Category Archives: Genome

Why we should know our genome: Massimo Delledonne | Massimo Delledonne | TEDxLakeComo
This talk was given at a local TEDx event, produced independently of the TED Conferences. Genecisticist. Massimo Delledonne is one of the greatest Italian experts in genome, both of plants...

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Why we should know our genome: Massimo Delledonne | Massimo Delledonne | TEDxLakeComo - Video

PUBLIC RELEASE DATE:

19-Nov-2014

Contact: Steven Benowitz steven.benowitz@gmail.com 301-451-8325 NIH/National Human Genome Research Institute @genome_gov

Looking across evolutionary time and the genomic landscapes of humans and mice, an international group of researchers has found powerful clues to why certain processes and systems in the mouse - such as the immune system, metabolism and stress response - are so different from those in people. Building on years of mouse and gene regulation studies, they have developed a resource that can help scientists better understand how similarities and differences between mice and humans are written in their genomes.

Their findings - reported by the mouse ENCODE Consortium online Nov. 19, 2014 (and in print Nov. 20) in four papers in Nature and in several other publications - examine the genetic and biochemical programs involved in regulating mouse and human genomes. The scientists found that, in general, the systems that are used to control gene activity have many similarities in mice and humans, and have been conserved, or continued, through evolutionary time.

The results may offer insights into gene regulation and other systems important to mammalian biology. They also provide new information to determine when the mouse is an appropriate model to study human biology and disease, and may help to explain some of its limitations.

The latest research results are from the mouse ENCODE project, which is part of the ENCODE, or ENCyclopedia Of DNA Elements, program supported by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. ENCODE is building a comprehensive catalog of functional elements in the human and mouse genomes. Such elements include genes that provide instructions to build proteins, non-protein-coding genes and regulatory elements that control which genes are turned on or off, and when.

"The mouse has long been a mainstay of biological research models," said NHGRI Director Eric Green, M.D., Ph.D. "These results provide a wealth of information about how the mouse genome works, and a foundation on which scientists can build to further understand both mouse and human biology. The collection of mouse ENCODE data is a tremendously useful resource for the research community."

"This is the first systematic comparison of the mouse and human at the genomic level," said Bing Ren, Ph.D., co-senior author on the Consortium's main Nature study and professor of cellular and molecular medicine at the University of California, San Diego. "We have known that the mouse was mostly a good model for humans. We found that many processes and pathways are conserved from mouse to human. This allows us to study human disease by studying those aspects of mouse biology that reflect human biology."

In many cases, the investigators found that some DNA sequence differences linked to diseases in humans appeared to have counterparts in the mouse genome. They also showed that certain genes and elements are similar in both species, providing a basis to use the mouse to study relevant human disease. However, they also uncovered many DNA variations and gene expression patterns that are not shared, potentially limiting the mouse's use as a disease model. Mice and humans share approximately 70 percent of the same protein-coding gene sequences, which is just 1.5 percent of these genomes.

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New view of mouse genome finds many similarities, striking differences with human genome

Geneticists have a dirty little secret. More than a decade after the official completion of the Human Genome Project, and despite the publication of multiple updates, the sequence still has hundreds of gaps many in regions linked to disease. Now, several research efforts are closing in on a truly complete human genome sequence, called the platinum genome.

Its like mapping Europe and somebody says, Oh, theres Norway. I really dont want to have to do the fjords, says Ewan Birney, a computational biologist at the European Bioinformatics Institute near Cambridge, UK, who was involved in the Human Genome Project. Now somebodys in there and mapping the fjords.

The efforts, which rely on the DNA from peculiar cellular growths, are uncovering DNA sequences not found in the official human genome sequence that have potential links to conditions such as autism and the neuro-degenerative disease amyotrophic lateral sclerosis (ALS).

In 2000, then US President Bill Clinton joined leading scientists to unveil a draft human genome. Three years later, the project was declared finished. But there were caveats: that human reference genome was more than 99% complete, but researchers could not get to 100% because of method limitations.

Sequencing machines cannot process entire chromosomes, so scientists must first make many identical copies of the DNA and cut them into short stretches, with the breaks in different places. After sequencing, a computer program looks for overlapping patterns to stitch the resulting segments back together.

This approach worked for most of the genome, because DNA sequences are almost identical across its three billion letters (the As, Cs, Ts and Gs). But in some parts, big differences exist between the versions of chromosomes that an individual inherits from the mother and father. Attempts to stitch together these regions to sequence the DNA led to gaps when the differing sequences gave conflicting solutions.

Theres a whole level of genetic variation that were missing.

The problem can be likened to assembling a single jigsaw puzzle from the mixed-up pieces of similar, but not identical, puzzles. If one puzzle piece is identical across the sets, any copy of it will do. But if one set contains a much larger version of the matching piece, or if a piece is missing, the puzzle will not fit together. In particular, long, repetitive stretches near genes vexed the computer algorithms used to analyse the data. And the problem was made worse because DNA from multiple people was used, adding to the variation between the genomes.

As a result, when a persons genome is sequenced for instance, to look for the cause of a disease crucial bits of DNA may be overlooked because they do not have counter-parts in the published genome. Theres a whole level of genetic variation that were missing, says Evan Eichler, a genome scientist at the University of Washington in Seattle, a leading proponent of the platinum-genome efforts. To plug the gaps, researchers need a supply of human cells with just a single version of each chromosome, to remove the possibility of conflicting solutions a single set of puzzle pieces, in other words.

Sperm and egg cells contain a single copy of each chromosome, but these cells cannot divide and produce copies of themselves. So in recent years, geneticists have turned to cells from growths called hydatidiform moles, created when a sperm fertilizes an egg that is missing its own genetic material (see To simplify a sequence). The fertilized cell copies its genome and starts dividing, just as the cells in a normal fertilized egg would. The resulting ball of cells, which is usually removed in the first trimester of pregnancy, contains identical copies of each human chromosome.

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Platinum genome takes on disease

A group of international researchers has just discovered the keys to explaining why certain processes and systems in mice, like the immune system, metabolism and stress response, are so different to those in humans. The scientists have detailed the functional parts of the mouse genome and have compared them with those in humans. A whole set of data has come out of this -- which is now to available to the scientific community -- which will be significant for research into mammalian biology as well as the study of human illness mechanisms.

The comparison focuses on the genetic and biochemical processes regulating genome activity in humans and mice. The scientists have found that, in general, the systems for controlling genome activity in the two species are very alike, and have been preserved through time. However, they have also detected certain differences in the DNA, and patterns of gene expression that are not shared. "Finding these similarities and studying the aspects of mouse biology that may reflect human biology, allows us to approach the study of human illnesses in a better way," affirms Bing Ren, one of the principal authors from the ENCODE Consortium and a lecturer in molecular and cellular medicine at the University of California -- San Diego.

"The mouse is one of the most utilised models for studying human biology and we use it for creating models of human illnesses and testing new drugs and therapies. Our study goes a long way towards validating the usefulness of this animal model and provides enormous support for its use in human illnesses. We have found that there are many well-preserved cell processes in the two species, for example, in embryonic development. Understanding these similarities will allow us to carry out more accurate studies on human biology," explains Roderic Guig, one of the main researchers involved in the work and coordinator of the Bioinformatics and Genomics programme at the CRG.

The researchers have compared various processes involved in gene expression, such as gene transcription and chromatin modification, and have repeated this in different tissues and cell types from both humans and mice. "Our lab took part in analysing the group of RNA or transcriptome, that results from transcription, the process by which the instructions in the genes are read. We have discovered that human and mice transcriptome contains both preserved and divergent elements. Surprisingly we have found that the differences seem bigger between species rather than between fabrics when initially we thought that the gene activity in the same kinds of tissues would be similar," adds Alessandra Breschi, one of the first co-authors of the main work published in Nature and a researcher in Roderic Guig's lab at the CRG.

The project makes it clear that there is a wide variety of options available for achieving gene expression. By comparing these two genomes they have also found that there is a common "language" that the cells use at the molecular level but which, at the same time, is tremendously flexible and has varied greatly throughout evolution. For example, if we used the analogy of electrical circuits, we would find cables, plugs, switches, etc. By combining the pieces in one way or another, we would obtain very different circuits (as happens between mice and humans) although the basic mechanisms governing the operation are based on the same methods and available resources.

An additional study, currently available at bioRxiv, led by the researchers from the CRG and Cold Spring Harbour Laboratory, highlights the fact that a substantial part of human and mice genes have maintained an essentially constant expression throughout evolution, in tissues and various organs. In addition, the researchers have quantified the preservation level of this gene expression between humans and mice. This allows the identification of those genes that have the same expression in the two species, and for which the mouse represents a good model of human biology.

"ENCODE is a living project and the maps that are generated are constantly updated and improved, with information being added on new types of cells and tissues or new complementary genome assays. We hope that the project can keep providing this data as it has up to now, making it available to everyone and treating it in a systematic and coherent way," concludes Dr. Guig, the only principal investigator in Europe involved in this work.

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The above story is based on materials provided by Center for Genomic Regulation. Note: Materials may be edited for content and length.

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Humans and mice: Similar enough for studying disease and different enough to give us new clues about evolution

A ground-breaking study involving The Genome Analysis Centre (TGAC) in Norwich is likely to be a major first step forward in the study of influenza, cystic fibrosis and other human disease such as heart conditions and diabetes.

The study reveals clues found by scientists in the ferret genome regarding how the respiratory system responds to pandemic flu and cystic fibrosis and was published in the online advanced publication of leading science journal Nature Biotechnology.

The international research effort has been funded by the National Institute of Allergy and infectious Diseases (NIAID) coordinated by Michael Katze and Xinxia Peng at the University of Washington in Seattle and Federica Di Palma at The Genome Analysis Centre (TGAC), formally at the Broad Institute of MIT and Harvard.

The researchers sequenced the ferret genome and used the data to analyse how influenza and cystic fibrosis affected respiratory tissues at the cellular level.

By creating a high quality genome and transcriptome resource for the ferret, we have demonstrated how studies in non-conventional model organisms can facilitate essential bioscience research underpinning health, said Federica Di Palma, director of science (Vertebrate & Health Genomics) at TGAC.

Ferrets have long been considered the best animal model for studying a number of human diseases, particularly influenza, because the strains that infect humans also infect ferrets and spread from ferret to ferret much as from human to human.

In the study, scientists at Broad Institute of MIT and Harvard, led by Federica Di Palma and Jessica Alfoldi, first sequenced and annotated the genome of a domestic sable ferret, Mustela putorius furo, and then collaborated with the Katze group on the subsequent analysis.

A technique called transcriptome analysis was used to reveal which genes were being turned on, or expressed, in ferret tissues when challenged by influenza and in a knock out model of cystic fibrosis.

This is a big deal, said Michael Katze, UW professor of Microbiology who led the research effort. Every time you sequence a genome, it allows you to answer a wide range of questions you couldnt before. Having the genome changes a field forever.

In the influenza portion of the study, Yoshihiro Kawaokas group at the University of Wisconsin-Madison exposed ferrets to a reconstructed version of the virus that caused the deadly pandemic flu of 1918, the so-called Spanish flu, which killed 25 million people worldwide, and the so-called swine flu virus that caused the worldwide pandemic of 2009-2010 and continues to cause disease today.

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Ferret genome clue to flu and cystic fibrosis

PUBLIC RELEASE DATE:

18-Nov-2014

Contact: Joel Winston joel.winston@biomedcentral.com 44-203-192-2081 BioMed Central @biomedcentral

A new method for examining the Ebola virus genome could make surveillance quicker and cheaper for West African nations, and help detect new forms of the virus. The detailed procedure is being shared with the research community along with the study paper, which is freely available in the open access journal Genome Biology.

With over 13,000 cases and nearly 5,000 deaths in eight affected countries, the current Ebola outbreak in West Africa is the largest to date, the first to spread to densely populated urban areas, and represents the first time the virus has been diagnosed outside of Africa.

To help contain the current outbreak, experts say that surveillance remains key. Detecting viral RNA genomes in suspected fever patients helps confirm diagnoses of Ebola, and aids decisions to quarantine patients and begin tracing their contacts. Yet sequencing viral genomes directly from blood samples holds many challenges. Samples contain very little viral RNA and are heavily contaminated with human RNA, while hot climates cause rapid degradation of viral RNA material and biosafety measures bring further complications for handling samples. As such few Ebola genomes have been sequenced.

Research led by the Broad Institute, USA, has now revealed a new method to sequence genomes of the Ebola virus, that lowers contaminating human RNA from 80% to less than 0.5%, and was proven to work through the rapid sequencing of nearly 100 Ebola patient blood samples from the current outbreak, with a turnaround time of 10 days. The method is also cost-effective, and may help West African nations rapidly and effectively track outbreaks with limited resources.

The research team was initially developing a method for sequencing Lassa virus that causes hemorrhagic fever prevalent in West Africa. They were able to define a laboratory procedure using enzymes and chemical reagents which led to almost complete removal of contaminant human RNA from their Lassa fever samples. Once the Ebola outbreak spread to their research site in Sierra Leone, they were asked to put their newly developed sequencing method to the test.

Using their improved sequencing approach, the team processed samples from 78 Ebola patients and reduced the normal length of the process threefold. Their method also lowered costs by allowing them to sequence and assemble more viral genomes using fewer steps with a higher success rate.

Lead author Christian Matranga from the Broad Institute said: "We were surprised that our strategy worked so well with such diverse, and often difficult samples of undefined quality and quantity. And because of the speed of our approach, we were rapidly able to make the viral genetic data available to the scientific community to provide timely insights for ongoing surveillance and control efforts in the area."

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Ebola surveillance may become quicker and cheaper

PUBLIC RELEASE DATE:

17-Nov-2014

Contact: Michael McCarthy leilag@uw.edu 206-543-3620 University of Washington Health Sciences/UW Medicine

In what is likely to be a major step forward in the study of influenza, cystic fibrosis and other human diseases, an international research effort has a draft sequence of the ferret genome. The sequence was then used to analyze how the flu and cystic fibrosis affect respiratory tissues at the cellular level.

The National Institute of Allergy and infectious Diseases, of the National Institutes of Health, funded the project that was coordinated by Michael Katze and Xinxia Peng at the University of Washington in Seattle and Federica Di Palma and Jessica Alfoldi at the Broad Institute of MIT and Harvard.

"The sequencing of the ferret genome is a big deal," said Michael Katze, UW professor of microbiology who led the research effort. "Every time you sequence a genome, it allows you to answer a wide range of questions you couldn't before. Having the genome changes a field forever."

Ferrets have long been considered the best animal model for studying a number of human diseases, particularly influenza, because the strains that infect humans also infect ferrets. These infections spread from ferret to ferret much as they do from human to human.

In the study, scientists at Broad Institute of MIT and Harvard, led by Federica Di Palma and Jessica Alfoldi, first sequenced and annotated the genome of a domestic sable ferret, Mustela putorius furo. They then collaborated with the Katze group on the subsequent analysis. A technique called transcriptome analysis. This technique identifies all the RNA that is being produced, or transcribed, from areas of the genome that are being activated at a given point in time. This makes it possible to see how the ferret cells are responding when challenged by influenza and in cystic fibrosis.

"By creating a high quality genome and transcriptome resource for the ferret, we have demonstrated how studies in non-conventional model organisms can facilitate essential bioscience research underpinning health," said Federica Di Palma, director of science in Vertebrate & Health Genomics at TGAC, The Genome Analysis Centre.

In the influenza portion of the study, Yoshihiro Kawaoka's group at the University of Wisconsin-Madison exposed ferrets to a reconstructed version of the virus that caused the deadly pandemic flu of 1918, the so-called Spanish flu, which killed 25 million people worldwide, and the swine-flu virus that caused the worldwide pandemic of 2009-2010 and continues to cause disease today.

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Ferret genome sequenced, holds clues to respiratory diseases

PUBLIC RELEASE DATE:

18-Nov-2014

Contact: Steven Salzberg salzberg@jhu.edu 410-614-6112 PeerJ @ThePeerJ

As genome sequencing has gotten faster and cheaper, the pace of whole-genome sequencing has accelerated, dramatically increasing the number of genomes deposited in public archives. Although these genomes are a valuable resource, problems can arise when researchers misapply computational methods to assemble them, or accidentally introduce unnoticed contaminations during sequencing.

The first complete bacterial genome, Haemophilus influenzae, appeared in 1995, and today the public GenBank database contains over 27,000 prokaryotic and 1,600 eukaryotic genomes. The vast majority of these are draft genomes that contain gaps in their sequences, and researchers often use these draft sequences for future analyses.

Each genome sequencing project begins with a DNA source, which varies depending on the species. For animals, blood is a common source, while for smaller organisms such as insects the entire organism or a population of organisms may be required to yield enough DNA for sequencing. Throughout the process of DNA isolation and sequencing, contamination remains a possibility. Computational filters applied to the raw sequencing reads are usually effective at removing common laboratory contaminants such as E. coli, but other contaminants may be more difficult to identify.

In a new study in PeerJ , authors from Johns Hopkins University discovered contaminating bacterial and viral sequences in "draft" assemblies of animal and plant genomes that had been deposited in GenBank. These may cause particular problems for the rapidly growing field of microbiome analysis, when sequences labeled as animal in origin actually turn out to be microbial.

In an even more surprising finding, the authors discovered the presence of cow and sheep DNA in the supposedly finished genome of a pathogenic bacterium, Neisseria gonorrhoeae. Although deposited in GenBank as a finished genome, the bacterium apparently was a draft genome that was submitted as complete, with erroneous DNA inserted in five places. If taken at face value, this data would appear to be a startling case of lateral gene transfer, but the correct explanation appears to be more mundane.

These findings highlight the importance of careful screening of DNA sequence data both at the time of release and, in some cases, for many years after publication.

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Unexpected cross-species contamination in genome sequencing projects

PUBLIC RELEASE DATE:

17-Nov-2014

Contact: Adrienne Vienneau avienneau@cheo.on.ca 613-737-7600 x4144 Children's Hospital of Eastern Ontario Research Institute

OTTAWA and VANCOUVER, November 17, 2014--What do a mouse, a fly, a zebrafish, a worm and yeast have in common? Together these five organisms hold the keys for scientists to better understand the basic molecular function of genes and specific gene mutations. The Canadian Institutes of Health Research (CIHR), in partnership with Genome Canada, has awarded the Canadian Rare Diseases Models and Mechanisms (RDMM) Network -- a first of its kind collaboration -- $2.3 million to investigate these molecular mechanisms and advance rare disease research.

Rare diseases are usually not the focus of research laboratories, which greatly limits our ability to discover effective therapies. We can gain insight into most rare human diseases by analyzing the equivalent genes and pathways in experimental organisms, because nature uses the same building blocks to construct organisms such as yeast, worms, flies, fish, mice and humans. This approach will underpin the RDMM Network, which is led by Drs. Phil Hieter, Kym Boycott and Janet Rossant.

"Our efforts will build on Canada's proven leadership in rare disease gene discovery through national engagement," said Hieter, senior scientist at the University of British Columbia. "We will mobilize the entire Canadian biomedical community of clinicians and model organism researchers to communicate and connect, integrate and share their resources and expertise, and work together to provide functional insights into newly discovered rare disease genes."

The RDMM Network includes all basic science researchers studying gene function in model systems and clinician scientists discovering novel disease genes in Canada. It will study biological mechanisms underlying rare diseases at the levels of genes, pathways and networks by analyzing the equivalent (orthologous) genes in the five model organisms.

"The key to success will be increased collaboration between clinicians and scientists as early as possible following the discovery of new gene mutations that cause disease," said Boycott, senior scientist at the Children's Hospital of Eastern Ontario (CHEO) and associate professor in the University of Ottawa Faculty of Medicine. "Our goal is to better understand new aspects of human biology and disease and identify therapeutic pathways that might lead to the development of new treatments for rare disease patients."

The RDMM Network, through its scientific advisory committee, will fund at least 24 catalyst projects annually. Its goals are to validate genetic variants that cause disease, advance understanding of disease mechanisms, create the rationale for treatment (e.g., identification of candidate drug targets) and establish longer-term collaborations between scientists and clinicians that will lead to subsequent funding of outstanding laboratory and/or applied research.

"Together, with our partners at Genome Canada, the Canadian Institutes of Health Research is proud to support the RDMM network, to advance efforts in rare disease research," said Dr. Paul Lasko, scientific director of the CIHR Institute of Genetics. "Their work will guide the development and improvement of treatments and therapeutics for the more than 350 million people worldwide who suffer from a rare disease."

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From mice to yeast: New network to use model organisms to study rare disease

By Lisa M. Krieger lkrieger@mercurynews.com

SAN FRANCISCO -- In a provocative cross-species experiment, scientists are striving to rewrite the pig genome so the animal grows lungs that could be transplanted into humans.

"We are re-engineering the pig, changing its genetic code," said genome pioneer Craig Venter at SynBioBeta 2014, an annual synthetic biology conference in San Francisco. "If we succeed with rewriting the pig genome, we will have replacement organs for those who need them," he said Friday.

His team at Synthetic Genomics is designing the project, he said, creating on computers the code needed to build the hybrid. By changing as few as five genes, they have created lungs that survived for a year in baboons, he said.

In other major news at the conference, Google confirmed that Stanford University bioengineer Drew Endy has joined its team at the secretive Google X, which created such projects as Google Glass, driverless cars and high-altitude Wi-Fi balloons.

The hiring of Endy, brought to Stanford's School of Engineering from the Massachusetts Institute of Technology, suggests that Google seeks to explore the design and construction of made-to-order organisms.

Led by scientists like Venter and Endy, the once-fledgling field of synthetic biology has surged in commercial interest, according to SynBioBeta founder John Cumbers. Synthetic biology companies raised more than $500 million in 2014, and at least 20 startups were launched.

Venter is a La Jolla-based entrepreneur and molecular biologist who gained fame in a historic race with government scientists to decode the human genome.

In the Mojave Desert, he is testing a device that he says can help find extraterrestrial life on Mars by detecting and decoding its DNA -- then fax back the code.

The downloaded data could be used to reconstruct the alien organism in bio-secure labs, he said.

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Synthetic biologist aims to create pig with human lungs