Category Archives: Genome

Photo: Ava Helen and Linus Pauling Papers/ Oregon State University Libraries Photo 51: This historic X-ray diffraction image of DNA, taken in 1952 by Rosalind Franklin and Raymond Gosling, was obtained by stretching a fragile thread of crystalline DNA across a paper clip stuck in a cork, passing an X-ray beam through it for 100 hours, and capturing the results on photographic paper. Click on image to enlarge.

Next month marks the 60th anniversary of the discovery of the double helix structure of DNA by James Watson and Francis Crick. To ordinary folks, the image (known as Photo 51) that confirmed the Watson-Crick model doesnt look like anything. But without this imageand without the brilliant work of X-ray crystallographer Rosalind Franklinthe Cambridge lads had a theory and a model but no actual proof that DNA was indeed the molecule of life. It took Franklins technical know-how and perseverance for that secret to be revealed.

Biology is now one of many sciences thats almost completely dependent on technology: The technologies that allow us to view human biology at the molecular level have driven the genomic revolution. Automation, robotics, high-speed processors, and sophisticated computer programs have taken what was once the painstaking handwork of DNA identification, isolation, preparation, and sequencing and turned them into digital processes. The first sequencing of the human genome took 13 years and US $3 billion. Now machines the size of a multipurpose office printer will soon be able to do the same for sums of about $1000, and all in a days time.

But what will this mean on a human level? Eliza Stricklands article in this issue, The Gene Machine and Me, is about her very personal experience with Ion Torrents semiconductor-based genome-sequencing machines. These machines, which turn chemical signals into digital form, are the latest demonstration of the powerful electronic technologies driving all things genomic. In an echo of events 60 years ago, when several labs [PDF] competed to discover the true nature of DNA, several companies are now racing to create genomic technology for widespread use.

Why is this significant? After all, for $100 you can already send away a bit of spit to a direct-to-consumer DNA testing company like 23andMe. Their results will tell you if youre related to Genghis Khan, carry disease traits you could pass on to your children, or have an elevated risk of developing diabetes. These companies use a technology that examines the million points on the genome that vary among individuals.

But being able to predict, prevent, or treat disease based on the sequencing of your entire genomewhich is made up of 3 billion componentsis a far more complicated business. Its also more rewarding. The collection and analysis of large sets of individual genomes should eventually help researchers establish the root causes of complex diseases and allow them to create individualized treatment and even cures.

Patient-driven, personalized, precision medicine has significant hurdles to overcome, and not just technical ones. One of the most important is how to sequence millions, if not billions, of people to broaden our understanding of which genes correspond to which disease vulnerabilities, as well as other inherited characteristics. And while were doing that, well need to develop more big-data software programs to sift through all the information from these genomesa single human genome alone is about 4 gigabytes.

Other big challenges include training doctors to use genomic information in their practices, getting pharmaceutical companies to give up their blockbuster drug revenue model, and goading insurance companies into abandoning their rigid reliance on actuarial tables. And all this must happen as we simultaneously take on the inevitable genetic discrimination problems and myriad other ethical issues that will spring up.

As the former editor of a biotechnology journal, I have seen lots of breakthroughs, revolutions, and quantum leaps heralded as being on the brink of transforming our lives forever. But these transformations never occur overnight and take years, often decades, to reveal themselves.

Thats the case with human genomics and its impact on medicine. Genetics has been poised to change medicine since Gregor Mendel tended his peas. In 10 years or so, after weve all had our genomes sequenced and are toting them around on our tricorders, the benefits for medicine of genome sequencing and its attendant technologies should become truly apparentas will all the tics and bumps that make each of us uniquely human.

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Genome to Go

March 2, 2013

Brett Smith for redOrbit.com Your Universe Online

According to a report in the journal Nature Genetics, an international team of geneticists has announced the successful sequencing of the sea lamprey genome.

The sea lamprey makes for an interesting genetic case from an evolutionary standpoint, being a jawless vertebrate that diverged from jawed vertebrates millions of years ago.

The sea lamprey is a primitive jawless vertebrate that diverged from other jawed vertebrates early in the vertebrate ancestry, said co-author David McCauley, from Oklahoma University, in a statement. Because of its early divergence from other living vertebrates, the sea lamprey genome can provide insights for understanding how vertebrate genomes have evolved, and the origins of vertebrate character traits.

McCauley explained that vertebrates have multiple copies of many genes in their genome as the result of two whole-genome rounds of genetic duplication.

One outstanding question has been the timing of these duplications in vertebrate history, he said. Results from this project suggest that two rounds of duplication predated the divergence of the ancestral lamprey from modern jawed vertebrates. This result is important for understanding how vertebrate genomes have evolved, and in particular, for understanding if the organization of the genome is common to all vertebrates.

The OU geneticist added that the lampreys unique neural physiology makes for an interesting genomic and evolutionary study.

Most vertebrates contain an insulating layer of cells that surround nerve cells, he said. Cells that wrap around a nerve fiber, or axon, are enriched in a protein known as myelin. The insulating properties of myelin allow signals to be conducted rapidly along the nerve fiber, and the loss of myelin results in numerous neurodegenerative diseases in humans.

McCauley said the neurons within lampreys are unwrapped, suggesting that the insulation is specific to jawed vertebrates.

Excerpt from:
Geneticists Complete Sea Lamprey Genome Sequencing

Public release date: 28-Feb-2013 [ | E-mail | Share ]

Contact: Angela Startz astartz@ou.edu 405-325-6664 University of Oklahoma

Beginning in 2004, a group of scientists from around the globe, including two University of Oklahoma faculty members, set out to map the genome of the sea lamprey. The secrets of how this jawless vertebrate separated from the jawed vertebrates early in the evolutionary process will give insight to the ancestry of vertebrate characters and may help investigators more fully understand neurodegenerative diseases in humans.

David McCauley, associate professor in the Biology Department in the OU College of Arts and Sciences, and Sandra W. Clifton, with the OU Center for Advanced Genome Technology, collaborated with scientists from Japan, Germany, the United States, Canada and Great Britain.

McCauley isolated and prepared the liver tissue from the single adult female sea lamprey, from which genomic DNA was isolated for sequencing. Clifton was involved in management of the sea lamprey sequencing project at the Genome Institute at Washington University in St. Louis until her retirement in 2010. The project then was taken over by Patrick Minx. Clifton participated in the discussions regarding the paper preparation, and she is a senior author on the paper. Sequencing was performed at the Genome Institute and the project was directed by Weiming Li at Michigan State University with funding provided by the National Human Genome Research Institute at the National Institutes of Health.

"The sea lamprey is a primitive jawless vertebrate that diverged from other jawed vertebrates early in the vertebrate ancestry," writes McCauley. "Because of its early divergence from other living vertebrates, the sea lamprey genome can provide insights for understanding how vertebrate genomes have evolved, and the origins of vertebrate character traits. Several important findings arise from sequencing the sea lamprey genome: Vertebrates have undergone two 'whole-genome' rounds of duplication, resulting in multiple copies of many genes present in vertebrates. One outstanding question has been the timing of these duplications in vertebrate history. Results from this project suggest that two rounds of duplication predated the divergence of the ancestral lamprey from modern jawed vertebrates. This result is important for understanding how vertebrate genomes have evolved, and in particular, for understanding if the organization of the genome is common to all vertebrates.

"Most vertebrates contain an insulating layer of cells that surround nerve cells. Cells that wrap around a nerve fiber, or axon, are enriched in a protein known as myelin. The insulating properties of myelin allow signals to be conducted rapidly along the nerve fiber, and the loss of myelin results in numerous neurodegenerative diseases in humans."

McCauley adds that lampreys lack these "wrapped" neurons, suggesting the insulated neurons are specific to jawed vertebrates. "Somewhat surprisingly, the sea lamprey genome contains multiple proteins involved in the synthesis of myelin, including its basic protein. This important finding suggests the origin of myelin predated the divergence of lampreys from the lineage leading to jawed vertebrates, but the role of these proteins in lampreys is not known. Other important findings shed light on evolution of the vertebrate adaptive immune system, and the evolution of paired appendages, such as fins in fish and fore-limbs and hind-limbs in tetrapod vertebrates such as humans and animals."

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The findings recently were published in the March issue of Nature Genetics. To read the full article, visit http://www.nature.com/ng.

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Sea lamprey genome mapped with help from scientists at OU

Feb. 28, 2013 Beginning in 2004, a group of scientists from around the globe, including two University of Oklahoma faculty members, set out to map the genome of the sea lamprey. The secrets of how this jawless vertebrate separated from the jawed vertebrates early in the evolutionary process will give insight to the ancestry of vertebrate characters and may help investigators more fully understand neurodegenerative diseases in humans.

David McCauley, associate professor in the Biology Department in the OU College of Arts and Sciences, and Sandra W. Clifton, with the OU Center for Advanced Genome Technology, collaborated with scientists from Japan, Germany, the United States, Canada and Great Britain.

McCauley isolated and prepared the liver tissue from the single adult female sea lamprey, from which genomic DNA was isolated for sequencing. Clifton was involved in management of the sea lamprey sequencing project at the Genome Institute at Washington University in St. Louis until her retirement in 2010. The project then was taken over by Patrick Minx. Clifton participated in the discussions regarding the paper preparation, and she is a senior author on the paper. Sequencing was performed at the Genome Institute and the project was directed by Weiming Li at Michigan State University with funding provided by the National Human Genome Research Institute at the National Institutes of Health.

"The sea lamprey is a primitive jawless vertebrate that diverged from other jawed vertebrates early in the vertebrate ancestry," writes McCauley. "Because of its early divergence from other living vertebrates, the sea lamprey genome can provide insights for understanding how vertebrate genomes have evolved, and the origins of vertebrate character traits. Several important findings arise from sequencing the sea lamprey genome: Vertebrates have undergone two 'whole-genome' rounds of duplication, resulting in multiple copies of many genes present in vertebrates. One outstanding question has been the timing of these duplications in vertebrate history. Results from this project suggest that two rounds of duplication predated the divergence of the ancestral lamprey from modern jawed vertebrates. This result is important for understanding how vertebrate genomes have evolved, and in particular, for understanding if the organization of the genome is common to all vertebrates.

"Most vertebrates contain an insulating layer of cells that surround nerve cells. Cells that wrap around a nerve fiber, or axon, are enriched in a protein known as myelin. The insulating properties of myelin allow signals to be conducted rapidly along the nerve fiber, and the loss of myelin results in numerous neurodegenerative diseases in humans."

McCauley adds that lampreys lack these "wrapped" neurons, suggesting the insulated neurons are specific to jawed vertebrates. "Somewhat surprisingly, the sea lamprey genome contains multiple proteins involved in the synthesis of myelin, including its basic protein. This important finding suggests the origin of myelin predated the divergence of lampreys from the lineage leading to jawed vertebrates, but the role of these proteins in lampreys is not known. Other important findings shed light on evolution of the vertebrate adaptive immune system, and the evolution of paired appendages, such as fins in fish and fore-limbs and hind-limbs in tetrapod vertebrates such as humans and animals."

The findings recently were published in the March issue of Nature Genetics.

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Sea lamprey genome mapped

The human genome can generate molecular hoops similar in makeup to DNA that could potently interfere with genetic activity, researchers say.

These findings reveal there are secrets within the genomes of humans and other animals that scientists are still uncovering, and the old belief that life has useless junk DNA is more false than ever, scientists added.

Discovering more about circular versions of RNA (a molecule similar to DNA that can carry genetic information) could also lead to new ways of fighting diseases such as diabetes, brain tumors and Parkinson's disease, investigators added.

The human genome the blueprint for human life is made of DNA. From the genome, intermediate molecules known as RNA are created that help manufacture key biomolecules such as proteins, which then carry out cellular processes.

After international teams of researchers completely sequenced the human genome, they found about 95 percent of it unexpectedly did not code for proteins. Since this noncoding DNA initially seemed to have no known biological function, some scientists referred to it as junk DNA. [Unraveling the Human Genome: 6 Molecular Milestones]

However, over time, researchers have discovered this noncoding DNA can serve a wide variety of vital purposes. For instance, noncoding DNA can give rise to snippets of RNA known as micro-RNA that can suppress the so-called messenger RNA that normally helps manufacture proteins. This micro-RNA serves a key role in controlling genetic activity, and scientists are developing therapies based on micro-RNA to dampen harmful, malfunctioning genes.

Now researchers find the genomes of humans and other animals can generate circular RNA, highly stable rings that can sponge up micro-RNA, apparently keeping them from interfering with genetic activity if necessary.

"There seems to be a whole new layer of gene regulation," researcher Jrgen Kjems, a molecular biologist at Aarhus University in Denmark, told LiveScience.

For instance, Kjems and his colleagues found high levels of a circular RNA they dubbed ciRS-7 in the human and mouse brain. This molecule potently suppresses a micro-RNA named miR-7, which is found in everything from worms to humans. They also found a circular RNA known as Sry that is specific to testicles and targets a micro-RNA known as miR-138, suggesting that circular RNA might play a role in sex development.

In addition, when Nikolaus Rajewsky at the Max Delbrck Center for Molecular Medicine in Berlin and his colleagues analyzed human, mouse and nematode worm RNA, they detected thousands of circular RNAs. These were often linked with specific tissues or developmental stages.

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Weird Molecular Hoops Made From Human Genome

Genome MIDI Sequencer running Yamaha MU15
Using Genome MIDI Sequencer to trigger multiple channels on the MU15.

By: Ashley Elsdon

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Genome MIDI Sequencer running Yamaha MU15 - Video

Feb. 27, 2013 Researchers with the U.S. Department of Energy (DOE)'s Lawrence Berkeley National Laboratory (Berkeley Lab) have achieved a major advance in understanding how genetic information is transcribed from DNA to RNA by providing the first step-by-step look at the biomolecular machinery that reads the human genome.

"We've provided a series of snapshots that shows how the genome is read one gene at a time," says biophysicist Eva Nogales who led this research. "For the genetic code to be transcribed into messenger RNA, the DNA double helix has to be opened and the strand of gene sequences has to be properly positioned so that RNA polymerase, the enzyme that catalyzes transcription, knows where the gene starts. The electron microscopy images we produced show how this is done."

Says Paula Flicker of the National Institutes of Health's National Institute of General Medical Sciences, which partly funded the research, "The process of transcription is essential to all living things so understanding how it initiates is enormously important. This work is a beautiful example of integrating multiple approaches to reveal the structure of a large molecular complex and provide insight into the molecular basis of a fundamental cellular process."

Nogales, who holds joint appointments with Berkeley Lab, the University of California (UC) at Berkeley, and the Howard Hughes Medical Institute (HHMI), is the corresponding author of a paper describing this study in the journal Nature. The paper is titled "Structural visualization of key steps in human transcription initiation." Co-authors are Yuan He, Jie Fang and Dylan Taatjes.

The fundamental process of life by which information in the genome of a living cell is used to generate biomolecules that carry out cellular activities is the so-called "central dogma of molecular biology." It states that genetic information flows from DNA to RNA to proteins. This straightforward flow of information is initiated by an elaborate system of proteins that operate in a highly choreographed fashion with machine-like precision. Understanding how this protein machinery works in the context of passing genetic information from DNA to RNA (transcription) is a must for identifying malfunctions that can turn cells cancerous or lead to a host of other problems.

Berkeley Lab researchers have produced the first step-by-step snapshots of the assembly of transcription factors and RNA polymerase into a transcription pre-initiation complex. (Image courtesy of Nogales group)

Nogales and members of her research group used cryo-electron microscopy (cryo-EM), where protein samples are flash-frozen at liquid nitrogen temperatures to preserve their structure, to carry out in vitro studies of reconstituted and purified versions of the "transcription pre-initiation complex." This complex is a large assemblage of proteins composed of RNA polymerase II (Pol II) plus a class of proteins known as general transcription factors that includes the TATA-binding protein (TBP), TFIIA, TFIIB, TFIIF, TFIIE and TFIIH. All of the components in this complex work together to ensure the accurate loading of DNA into Pol II at the start of a gene sequence.

"There's been a lack of structural information on how the transcription pre-initiation complex complex is assembled, but with cryo-EM and our in vitro reconstituted system we've been able to provide pseudo-atomic models at various stages of transcription initiation that illuminate critical molecular interactions during this step-by-step process," Nogales says.

The in vitro reconstituted transcription pre-initiation complex was developed by Yuan He, lead author on the Nature paper and a post-doctoral student in Nogales's research group.

"This reconstituted system provided a model for the sequential assembly pathway of transcription initiation and was essential for us to get the most biochemically homogenous samples," Nogales says. "Also essential was our ability to use automated data collection and processing so that we could generate all our structures in a robust manner."

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Reading the human genome: First step-by-step look at transcription initiation

A genome sequencing platform to help physicians screen patients for the most appropriate drugs for their conditions such as for cancer treatments is one component of a new company thats a spinout from a collaboration between Philadelphia-area Coriell Institute for Medical Research and its technology partner IBM.

Coriell Institute CEO Michael Christman and Scott Megill, Coriells chief information officer, who is leading the spinout, told MedCity News in a phone interview how the startup will work and explained its timeline.

Coriell Life Sciences in Camden, New Jersey,will be at the center of a genome ecosystem transmitting queries from physicians to genomic-sequencing interpreters. It will also provide cloud-based storage for each patients genomic sequence. It sees itself as something of an Amazon.com for genomic sequencing. It does not own the content, but through the ecosystem it is setting up, it is facilitating the interaction between physicians, researchers and the interpreters of that data. The company is making it easier to order, store and interpret genome sequence data for physicians.

Heres how it works: A physician would order a test that requires genomic sequencing the same way he or she would order a diagnostic test. Coriell sends the sequencing order to a network of third-party interpreters it is in the process of assembling. The results will be transmitted to the patients medical records and the genome would be stored in its cloud-based vault. Physicians could use it to order follow-up tests or researchers could utilize the de-identified data.

Megill said he expects Coriell Life Sciences genome vault will be ready by early summer and its genomic exchange product is expected to be ready sometime this fall.

Christman said the startups programs would provide a huge economic benefit by helping the right patients get the right care at the right time. We are at a special time [for genomic sequencing] where doctors want to use this tool.For example, it would be able to identify patients who wont respond well to Plavix an anticlotting drug thats ineffective for about 25 percent of the patients for whom it is prescribed. Instead, they could be prescribed U.S. Food and Drug Administration-approved alternative drugs and save a lot of money. Thats just the tip of the iceberg, Christman said. He also pointed out that genomic sequencing is increasingly being done in utero through the mothers blood and negates a potentially more risky approach using amniocentesis.

IBM has been helping to build the technology platform for the spinout that will transmit the information gathered from the genomic sequencing data back to the patients medical records. It will also provide a secure way to store the cloud-based data.

The partnership with IBM dates back to 2011, when the company provided monitoring software to instantly alert Coriell researchers before any mechanical failure occurs and in turn, protect the integrity of its biological samples.

[Photo from Flickr user andylepp]

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Cloud-based genome sequencing exchange could make personalized medicine easier for physicians

HGS Episode #5 - Mr Excel #39;s Mysterious Genome
Human Genome Sprapp Episode #5 dives into DNA Base sequence analysis by charting a 420 character string identified in Episode #4. The supreme leader of Excel provided me with this genome data, trying to figure out the specific chromosome (and species potentially) that provided these nucleotides.

By: Ken Braverman

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HGS Episode #5 - Mr Excel's Mysterious Genome - Video

Scientists find genes linked to human neurological disorders in sea lamprey genome
Jennifer Morgan and Ona Bloom are using an ugly fish with a beautiful spinal cord, the sea lamprey, to study mechanisms of recovery from spinal cord injury at the MBL in Woods Hole, Mass. Credit: Diana Kenney/MBL

By: h2so4hurts

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Scientists find genes linked to human neurological disorders in sea lamprey genome - Video