ends in this issue). Mardis said in a statement that she is “convinced that Pacific Biosciences has the technology that will allow for dramatic advances in sequencing and truly enable ultra fast, accurate, and inexpensive DNA sequencing.”

BGI Assembling Panda Genome De Novo from Short Reads; 10 More Large Genomes Underway
The Beijing Genomics Institute in Shenzhen is assembling the panda genome de novo from short sequence reads generated on Illumina’s Genome Analyzer and has embarked on 10 additional de novo sequencing projects of plants and animals, according to Illumina.
BGI said in October that it had completed sequencing the panda genome, a project it started in March, but provided no details on the accomplishment (see In Sequence 10/21/2008).
In a newsletter published by Illumina last month, BGI Director of Bioinformatics Ruiqiang Li said that he and his colleagues generated paired-end reads of 50- to 75-base pair length at 50-fold coverage in less than one month for the panda genome.
He and his team are developing new analysis tools and are currently able to assemble a large genome like the panda’s in approximately two days, according to Li, using SOAPdenovo, a new de novo genome assembly software that is part of the Short Oligonucleotide Alignment Program.
According to the Illumina article, BGI has already started 10 additional de novo sequencing projects of plants and animals.

Fluidigm Licenses IP from Stanford's Quake Lab for Fetal Genetic Screening in Maternal Plasma Using Next-Gen Sequencing
Fluidigm said this week that it has taken co-exclusive licenses to intellectual property developed at Stanford University for detecting fetal genetic characteristics in maternal plasma, including the use of a combination of digital PCR and high-throughput sequencing for that application.
The licenses cover a technique published by Stanford’s Stephen Quake and colleagues in October (see In Sequence 10/14/2008) that used Illumina’s Genome Analyzer to detect trace amounts of fetal DNA in a pregnant woman's blood to determine whether any chromosomes are overrepresented. The researchers believe this noninvasive technique can provide a much earlier and safer diagnosis for fetal aneuploidy than current invasive testing procedures such as amniocentesis and chorionic villus sampling.
At the time, Quake said his team also planned to test the method with other sequencing technologies, including the Helicos BioSciences platform, which is based on a single-molecule sequencing approach that Quake pioneered. The reason for this is a slight G/C bias the scientists observed using the Illumina sequencing platform.
Specifically, the licenses cover Stanford inventions relating to noninvasive fetal genetic screening by digital analysis, noninvasive diagnosis of fetal aneuploidy by sequencing, and digital PCR for rapid prenatal diagnosis of fetal aneuploidy.
In the study published by Quake and colleagues in October, the researchers used Fluidigm's BioMark Digital Array digital PCR technology to count individual molecules and “set the exact parameters for sequencing steps that helped determine the amounts of critical fetal DNA,” Fluidigm said in a statement.
Quake is a co-founder of Fluidigm and the chair of the company's scientific advisory board.
Sequenom is also developing methodologies for noninvasive fetal genetic screening, including methods based on sequencing and digital PCR. The company has published several papers describing its approach, including two studies in PNAS that were published online last week and this week (see below).

Sequenom, Collaborators Publish Study on Sequencing-Based Method to Detect Down Syndrome
Sequenom and collaborators at the Chinese University of Hong Kong have published a study that validates the use of a sequencing-based method for noninvasive prenatal testing for Down syndrome, the company said this week.
In a paper scheduled to be published online in PNAS this week, the collaborators demonstrate that the method, based on sequencing with the Illumina Genome Analyzer, “accurately quantified maternal plasma DNA sequences for fetal Trisomy 21, or Down syndrome, in samples taken from women in the first and second trimesters of pregnancy,” the company said.
While the approach is similar to one under development by Stephen Quake and colleagues at Stanford University that was published in October (see above), Sequenom said that its study is the first to suggest that the approach can be effective in women in the first or second trimester of pregnancy, most of whom had not undergone invasive procedures.
Sequenom’s study used the Illumina Genome Analyzer to quantify maternal plasma DNA sequences in samples from 28 women in the first and second trimesters of pregnancy. All 14 Down syndrome fetuses and normal fetuses were correctly identified, the company said.
Dennis Lo, a co-author of the study and a professor of medicine at the Chinese University of Hong Kong, said in a statement that the new method is likely “several years away as a commercially viable test,” but may offer “a complementary approach” to an RNA SNP allelic ratio approach that Sequenom and the university are developing for Trisomy 21 detection that is slated for launch next June. “The two approaches have performance and cost profiles which would potentially be synergistic to one another," he said.
Sequenom has licensed the exclusive rights to the methods used in the current study from the university.
Harry Stylli, president and CEO of Sequenom, said in a statement that while the company continues to “evaluate other promising approaches” for noninvasive fetal diagnostics, “we believe massively parallel genomic sequencing is a promising approach to prenatal diagnostics that may offer a future extension to our SEQureDx prenatal diagnostics franchise.”
In addition to the IP developed at the Chinese University of Hong Kong, Sequenom also holds exclusive licenses to methods for noninvasive prenatal diagnostics developed at the University of Oxford. The company noted that because its rights to these methods are platform-independent, they provide “exclusivity (with the narrow exception in Europe for RT-PCR-based Rhesus D tests) for development and commercialization of noninvasive prenatal screens and tests on any platform and are not limited to the company's MassARRAY platform.”
This week’s study follows a paper that Sequenom and its collaborators published last week in PNAS that described a size-selection strategy to enrich for fetal DNA in maternal blood.
For that study, the researchers used Fluidigm’s Biomark system and Digital Arrays as part of a method called relative mutation dosage, or RMD, to compare the relative amounts of mutated and normal DNA sequence present in each sample.
A Sequenom official told In Sequence’s sister publication GenomeWeb Daily News last week that other than the use of the Fluidigm products, Sequenom has exclusive rights to the technology described in that paper, and that “everything” described in the study “is proprietary, including the use of digital PCR for prenatal diagnostics."
Fluidigm said this week that it has licensed rights to IP developed at Stanford University for detecting fetal genetic characteristics in maternal plasma, including the use of digital PCR for that application (see above).

Following ABI and Invitrogen’s Merger to Form Life Tech, All ABI Shareholders to Receive Cash and Stock
Life Technologies, the new entity formed by the merger of Applied Biosystems and Invitrogen on Nov. 21, said last week that all ABI shareholders will receive a mix of cash and Life Technologies stock, including those shareholders who elected to receive all cash, because the available cash consideration for the merger was oversubscribed. 
In an SEC filing last week, Life Tech said that the consideration for the merger, which closed Nov. 21, consisted of $3.23 billion in cash and 80,835,108 shares of its stock. Invitrogen’s shares closed at $22.23 that day.
The company said earlier last week that around 80 percent of ABI shareholders elected to receive all cash, while 2 percent elected to receive Life Tech stock and 7 percent elected to receive a mixed consideration of cash and stock. Another 11 percent did not make a valid election and therefore will receive mixed consideration.
Under the terms of the pro-rated merger consideration, those shareholders who elected to receive cash will receive $18.65 in cash and .4427 shares of Life Tech stock for each share of ABI stock. Those who elected to receive stock will receive $1.91 in cash and .8261 shares of Life Tech stock for every share of ABI stock owned. Shareholders who opted for the mixed consideration and those who did not make a valid election will receive $18.15 in cash and .4543 shares of Life Tech stock for every share of ABI stock owned.
Life Tech said that it will disburse these proceeds this week.
The original terms of the merger agreement called for ABI shareholders to receive $38 for each share of ABI stock they owned in the form of Invitrogen common stock and cash, but this offer was contingent on the 20-day volume-weighted average price of Invitrogen common stock being in the range of between $43.69 and $46.00 three business days prior to the close of the transaction.
Life Technologies began trading on the Nasdaq exchange under the symbol “LIFE” last week.

International Cancer Genome Consortium Announces Eight New Projects
The International Cancer Genome Consortium said last month that eight countries and 11 funding agencies have signed on to participate in comprehensive analyses of the genomic changes underlying eight types of cancer.
The new projects are designed to complement the Cancer Genome Atlas pilot projects on brain, lung, and ovarian cancers. The goal is to map the genetic and genomic changes occurring in different types and stages of cancer in an effort to understand disease biology and develop new preventive strategies, diagnostics, and therapies.
Each participating organization will tackle one or more types of cancer using samples collected from about 500 individuals. Data collection and analysis will be standardized and is to follow ICGC guidelines released in April. Participating countries and agencies will also use common informed consent and ethical oversight standards. The estimated cost of each project is $20 million.
The ICGC anticipates additional countries and groups joining the effort through other projects in the next decade and eventually plans to study 50 types of cancer. Overall, the ICGC expects to generate some 25,000 times more data than the Human Genome Project.
ICGC data will be made available to the research community freely and rapidly, and participants are expected to agree that they will not file patents or make intellectual property claims on ICGC project primary data.
The new ICGC projects are:
  • An Australian study funded by the National Health and Medical Research Council (the tumor type has not yet been announced)
  • A Canadian study funded by the Ontario Institute for Cancer Research on pancreatic cancer
  • A Chinese study funded by the Chinese Cancer Genome Consortium on stomach cancer
  • French studies on alcohol-related liver cancer and HER2-positive breast cancers funded by the Institut National du Cancer
  • An Indian study on oral cavity cancer funded by the Department of Biotechnology Ministry of Science and Technology
  • A study of virus-related liver cancer in Japan, funded by RIKEN, the National Cancer Center, and the National Institute of Biomedical Innovation
  • A Spanish study of chronic lymphocytic leukemia funded by the Spanish Ministry of Science and Innovation
  • A study of several breast-cancer subtypes in the UK, funded by the Wellcome Trust and the Wellcome Trust Sanger Institute

Transgenomic Gets SBIR Grant to Develop Technology for Whole-Genome Analysis
Transgenomic said last month that it has received a $100,000 Small Business Innovation Research grant to support the development of the firm’s Surveyor Endonuclease Adaptor-ligated Libraries technology.
The SEAL technology is a high-throughput method for whole-genome analysis (see In Sequence 6/24/2008). The Omaha, Neb.-based firm said that it can identify DNA variations between a reference genome and a test genome and could potentially reduce the cost of whole-genome analysis of such variations to under $10,000.
By focusing on regions of DNA variation, the SEAL technology eliminates the sequencing of vast amounts of non-variant DNA, said Transgenomic, but it also is not limited to assessment of known common SNPs.
Craig Tuttle, president and CEO of Transgenomic, said that the grant, which lasts six months, supports the firm’s belief that its technology “will have a significant impact on whole-genome analysis for pharmacogenomic studies in personalized medicine and bacterial drug resistance research.”

Geospiza Acquires GeneSifter Microarray Software from VizX
Geospiza said last month that it will acquire the GeneSifter Data Analysis product from VizX Labs.
Seattle-based Geospiza said GeneSifter is a gene expression analysis platform for both microarrays and next-generation sequencing. It expects the integration of GeneSifter with its own FinchLab will be “fast and seamless.”
“GeneSifter will expand our market by addressing the demand for sophisticated data analysis across microarray, capillary electrophoresis, and next-generation sequencing platforms," Geospiza President Rob Arnold said in a statement.

Myriad Wins BRCA1 Patent Appeal in Europe; Scope Limited
A technical board of appeal of the European Patent Office decided last month that Myriad Genetics’ patent covering the BRCA1 gene be maintained but in an amended and more limited form.
The patent, EP 699754, was granted in May 2001 and covers methods for using the BRCA1 and BRCA2 genes for diagnosing predisposition to breast and ovarian cancer. Later that year, a number of parties, including several French research institutes and various national centers for human genetics, filed an opposition to the patent. That opposition led the Opposition Division of the EPO to revoke the patent.
Myriad then filed an appeal, requesting that its patent be maintained in a form that restricts the original patent claims. The board of appeal has now decided to maintain the patent in an amended form.
“The patent now relates to diagnostic methods for the detection of a predisposition for breast and ovarian cancer caused by a specific group of mutations of the gene, so-called shift mutations,” the EPO said in a statement. “It does not contain claims directed to the BRCA1 gene itself or to mutated forms thereof.”
The EPO said that the patent cannot be further contested at the European level.
The EPO’s decision may interfere with genetic testing for breast and ovarian cancer in many European countries, according to a statement issued by geneticists from the Center for Human Genetics at the University of Leuven in Belgium and the Institut Curie in Paris. However, they said the anticipated impact will be small.
“For a molecular geneticist, the latest decisions hardly make sense,” they said. “Also, after seven years of discussing the content of these patents, the latest decisions do not appear to make it any clearer at all how the claimed inventions, which are limited to certain mutations and exclude other mutations, will have to be interpreted in practice.”
Myriad uses the BRCA1 and BRCA2 genes in its BRACAnalysis testing service for assessing a woman’s risk of developing breast or ovarian cancer.

Researchers Report Early Results from Woolly Mammoth Genome Project
Scientists have obtained sequence data for the majority of the woolly mammoth’s nuclear genome.
An international research team applied metagenomics to preserved woolly mammoth hair taken from two different animals in order to sequence more than three billion bases of mammoth nuclear DNA. The research, appearing online two weeks ago in Nature provides information about mammoth evolutionary history and population structure — supporting the notion that more than one group of mammoths roamed Siberia. And, researchers say, it may offer a valuable glimpse into the genetics of extinction.
“This study shows that nuclear genome sequencing of extinct species can reveal population differences not evident from the fossil record, and perhaps even discover genetic factors that affect extinction,” senior author Stephan Schuster, a professor of biochemistry and molecular biology at Pennsylvania State University, and his colleagues wrote.
Researchers from two independent groups first extracted DNA from preserved mammoth samples in the mid-1990s. Since then, several studies have been done on woolly mammoth mitochondrial DNA, including a paper by Schuster and his colleagues in PNAS this June (see In Sequence 6/17/2008). Based on carbon-dating and mitochondrial genome sequence, the team concluded that at least two distinct groups of mammoths lived in Siberia, becoming extinct thousands of years apart.
To minimize degradation problems, Schuster and his colleagues analyzed DNA extracted from woolly mammoth hair shafts rather than bone. Hair is particularly useful because it can be more easily decontaminated than bone samples, Schuster told In Sequence’s sister publication, GenomeWeb Daily News. And though it’s been debated in the past, he believes hair yields better quality DNA that has undergone less damage.
Using Roche 454 sequencing, the researchers generated 4.17 gigabases of sequence data from hair samples taken from two animals: a Siberian mammoth specimen called M4 that lived roughly 20,000 years ago and a mammoth specimen dubbed M25 that lived about 59,000 years ago.
Of the more than four billion bases, 3.3 gigabases appear to represent mammoth sequence — 2.982 gigabases from M4 and 239 megabases from M25. Overall, about 90 percent of the DNA sequenced from the younger specimen appeared to come from the mammoth, compared with nearly 60 percent from the older sample.
The source of the remaining DNA is currently under investigation, Schuster said. Some may belong to the mammoths while some may come from associated bacteria and fungi. That should become clearer as researchers working on the Mammoth Biome Project discern which organisms were associated with mammoth specimens, Schuster noted.
The team was shooting for about one-fold coverage of the mammoth genome, which they originally estimated to be about 3.3 billion bases. But they now believe the genome is actually more than four billion base pairs — about the same size estimated for the African elephant genome. That means they likely achieved somewhere around 0.7 to 0.8 times coverage of the genome, Schuster explained.
“Only after the genome of the African elephant has been completed will we be able to make a final assessment about how much of the full woolly-mammoth genome we have sequenced,” lead author Webb Miller, a Penn State researcher who spearheaded the bioinformatics portion of the project, said in a statement.
The African savanna elephant genome is currently being sequenced by researchers at the Broad Institute, who shared elephant sequence data with those involved in the mammoth project.
Although they haven’t yet been able to decipher a great deal of information about protein-coding sequences present in the genome, the researchers discovered that mammoths had distinct amino acid sequences in regions that are very well conserved in the 50 other mammalian genomes — potentially due to the lifestyle or habitat differences, Schuster suggested.
The draft genome also appears to confirm the notion — proposed from mitochondrial DNA data — that there were at least two genetically distinct groups of mammoths in Siberia. “We believe that there may have been a sub-species, at least,” Schuster said.
In addition, the nuclear sequence corroborated previous divergence times between mammoths and elephants and between mammoth sub-groups. Based on their results, the team concluded that mammoths diverged from African elephants about 7.6 million years ago and from Indian elephants roughly 6.7 million years ago, while the two known mammoths groups diverged from one another between 1.5 and 2 million years ago.
The researchers estimated that the M4 mammoth shares about 99.4 percent sequence identity with the African elephant. In general, Schuster said, the rate of divergence in the elephant lineage appears to be about half that described for primates.
Based on the available woolly mammoth sequence so far, the researchers determined that it will be possible to get high-fidelity, high-coverage data on the mammoth genome once the African elephant genome has been sequenced to between ten and 30-fold coverage. Schuster said the future of the woolly mammoth project will depend on available funding, but he eventually hopes to sequence two complete mammoth genomes to the same level of resolution currently used for living organisms.
And though sequencing ancient DNA “seems cool and intriguing,” Schuster emphasized that this sort of research also provides hints about the “biology of extinction and preservation” that could aid living organisms. For instance, the researchers found that mammoths have the same low genetic diversity associated with modern endangered species.
Schuster noted that he and his team are currently funded for a Tasmanian devil project comparing the genetics of animals that are sensitive and resistant to the deadly facial tumor disease that’s been devastating Tasmanian devil populations (see feature article in this issue).
Information about the Mammoth Genome Sequencing Project is housed on a new website aimed at providing information to both the research community and the public. “We hope that this will become a portal for mammoth sequencing and research,” Schuster said.
— By Andrea Anderson; originally published on GenomeWeb Daily News

International Consortium Sets Sights on Turkey Genome
An international team of researchers has started sequencing the turkey genome, Virginia Tech’s Virginia Bioinformatics Institute said last month.
The Turkey Genome Sequencing Consortium, which includes researchers from Virginia Tech, Michigan State University, the University of Minnesota, Utah State University, and the University of Edinburgh’s Roslin Institute, plans to sequence the genome of the domesticated turkey (Meleagris gallopavo) using the Roche GS-FLX platform and the Roche GS FLX Titanium PicoTiterPlate device and reagents. The genome will be assembled with shotgun fragments and both short and long paired-end reads.
During the pilot phase of the project, researchers plan to generate two-fold coverage of the turkey genome at VBI’s Core Laboratory Facility. Eventually, they hope to sequence more than 95 percent of the genome.
Funding for the pilot phase of the project was provided by consortium members, VBI Associate Director of Technology Development Otto Folkerts said in a statement. Roche Applied Sciences is providing in-kind support. Folkerts said the team intends to go after federal and industry support for a full sequencing effort next year.
The goal is to get genetic and genomic information that helps breeders improve commercial turkey breeds — unraveling the genetics of traits such as meat yield and quality, disease resistance, and fertility.
Once they have the assembled genome sequence in hand, the researchers will be able to integrate turkey research tools — such as genetic linkage and cytogenetic maps, ESTs, predicted protein and gene sequences and regulatory regions — and develop new tools such as high-throughput gene expression arrays and marker maps. They also plan to compare the turkey and chicken genomes to look at the similarities and differences in their organization.
“We have learned much from studies that compare the genetic map of the turkey genome with the chicken whole genome sequence,” University of Minnesota researcher Kent Reed said in a statement. “This effort will not only provide information on the turkey genome, but will benefit the chicken genome sequence as well.”
The assembled and annotated turkey genome sequence will be made freely available to the research community and will be publicly released to GenBank.

Australian Researchers Map Model Kangaroo Genome
Australian researchers said last month that they have completed the first stage of the kangaroo genomics project: mapping the genome of the tammar wallaby, a model kangaroo.
Researchers from the University of Melbourne, Australian National University, the Walter and Eliza Hall Institute of Medical Research, the University of Sydney, the University of New South Wales, and the Australian Genome Research Foundation teamed up as part of the Australian Research Council Centre of Excellence for Kangaroo Genomics, or KanGO, to build the wallaby genetic map, which will act as a framework for kangaroo genome assembly.
When completed, the kangaroo genome is expected to provide new insights into mammalian genome organization, function, and evolution — as well as development and reproduction. For instance, information in the kangaroo and other marsupial genomes may provide insights into the nature of gene regulation during mammalian development.
“Kangaroos are a marvelous model for studying human development and reproduction because they are born very early and complete much of their development in the pouch rather than the womb,” University of Melbourne zoologist Marilyn Renfree said in a statement. “This makes them a powerful tool for studying the genes and hormones involved in mammalian reproduction and development.” Renfree is taking over as KanGO director.
KanGO was established in early 2004 with funding from the Australian Research Council, partner institutions, and the Victoria government. In 2007, the project received renewed funding as an Australian Research Council Centre of Excellence for 2008 through 2010.
The Tammar Wallaby Genome Sequencing Project also received funding from commercial entities and the US National Institutes of Health. Whole-genome shotgun sequencing efforts for the project so far have taken place at the Australian Genome Research Facility and Baylor College of Medicine’s Human Genome Sequencing Center.
The tammar wallaby is being used as a model kangaroo because it is easily bred in a research setting and has proven valuable for studying kangaroo physiology, development, and ecology. Its genome is an estimated 3.3 billion base pairs.

The goal of the KanGO project, according to the organization’s website, is to “map and provide essential data for the completion of the sequence and assembly of the entire wallaby genome as a representative kangaroo and to explore functional biology of marsupial models for understanding genomics, reproduction, and development of mammals.”

The Scan

UK Team Presents Genetic, Epigenetic Sequencing Method

Using enzymatic DNA preparation steps, researchers in Nature Biotechnology develop a strategy for sequencing DNA, along with 5-methylcytosine and 5-hydroxymethylcytosine, on existing sequencers.

DNA Biobank Developed for French Kidney Donors, Recipients

The KiT-GENIE biobank described in the European Journal of Human Genetics contains DNA samples, genotyping profiles, immune patterns, and clinical features for thousands of kidney donors or transplant recipients in Nantes, France.

Cardiometabolic Disease May Have Distinct Associations With Microbial Metabolites in Blood, Gut

By analyzing gut microbes in combination with related metabolites in feces and blood, researchers in Nature Communications found distinct cardiometabolic disease relationships at each site.

Study Reveals New Details About Genetics of Major Cause of Female Infertility

Researchers in Nature Medicine conducted a whole-exome sequencing study of mote than a thousand patients with premature ovarian insufficiency.