Category Archives: Genome

Our Genome Ourselves - Full Program
There is a revolution underway in the world of medicine. As researchers identify the genetic variants responsible for cancer, schizophrenia and diabetes, and...

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Our Genome Ourselves - Full Program - Video

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Newswise Researchers at the Department of Energys Oak Ridge National Laboratory are the first team to sequence the entire genome of the Clostridium autoethanogenum bacterium, which is used to sustainably produce fuel and chemicals from a range of raw materials, including gases derived from biomass and industrial wastes.

The ORNL work was funded by LanzaTech, a biotechnology company based in Illinois with an innovative carbon recycling process. LanzaTechs gas fermentation platform uses proprietary microbes for efficiently converting carbon-rich waste gases and residues into useful fuels and chemicals.

Successfully sequencing Clostridium autoethanogenumclassified as a complex, class III microbe because of its many repeating units of DNA baseshas been of significant interest to the biotechnology industry. A Biotechnology for Biofuels paper co-authored by ORNLs Steve Brown and Miriam Land, University of Tennessee doctoral student Sagar Utturkar and collaborating LanzaTech researchers generated a top-5-percent rating from Altmetric, an online rating system that measures the volume and value of recognition an article receives from research communities and media outlets.

With the complete genomic sequence, we will have a better understanding of the microbes metabolism and mutations that will enable LanzaTech to make modifications to the wild-type, or naturally occurring, strain for optimizing the conversion of waste into fuel, Brown said. Our ORNL lab has a lot of experience sequencing genomes, and we have the analytic capability to tackle this project.

The research team sequenced the more than 4.3 million base pairs of DNA that make up the organisms genome using RS-II long-read sequencing technology developed by Pacific Biosciences (PacBio).

Although long-read sequencing technologies still struggle with high error rates, they promise to advance the biotechnology industry by making it possible to sequence microorganisms with many repeating sequences, such as Clostridium autoethanogenum, within a reasonable amount of time at reasonable cost. The ORNL team performed a greater number of reads and used data algorithms to correct for errors associated with the long-read technology. The team also compared the RS-II long-read results to two short-read technologies, concluding the short-read technologies were unable to sequence the entire genome because of the bacteriums repetitive sequences, as expected.

In our paper we compared three generations of sequencing technologies and explained why the long-read technology was able to finish the genome, Brown said. Now, ORNL is independently looking at six different organisms using PacBio to compare and contrast experiences using this technology.

The project also revealed information about the genetic history of Clostridium autoethanogenum through short DNA sequences known as CRISPR systems, which retain genetic mutations such as those created during a viral infection that are subsequently passed on to future generations of a microbe. CRISPR systems are important indicators of strengths and vulnerabilities that biotechnology companies like LanzaTech look for when genetically modifying a microbe.

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ORNL Team First to Fully Sequence Bacterial Genome Important to Fuel and Chemical Production

Science in Action: Butterfly Genome | California Academy of Sciences
SUBSCRIBE: http://bit.ly/SubscribeToCAS About the Academy: The California Academy of Sciences is the only place on the planet with an aquarium, a planetarium, a natural history museum, and...

By: California Academy of Sciences

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Science in Action: Butterfly Genome | California Academy of Sciences - Video

Researchers from the Broad Institute and Massachusetts Institute of Technology have created a new mouse model to simplify application of the CRISPR-Cas9 system for in vivo genome editing experiments. The researchers successfully used the new "Cas9 mouse" model to edit multiple genes in a variety of cell types, and to model lung adenocarcinoma, one of the most lethal human cancers. The mouse has already been made available to the scientific community and is being used by researchers at more than a dozen institutions. A paper describing this new model and its initial applications in oncology appears this week in Cell.

In recent years, genetic studies have found thousands of links between genes and various diseases. But in order to prove that a specific gene is playing a role in the development of the disease, researchers need a way to perturb it -- that is, turn the gene off, turn it on, or otherwise alter it -- and study the effects.

The CRISPR-Cas9 genome-editing system is one of the most convenient methods available for making these alterations in the genome. While the tool is already being used to test the effects of mutations in vitro -- in cultured cell lines, for instance -- it is now possible to use this tool to study gene functions using intact biological systems.

The CRISPR-Cas9 system relies on two key features to edit the genome: Cas9, a "cleaving" enzyme capable of cutting DNA; and guide RNA, a sequence that directs Cas9 to the DNA target of interest in the genome. However, the Cas9 enzyme presents some delivery challenges for in vivo applications.

"By equipping the mouse with Cas9, we relieved the burden of delivery. This frees up space for the delivery of additional elements -- whether by viruses or nanoparticles -- making it possible to simultaneously mutate multiple genes and even make precise changes in DNA sequences," said Randall Platt, a graduate student at MIT working at the Broad Institute in the lab of Feng Zhang, an assistant professor at the McGovern Institute for Brain Research at MIT, and a core member of the Broad Institute. Platt and Sidi Chen, a postdoctoral fellow at MIT's Koch Institute for Integrative Cancer Research working in the lab of Institute Professor Phillip Sharp, were co-first authors of the paper.

This ability to perturb multiple genes at the same time may be particularly useful in studying complex diseases, such as cancer, where mutations in more than one gene may be driving the disease. To demonstrate a potential application for cancer research, the authors used the "Cas9 mouse" to model lung adenocarcinoma. Previously, scientists working with animal models have had to knock out one gene at a time, or cross animal models to produce one with the needed genetic modifications, processes that are challenging and time consuming.

"The 'Cas9 mouse' allows researchers to more easily perturb multiple genes in vivo," said Zhang, who, along with Sharp, served as co-senior author of the Cell paper. "The goal in developing the mouse was to empower researchers so that they can more rapidly screen through the long list of genes that have been implicated in disease and normal biological processes."

Researchers contributing to the paper also found that cells derived from the "Cas9 mouse" could be extracted for use in lab experiments and were able to leverage the Cas9-expressing cells to edit immune dendritic cells even after the cells had been removed from the mouse, allowing the researchers to experiment with cells that aren't easily accessible and often lack the shelf life to conduct such experiments.

"As we demonstrated with immune cells, the mouse allows us to experiment with cells that only remain viable for a few days ex vivo by leveraging the fact that they already express Cas9. Absent the expression of Cas9, we would not have sufficient time for the CRISPR system to work its magic," said Broad core member and paper co-author Aviv Regev, who is an associate professor of biology at MIT. Regev's lab, along with the lab of Broad senior associate member Nir Hacohen (a faculty member at Massachusetts General Hospital and Harvard Medical School), used the mouse to investigate dendritic cells, as reported in the Cell study.

"Genetic manipulation is one of the most critical tools we have for investigating complex circuits, and the 'Cas9 mouse' will help us do it more effectively," said Regev.

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Researchers engineer 'Cas9' animal models to study disease, inform drug discovery

Personal Genome Sequencing from GeneHub
The announcement video for our personal genome sequencing service GeneHub.

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Personal Genome Sequencing from GeneHub - Video

As the cost of DNA sequencing plummets, the possibility of testing all cancer patients tumor genomes is becoming a reality. For just $1000 or so, a doctor might submit most any malignant specimen for a complete genetic work-up. The sample might be a core needle biopsy taken from a breast, a blood sample from a person with leukemia, or a snippet of a sarcoma removed in an operating room. In principle, checking a tumor for genetic changes should be straightforward, do-able.

But most cancer patients undergo surgery and other treatment long before their doctors consider sending a biopsy for full molecular evaluation. A recentpublishedsurvey among oncologists at two prestigious Boston teaching hospitals suggests that a significant proportion of specialists have a low level of confidence about their knowledge of cancer genomics. Aside from some kinds of lymphoma and leukemia, some lung cancers and a few other malignancies, examining cancer cells for genetic mutations is not routine in oncology practice.

Genomic testing of cancer cells seems like it should be available to all patients, said Lori Marx-Rubiner.At age 48, shes carried a diagnosis of metastatic breast cancer for five years. She lives in Los Angeles with her husband and teenage son, and blogs about her condition atRegrounding. Recently she took thehelm atMetavivor, a non-profit organization that promotes research inmetastatic disease.

Now I learn as much as possible about my condition and treatment options, she said. Marx-Rubiner, who holds a masters degree in social work, participates in scientific meetings and advocates for people affected by breast cancer. Most of her treatments so far have been selected to interfere with hormone signaling. Thats because her biopsy evaluated with old pathology methods when she received her initial, stage 2 diagnosis back in 2002 showed high levels of estrogen receptors in the tumor cells.Such an old approach didnt seem adequate for managing her case.

In the spring of 2014, she requested that her tumor be checked for genetic mutations. I wanted to see if I might be eligible for a CDK inhibitor or another targeted drug, she said. If Im going to take a risk on a new drug, I want the best shot possible.

But finding the specimen taken years ago and getting her insurance to cover the cost of genomic analysis proved challenging.After weeks of frustration and hassle, the biopsy sample was found and sequenced. The findings havent yet affected her therapy plan. She is soon meeting with a new oncologist.

Carolyn Hutter, an epidemiologist and co-leader ofTheCancerGenomeAtlas (TCGA), has been working on tumor genomics for some time. The TCGA project, a collaborative work by NIHsCancerandHuman Genome ResearchInstitutes, aims to characterize over 10,000 human tumors at the molecular level. Sequencing genes in tumor cells and seeing how those differ from a persons germline, or inherited DNA segments helps us to better understand the biological causes of cancer, she said in a phone interview. Its also useful because it can point to new targeted therapies.

One example of a tumor-specific mutation that can direct treatment is anALKmutation in lung cancer. Using this kind of genetic information about an individuals tumor is not futuristic, she considered. Rather, its happening today. Doctors are using DNA sequencing results to make decisions about therapy, to select targeted drugs, she said. Already the FDA has approved two drugs for patients who have lung cancer with ALK abnormalities in the tumor cells Crizotinib(Xalkori, Pfizer) andCeritinib(Zykadia, Novartis).

Within the next few years, people with cancer arising in other organs such as the breast, colon or pancreas, for instance might have their tumors checked for ALK and other mutations. Whether or not their malignancy is called lung cancer because the growth originated in the lung, they might choose a drug based on having an ALK or other genetic variant for which a targeted medicine is available.

Were coming up with new definitions of cancer subtypes based on molecular findings, Hutter said. Genetic profiling has wide potential, in terms of planning patients treatment and understanding prognosis in many cancer types. But I dont think well completely abandon tissue of origin as a way of categorizing tumors, she added.

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The Potential Value of Cancer Genome Testing

As the cost of DNA sequencing plummets, the possibility of testing all cancer patients tumor genomes is becoming a reality. For just $1000 or so, a doctor might submit most any malignant specimen for a complete genetic work-up. The sample might be a core needle biopsy taken from a breast, a blood sample from a person with leukemia, or a snippet of a sarcoma removed in an operating room. In principle, checking a tumor for genetic changes should be straightforward, do-able.

But most cancer patients undergo surgery and other treatment long before their doctors consider sending a biopsy for full molecular evaluation. A recentpublishedsurvey among oncologists at two prestigious Boston teaching hospitals suggests that a significant proportion of specialists have a low level of confidence about their knowledge of cancer genomics. Aside from some kinds of lymphoma and leukemia, some lung cancers and a few other malignancies, examining cancer cells for genetic mutations is not routine in oncology practice.

Genomic testing of cancer cells seems like it should be available to all patients, said Lori Marx-Rubiner.At age 48, shes carried a diagnosis of metastatic breast cancer for five years. She lives in Los Angeles with her husband and teenage son, and blogs about her condition atRegrounding. Recently she took thehelm atMetavivor, a non-profit organization that promotes research inmetastatic disease.

Now I learn as much as possible about my condition and treatment options, she said. Marx-Rubiner, who holds a masters degree in social work, participates in scientific meetings and advocates for people affected by breast cancer. Most of her treatments so far have been selected to interfere with hormone signaling. Thats because her biopsy evaluated with old pathology methods when she received her initial, stage 2 diagnosis back in 2002 showed high levels of estrogen receptors in the tumor cells.Such an old approach didnt seem adequate for managing her case.

In the spring of 2014, she requested that her tumor be checked for genetic mutations. I wanted to see if I might be eligible for a CDK inhibitor or another targeted drug, she said. If Im going to take a risk on a new drug, I want the best shot possible.

But finding the specimen taken years ago and getting her insurance to cover the cost of genomic analysis proved challenging.After weeks of frustration and hassle, the biopsy sample was found and sequenced. The findings havent yet affected her therapy plan. She is soon meeting with a new oncologist.

Carolyn Hutter, an epidemiologist and co-leader ofTheCancerGenomeAtlas (TCGA), has been working on tumor genomics for some time. The TCGA project, a collaborative work by NIHsCancerandHuman Genome ResearchInstitutes, aims to characterize over 10,000 human tumors at the molecular level. Sequencing genes in tumor cells and seeing how those differ from a persons germline, or inherited DNA segments helps us to better understand the biological causes of cancer, she said in a phone interview. Its also useful because it can point to new targeted therapies.

One example of a tumor-specific mutation that can direct treatment is anALKmutation in lung cancer. Using this kind of genetic information about an individuals tumor is not futuristic, she considered. Rather, its happening today. Doctors are using DNA sequencing results to make decisions about therapy, to select targeted drugs, she said. Already the FDA has approved two drugs for patients who have lung cancer with ALK abnormalities in the tumor cells Crizotinib(Xalkori, Pfizer) andCeritinib(Zykadia, Novartis).

Within the next few years, people with cancer arising in other organs such as the breast, colon or pancreas, for instance might have their tumors checked for ALK and other mutations. Whether or not their malignancy is called lung cancer because the growth originated in the lung, they might choose a drug based on having an ALK or other genetic variant for which a targeted medicine is available.

Were coming up with new definitions of cancer subtypes based on molecular findings, Hutter said. Genetic profiling has wide potential, in terms of planning patients treatment and understanding prognosis in many cancer types. But I dont think well completely abandon tissue of origin as a way of categorizing tumors, she added.

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Cancer Genome Sequencing Will Mean More Targeted Therapies

These days, cancer is as much a target for researchers with number-crunching skills and their data-mining tools as it is for scientists in biomedical research labs. And one potentially powerful big-data approach to conquering cancerwhich involves discovering clever genetic tricks to make cancer cells kill themselveshas moved in a promising new direction this month.

Scottish, Israeli, and American researchers have reported a new discovery that analyzes existing cancer gene databases for clues to combinations of genes that together can kill tumor cells while leaving healthy cells untouched. The idea takes advantage of a phenomenon called synthetic lethality, which in oncology was first explored 17 years ago as a potentially fruitful new line of cancer treatment.

One of the new papers coauthors, Eytan Ruppin, director of the University of Marylands Center for Bioinformatics and Computational Biology, says cancer cells are like regular cells run amok. They, like regular cells, typically have some 10,000 genes. But in cancer cells, many more of these genes are inactivemeaning that for whatever reasons, those genes dont produce the proteins that a healthy version of the cell would be producing.

Since the 1920s, its been observed that all cells in fact have networks of secret self-destruct switches: When both of a key pair of genes become inactive, the entire cell begins the process of shutdown and cell death.

So, Ruppin says, the hurdle that needs to be overcome in order to make this possible broad-spectrum genetic cancer treatment work is discovering and cataloging as many of these secret synthetically lethal (SL) gene pair combinations as nature has provided. Then, when a patients cancer is biopsied, and its genome is taken, an oncologist can look to see which genes in the patients cancer cells are inactive.

For example, say that the oncologist discovers in an SL database that an inactive gene in a patients tumor (call it Gene A) happens to have a corresponding synthetically lethal partner gene (call it Gene B).

In this case, then, a drug that inactivates Gene B will trigger the cell death process in the tumor but not in the persons healthy cells. (Depending on what Gene B does, there might also be side effects from switching Gene B off. But so long as Gene A remains active throughout the rest of the persons body, those side-effects should not include cell death.)

Ruppin and his collaborators used a clever data mining technique to discover more than a thousand candidate SL gene combinations. They plumbed the U.S. National Cancer Institutes Cancer Genome Atlas, which itself contains thousands of genomes of different biopsied tumor samples.

They then ran searches for various inactive genes. So, for the sake of example, say they found some of the cancers in the database with Gene X inactivated. And some of the cancers in the database had Gene Y inactivated. If Genes X and Y dont form an SL pair, there should then be plenty of examples in the database of cancers where both X and Y were inactive. However, if Genes X and Y do form an SL pair, then there should be almost no examples of tumors in the database where those two genes are both inactive.

You would have expected them to be inactive together at a certain rate, given their individual inactive frequencies, Ruppin says. But when you look at the data, you find that they are never inactive together, Ruppin adds that this, is a very strong indication that they are synthetically lethal. Because whenever they were inactive together, they were actually eliminated from the population. Because these cells died.

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Hacking the Cancer Genome

Imagine going to the hospital with one disease and coming home with something much worse, or not coming home at all.

With the emergence and spread of antibiotic-resistance pathogens, healthcare-associated infections have become a serious threat. On any given day about one in 25 hospital patients has at least one such infection and as many as one in nine die as a result, according to the Centers for Disease Control and Prevention.

Consider Klebsiella pneumoniae, not typically a ferocious pathogen, but now armed with resistance to virtually all antibiotics in current clinical use. It is the most common species of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. As carbapenems are considered the antibiotic of last resort, CREs are a triple threat for their resistance to nearly all antibiotics, high mortality rates and ability to spread their resistance to other bacteria.

But there is hope. A team of Sandia National Laboratories microbiologists for the first time recently sequenced the entire genome of a Klebsiella pneumoniae strain, encoding New Delhi Metallo-beta-lactamase (NDM-1). They presented their findings in a paper published in PLOS One, "Resistance Determinants and Mobile Genetic Elements of an NDM-1 Encoding Klebsiella pneumoniae Strain."

The Sandia team of Corey Hudson, Zach Bent, Robert Meagher and Kelly Williams is beginning to understand the bacteria's multifaceted mechanisms for resistance. To do this, they developed several new bioinformatics tools for identifying mechanisms of genetic movement, tools that also might be effective at detecting bioengineering.

"Once we had the entire genome sequenced, it was a real eye opener to see the concentration of so many antibiotic resistant genes and so many different mechanisms for accumulating them," explained Williams, a bioinformaticist. "Just sequencing this genome unlocked a vault of information about how genes move between bacteria and how DNA moves within the chromosome."

Meagher first worked last year with Klebsiella pneumoniae ATCC BAA-2146 (Kpn2146), the first U.S. isolate found to encode NDM-1. Along with E.coli, it was used to test an automatic sequencing library preparation platform for the RapTOR Grand Challenge, a Sandia project that developed techniques to allow discovery of pathogens in clinical samples.

"I've been interested in multi-drug-resistant organisms for some time. The NDM-1 drug resistance trait is spreading rapidly worldwide, so there is a great need for diagnostic tools," said Meagher. "This particular strain of Klebsiella pneumoniae is fascinating and terrifying because it's resistant to practically everything. Some of that you can explain on the basis on NDM-1, but it's also resistant to other classes of antibiotics that NDM-1 has no bearing on."

Unlocking Klebsiella pneumoniae

Assembling an entire genome is like putting together a puzzle. Klebsiella pneumoniae turned out to have one large chromosome and four plasmids, small DNA molecules physically separate from and able to replicate independently of the bacterial cell's chromosomal DNA. Plasmids often carry antibiotic resistant genes and other defense mechanisms.

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Clues to superbug evolution: Microbiologists sequence entire genome of a Klebsiella pneumoniae strain

GENOME TVC

By: RAJKUMAR SENGUPTA TVC AND JINGLES

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GENOME TVC - Video