Category Archives: Genome

6. Genome Assembly
MIT 7.91J Foundations of Computational and Systems Biology, Spring 2014 View the complete course: http://ocw.mit.edu/7-91JS14 Instructor: David Gifford Prof. Gifford talks about two different...

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6. Genome Assembly - Video

20. Human Genetics, SNPs, and Genome Wide Associate Studies
MIT 7.91J Foundations of Computational and Systems Biology, Spring 2014 View the complete course: http://ocw.mit.edu/7-91JS14 Instructor: David Gifford This lecture by Prof. David Gifford...

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20. Human Genetics, SNPs, and Genome Wide Associate Studies - Video

7 Day Genome DNA Stem Cell Healing Course. Self Help/Practioner Cert.
to find out more about this healing course go to http://www.genomehealing.com or http://www.genomehealing.com.au.

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The Genome by Sergei Lukyanenko ePub download
"Download Ebook: http://ebooks-releases.com/the-genome-by-sergei-lukyanenko The Genome A Novel by Sergei Lukyanenko Ebook Download The Genome A Novel by Serg...

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Pre-clinical studies in mice reveal ways to reduce cancer risk with modified treatment

National Institutes of Health researchers have uncovered a key factor in understanding the elevated cancer risk associated with gene therapy. They conducted research on mice with a rare disease similar to one in humans, hoping their findings may eventually help improve gene therapy for humans. Researchers at the National Human Genome Research Institute (NHGRI), part of NIH, published their research in the Jan. 20, 2015, online issue of the Journal of Clinical Investigation.

"Effective and safe gene therapies have the potential to dramatically reverse diseases that are life-threatening for affected children," said NHGRI Scientific Director Dan Kastner, M.D., Ph.D. "This study is an important step in developing gene therapies that can be safely used to benefit patients."

Toxic side effects actually are rarely observed by researchers who have designed gene therapies using an adeno-associated virus (AAV) as a vector to deliver the corrected gene to a specific point in the cell's DNA. AAVs are small viruses that infect humans but do not cause disease. A vector is a DNA molecule of AAV used as a vehicle to carry corrected genetic material into a cell. AAV viruses are uniquely suited for gene therapy applications.

But one prior study did find an association between AAV and the occurrence of liver cancer. The present research addresses this problem in gene therapy for an inherited disease in children called methylmalonic acidemia, or MMA.

For 10 years, NHGRI researchers have worked toward a gene therapy to treat MMA. The condition affects as many as 1 in 67,000 children born in the United States. Affected children are unable to properly metabolize certain amino acids consumed in their diet, which can damage a number of organs and lead to kidney failure. MMA patients also suffer from severe metabolic instability, failure to thrive, intellectual and physical disabilities, pancreatitis, anemia, seizures, vision loss and strokes. The most common therapy is a restrictive diet, but doctors must resort to dialysis or kidney or liver transplants when the disease progresses.

In prior MMA gene therapy studies, researchers showed that mice bred to develop the condition could be restored to health by AAV gene therapy injection shortly after birth. The mice in the study survived into adulthood and were free from the effects of MMA.

"The corrected gene delivered by AAV is the most effective therapy we have developed so far to treat MMA," said Charles Venditti, M.D., Ph.D., senior author and investigator in NHGRI's Genetic and Molecular Biology Branch. "However, we have identified an important safety parameter related to the AAV gene therapy in our mouse models that is critical to understand before we move to human patient trials."

Now, in a long-term follow-up of the treated mice -- after mice reached about two years of age -- the researchers documented a 50-70 percent higher occurrence of liver cancer in AAV-treated mice compared with a 10 percent liver cancer rate in untreated mice. Dr. Venditti's team determined that the AAV vector triggered the cancer.

The research team performed additional experiments to detect where in the mouse genome the AAV vector delivered the corrected gene and how that related to any cancer development. In many mice that developed liver cancer, the AAV vector targeted a region of the mouse genome called Rian, near a gene called Mir341 that codes for a microRNA molecule. MicroRNAs are small, non-coding RNA molecules involved in the regulation of gene expression. When the AAV was inserted near Mir341, the vector caused elevated expression of the gene, which the researchers believe contributed to the occurrence of liver cancer in the mice. The authors note that Mir341 is found in the mouse genome, however, it is not present in humans.

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NIH researchers tackle thorny side of gene therapy

Scientists develop a computational method to estimate the importance of each letter in the human genome

Cold Spring Harbor, NY - There are 3 billion letters in the human genome, and scientists have endlessly debated how many of them serve a functional purpose. There are those letters that encode genes, our hereditary information, and those that provide instructions about how cells can use the genes. But those sequences are written with a comparative few of the vast number of DNA letters. Scientists have long debated how much of, or even if, the rest of our genome does anything, some going so far as to designate the part not devoted to encoding proteins as "junk DNA."

In work published today in Nature Genetics, researchers at Cold Spring Harbor Laboratory (CSHL) have developed a new computational method to identify which letters in the human genome are functionally important. Their computer program, called fitCons, harnesses the power of evolution, comparing changes in DNA letters across not just related species, but also between multiple individuals in a single species. The results provide a surprising picture of just how little of our genome has been "conserved" by Nature not only across species over eons of time, but also over the more recent time period during which humans differentiated from one another.

"In model organisms, like yeast or flies, scientists often generate mutations to determine which letters in a DNA sequence are needed for a particular gene to function," explains CSHL Professor Adam Siepel. "We can't do that with humans. But when you think about it, Nature has been doing a similar experiment on a very large scale as species evolve. Mutations occur across the genome at random, but important letters are retained by natural selection, while the rest are free to change with no adverse consequence to the organism."

It was this idea that became the basis of their analysis, but it alone wasn't enough. "Massive research consortia, like the ENCODE Project, have provided the scientific community with a trove of information about genomic function over the last few years," says Siepel. "Other groups have sequenced large numbers of humans and nonhuman primates. For the first time, these big data sets give us both a broad and exceptionally detailed picture of both biochemical activity along the genome and how DNA sequences have changed over time."

Siepel's team began by sorting ENCODE consortium data based on combinations of biochemical markers that indicate the type of activity at each position. "We didn't just use sequence patterns. ENCODE provided us with information about where along the full genome DNA is read and how it is modified with biochemical tags," says Brad Gulko, a Ph.D. student in Computer Science at Cornell University and lead author on the new paper. The combinations of these tags revealed several hundred different classes of sites within the genome each having a potentially different role in genomic activity.

The researchers then turned to their previously developed computational method, called INSIGHT, to analyze how much the sequences in these classes had varied over both short and long periods of evolutionary time. "Usually, this, kind of analysis is done comparing different species - like humans, dogs, and mice - which means researchers are looking at changes that occurred over relatively long time periods," explains Siepel. But the INSIGHT model considers the changes among dozens of human individuals and close relatives, such as the chimpanzee, which provides a picture of evolution over much shorter time frames.

The scientists found that, at most, only about 7% of the letters in the human genome are functionally important. "We were impressed with how low that number is," says Siepel. "Some analyses of the ENCODE data alone have argued that upwards of 80% of the genome is functional, but our evolutionary analysis suggests that isn't the case." He added, "other researchers have estimated that similarly small fractions of the genome have been conserved over long time evolutionary periods, but our analysis indicates that the much larger ENCODE-based estimates can't be explained by gains of new functional sequences on the human lineage. We think most of the sequences designated as 'biochemically active' by ENCODE are probably not evolutionarily important in humans."

According to Siepel, this analysis will allow researchers to isolate functionally important sequences in diseases much more rapidly. Most genome-wide studies implicate massive regions, containing tens of thousands of letters, associated with disease. "Our analysis helps to pinpoint which letters in these sequences are likely to be functional because they are both biochemically active and have been preserved by evolution." says Siepel. "This provides a powerful resource as scientists work to understand the genetic basis of disease."

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Harnessing data from Nature's great evolutionary experiment

Positional cloning is a genetic mapping technique used to pinpoint the location of specific traits of interest, such as disease-causing genes or mutations, within the genome. Very simply, this map-based technique involves crossing mutant individuals with wild-type individuals and examining the offspring in order to localize a candidate region in the genome for the mutation. By identifying genetic markers that are linked to the trait, progressively more precise areas on a chromosome are defined until the gene is identified.

This approach has contributed to the successful mapping of genes involved in numerous human diseases such as Huntington's disease and cystic fibrosis, an important first step in understanding these conditions.

In plants, the positional cloning method has been traditionally used in studies of model organisms such as rice and Arabidopsis, providing important insights into plant genetics. Researchers at Brigham Young University and Rutgers University have developed a protocol that highlights the utility of this technique in plant taxa with much larger genomes, such as maize. The detailed protocol is published in the January issue of Applications in Plant Sciences .

"Maize is the most important cereal crop in the United States, and one of the most important in the world," says Clinton Whipple, an author of the study. "We originally worried that the large size of the maize genome would make positional cloning unrealistic, requiring very large mapping populations. However, these fears turned out to be largely unwarranted, as we successfully utilized this technique with populations similar in size to Arabidopsis and rice, which have significantly smaller genomes."

With the complete sequence of the maize genome now available, positional cloning can be used to identify genes responsible for traits caused by mutations as well as by natural genetic variation.

Although this technique is not new and has been used by geneticists for quite some time, no general protocol has been previously published. "To my knowledge, a detailed step-by-step protocol on positional cloning has not been published previously (in any species), and we were hoping to fill that hole in the literature," says Whipple.

"While we have focused on maize, much of what we have described can be applied to any plant species that is genetically tractable and has a sequenced genome. Given the rapidly decreasing costs of sequencing, many more species are becoming sequenced, including emerging models important for evolutionary and ecological questions that could benefit from the functional insights that positional cloning can provide."

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The above story is based on materials provided by Botanical Society of America. Note: Materials may be edited for content and length.

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Mapping the maize genome

The Genome A Novel by Sergei Lukyanenko PDF download
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A new analysis opens the door to discovery of thousands of potential new cancer biomarkers.

Researchers at the University of Michigan Comprehensive Cancer Center analyzed the global landscape of a portion of the genome that has not been previously well-explored -- long non-coding RNAs. This vast portion of the human genome has been considered the dark matter because so little is known about it. Emerging new evidence suggests that lncRNAs may play a role in cancer and that understanding them better could lead to new potential targets for improving cancer diagnosis, prognosis or treatment.

"We know about protein-coding genes, but that represents only 1-2 percent of the genome. Much less is known about the biology of the non-coding genome in terms of how it might function in a human disease like cancer," says senior study author Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at the University of Michigan Medical School.

The researchers pulled together 25 independent datasets totaling 7,256 RNA sequencing samples. The data was from public sources such as The Cancer Genome Atlas project, as well as from the Michigan Center for Translational Pathology's archives. They applied high-throughput RNA sequencing technology to identify more than 58,000 lncRNA genes across normal tissue and a range of common cancer types.

Results of the study appear online in Nature Genetics.

"We used all of this data to decipher what the genomic landscape looks like in different tissues as well as in cancer," Chinnaiyan says. "This opens up a Pandora's box of all kinds of lncRNAs to investigate for biomarker potential."

The complete dataset, named the MiTranscriptome compendium, has been made available on a public website, http://www.mitranscriptome.org, for the scientific community to explore.

The researchers also identified one lncRNA, SChLAP1, as a potential biomarker for aggressive prostate cancer. SChLAP1 was more highly expressed in metastatic prostate cancer than in early stage disease. SChLAP1 was found primarily in prostate cancer cells, not in other cancers or normal cells, which gives researchers hope that a non-invasive test could be developed to detect SChLAP1. Such a test could be used to help patients and their doctors make treatment decisions for early stage prostate cancer.

"Some long non-coding RNAs tend to be exquisitely specific for cancer, while protein-coding genes are often not. That's what makes lncRNAs a very promising target for developing biomarkers," Chinnaiyan says. "We hope that researchers will investigate the MiTransciptome compendium and begin to nominate lncRNAs for further study and development. It's likely that only a subset of these have true function but as a previously untapped area, it holds great promise."

Additional authors: Matthew K. Iyer, Yashar S. Niknafs, Rohit Malik, Udit Singhal, Anirban Sahu, Yasuyuki Hosono, Terrence R. Barrette, John R. Prensner, Joseph R. Evans, Shuang Zhao, Anton Poliakov, Xuhong Cao, Saravana M. Dhanasekaran, Yi-Mi Wu, Dan R. Robinson, David G. Beer, Felix Y. Feng, Hariharan K. Iyer

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Researchers open 'Pandoras Box' of potential cancer biomarkers

Cancers Last Stand? The Genome Solution
The deadly scourge of cancer has confounded doctors since ancient Egypt. Now, The Cancer Genome Atlas (modeled after the Human Genome Project) promises a new...

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