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  • richardmitnick 5:55 pm on December 10, 2014 Permalink | Reply
    Tags: , , , Genomics,   

    From isgtw: “Supercomputer compares modern and ancient DNA” 

    international science grid this week

    December 10, 2014
    Jorge Salazar, Texas Advanced Computing Center

    What if you researched your family’s genealogy, and a mysterious stranger turned out to be an ancestor? A team of scientists who peered back into Europe’s murky prehistoric past thousands of years ago had the same surprise. With sophisticated genetic tools, supercomputing simulations and modeling, they traced the origins of modern Europeans to three distinct populations.The international research team’s results are published in the journal Nature.

    The Stuttgart skull, from a 7,000-year-old skeleton found in Germany among artifacts from the first widespread farming culture of central Europe. Right: Blue eyes and dark skin – how the European hunter-gatherer appeared 7,000 years ago. Artist depiction based on La Braña 1, whose remains were recovered at La Braña-Arintero site in León, Spain. Images courtesy Consejo Superior de Investigaciones Cientificas.

    “Europeans seem to be a mixture of three different ancestral populations,” says study co-author Joshua Schraiber, a National Science Foundation postdoctoral fellow at the University of Washington, in Seattle, US. Schraiber says the results surprised him because the prevailing view among scientists held that only two distinct groups mixed between 7,000 and 8,000 years ago in Europe, as humans first started to adopt agriculture.

    Scientists have only a handful of ancient remains well preserved enough for genome sequencing. An 8,000-year-old skull discovered in Loschbour, Luxembourg provided DNA evidence for the study. The remains were found at the caves of Loschbour, La Braña, Stuttgart, a ritual site at Motala, and at Mal’ta.

    The third mystery group that emerged from the data is ancient northern Eurasians. “People from the Siberia area is how I conceptualize it,” says Schraiber. “We don’t know too much anthropologically about who these people are. But the genetic evidence is relatively strong because we do have ancient DNA from an individual that’s very closely related to that population, too.”

    The individual is a three-year-old boy whose remains were found near Lake Baikal in Siberia at the Mal’ta site. Scientists determined his arm bone to be 24,000 years old. They then sequence his genome, making it the second oldest modern human sequenced. Interestingly enough, in late 2013 scientists used the Mal’ta genome to find that about one-third of Native American ancestry originated through gene flow from these ancient North Eurasians.

    The researchers took the genomes from these ancient humans and compared them to those from 2,345 modern-day Europeans. “I used the POPRES data set, which had been used before to ask similar questions just looking at modern Europeans,” Schraiber says. “Then I used software called Beagle, which was written by Brian Browning and Sharon Browning at the University of Washington, which computationally detects these regions of identity by descent.”

    The National Science Foundation’s XSEDE (Extreme Science and Engineering Discovery Environment) and Stampede supercomputer at the Texas Advanced Computing Center provided computational resources used in the study. The research was funded in part by the National Cancer Institute of the National Institutes of Health.

    See the full article here.

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  • richardmitnick 4:28 pm on October 16, 2014 Permalink | Reply
    Tags: , , Genomics   

    From WCG: “Project Launch: Uncovering Genome Mysteries” 

    16 Oct 2014
    To kick off World Community Grid’s 10th anniversary celebrations, we’re launching Uncovering Genome Mysteries to compare hundreds of millions of genes from many organisms that have never been studied before, helping scientists unearth some of the hidden superpowers of the natural world.

    From the realization that the Penicillium fungus kills germs, to the discovery of bacteria that eat oil spills and the identification of aspirin in the willow tree bark – a better understanding of the natural world has resulted in many improvements to human health, welfare, agriculture and industry.

    Diver collecting microbial samples from Australian seaweeds for Uncovering Genome Mysteries

    Our understanding of life on earth has grown enormously since the advent of genetic research. But the vast majority of life on this planet remains unstudied or unknown, because it’s microscopic, easy to overlook, and hard to study. Nevertheless, we know that tiny, diverse organisms are continually evolving in order to survive and thrive in the most extreme conditions. The study of these organisms can provide valuable insights on how to deal with some of the most pressing problems that human society faces, such as drug-resistant pathogens, pollution, and energy shortages.

    Inexpensive, rapid DNA sequencing technologies have enabled scientists to decode the genes of many organisms that previously received little attention, or were entirely unknown to science. However, making sense of all that genomic information is an enormous task. The first step is to compare unstudied genes to others that are already better understood. Similarities between genes point to similarities in function, and by making a large number of these comparisons, scientists can begin to sort out what each organism is and what it can do.

    In Uncovering Genome Mysteries, World Community Grid volunteers will run approximately 20 quadrillion comparisons to identify similarities between genes in a wide variety of organisms, including microorganisms found on seaweeds from Australian coastlines and in the Amazon River. This database of similarities will help researchers understand the diversity and capabilities that are hidden in the world all around us. For more on the project’s aims and methods, see here.

    Once published, these results should help scientists with the following goals:

    Discovering new protein functions and augmenting knowledge about biochemical processes in general
    Identifying how organisms interact with each other and the environment
    Documenting the current baseline microbial diversity, allowing a better understanding of how microorganisms change under environmental stresses, such as climate change
    Understanding and modeling complex microbial systems

    In addition, a better understanding of these organisms will likely be useful in developing new medicines, harnessing new sources of renewable energy, improving nutrition, cleaning the environment, creating green industrial processes and many other advances.

    The timing of this project launch is a perfect way to kick off celebrations of another important achievement – World Community Grid’s 10th anniversary. There’s much to celebrate and reflect upon from the past decade’s work, but it’s equally important to continue pushing forward and making new scientific discoveries. With your help – and the help of your colleagues and friends – we can continue to expand our global network of volunteers and achieve another 10 years of success. Here’s to another decade of discovery!

    To contribute to Uncovering Genome Mysteries, go to your My Projects page and make sure the box for this new project is checked.

    Please visit the following pages to learn more:

    Uncovering Genome Mysteries project overview
    Frequently Asked Questions

    See the full article here.

    World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”

    WCG projects run on BOINC software from UC Berkeley.

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.


    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-

    Say No to Schistosoma

    GO Fight Against Malaria

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    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

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  • richardmitnick 8:06 pm on August 27, 2014 Permalink | Reply
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    From Berkeley Lab: “Encyclopedia of How Genomes Function Gets Much Bigger” 

    Berkeley Logo

    Berkeley Lab

    August 27, 2014
    Dan Krotz 510-486-4019

    A big step in understanding the mysteries of the human genome was unveiled today in the form of three analyses that provide the most detailed comparison yet of how the genomes of the fruit fly, roundworm, and human function.

    The research, appearing August 28 in in the journal Nature, compares how the information encoded in the three species’ genomes is “read out,” and how their DNA and proteins are organized into chromosomes.

    The results add billions of entries to a publicly available archive of functional genomic data. Scientists can use this resource to discover common features that apply to all organisms. These fundamental principles will likely offer insights into how the information in the human genome regulates development, and how it is responsible for diseases.

    Berkeley Lab scientists contributed to an NHGRI effort that provides the most detailed comparison yet of how the genomes of the fruit fly, roundworm, and human function. (Credit: Darryl Leja, NHGRI)

    The analyses were conducted by two consortia of scientists that include researchers from the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab). Both efforts were funded by the National Institutes of Health’s National Human Genome Research Institute.

    One of the consortiums, the “model organism Encyclopedia of DNA Elements” (modENCODE) project, catalogued the functional genomic elements in the fruit fly and roundworm. Susan Celniker and Gary Karpen of Berkeley Lab’s Life Sciences Division led two fruit fly research groups in this consortium. Ben Brown, also with the Life Sciences Division, participated in another consortium, ENCODE, to identify the functional elements in the human genome.

    The consortia are addressing one of the big questions in biology today: now that the human genome and many other genomes have been sequenced, how does the information encoded in an organism’s genome make an organism what it is? To find out, scientists have for the past several years studied the genomes of model organisms such as the fruit fly and roundworm, which are smaller than our genome, yet have many genes and biological pathways in common with humans. This research has led to a better understanding of human gene function, development, and disease.

    Comparing Transcriptomes

    In all organisms, the information encoded in genomes is transcribed into RNA molecules that are either translated into proteins, or utilized to perform functions in the cell. The collection of RNA molecules expressed in a cell is known as its transcriptome, which can be thought of as the “read out” of the genome.

    In the research announced today, dozens of scientists from several institutions looked for similarities and differences in the transcriptomes of human, roundworm, and fruit fly. They used deep sequencing technology and bioinformatics to generate large amounts of matched RNA-sequencing data for the three species. This involved 575 experiments that produced more than 67 billion sequence reads.

    A team led by Celniker, with help from Brown and scientists from several other labs, conducted the fruit fly portion of this research. They mapped the organism’s transcriptome at 30 time points of its development. They also explored how environmental perturbations such as heavy metals, herbicides, caffeine, alcohol and temperature affect the fly’s transcriptome. The result is the finest time-resolution analysis of the fly genome’s “read out” to date—and a mountain of new data.

    “We went from two billion reads in research we published in 2011, to 20 billion reads today,” says Celniker. “As a result, we found that the transcriptome is much more extensive and complex than previously thought. It has more long non-coding RNAs and more promoters.”

    When the scientists compared transcriptome data from all three species, they discovered 16 gene-expression modules corresponding to processes such as transcription and cell division that are conserved in the three animals. They also found a similar pattern of gene expression at an early stage of embryonic development in all three organisms.

    This work is described in a Nature article entitled “Comparative analysis of the transcriptome across distant species.”

    Comparing chromatin

    Another group, also consisting of dozens of scientists from several institutions, analyzed chromatin, which is the combination of DNA and proteins that organize an organism’s genome into chromosomes. Chromatin influences nearly every aspect of genome function.

    Karpen led the fruit fly portion of this work, with Harvard Medical School’s Peter Park contributing on the bioinformatics side, and scientists from several other labs also participating. The team mapped the distribution of chromatin proteins in the fruit fly genome. They also learned how chemical modifications to chromatin proteins impact genome functions.

    Their results were compared with results from human and roundworm chromatin research. In all, the group generated 800 new chromatin datasets from different cell lines and developmental stages of the three species, bringing the total number of datasets to more than 1400. These datasets are presented in a Nature article entitled “Comparative analysis of metazoan chromatin organization.”

    Here again, the scientists found many conserved chromatin features among the three organisms. They also found significant differences, such as in the composition and locations of repressive chromatin.

    But perhaps the biggest scientific dividend is the data itself.

    “We found many insights that need follow-up,” says Karpen. “And we’ve also greatly increased the amount of data that others can access. These datasets and analyses will provide a rich resource for comparative and species-specific investigations of how genomes, including the human genome, function.”

    See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California

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  • richardmitnick 8:01 am on August 19, 2014 Permalink | Reply
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    From M.I.T.: “The History Inside Us” 

    MIT News

    August 19, 2014
    Christine Kenneally

    Improvements in DNA analysis are helping us rewrite the past and better grasp what it means to be human.


    Every day our DNA breaks a little. Special enzymes keep our genome intact while we’re alive, but after death, once the oxygen runs out, there is no more repair. Chemical damage accumulates, and decomposition brings its own kind of collapse: membranes dissolve, enzymes leak, and bacteria multiply. How long until DNA disappears altogether? Since the delicate molecule was discovered, most scientists had assumed that the DNA of the dead was rapidly and irretrievably lost. When Svante Pääbo, now the director of the Max Planck Institute for Evolutionary Anthropology in Germany, first considered the question more than three decades ago, he dared to wonder if it might last beyond a few days or weeks. But Pääbo and other scientists have now shown that if only a few of the trillions of cells in a body escape destruction, a genome may survive for tens of thousands of years.

    An example of the results of automated chain-termination DNA sequencing.

    In his first book, Neanderthal Man: In Search of Lost Genomes, Pääbo logs the genesis of one of the most groundbreaking scientific projects in the history of the human race: sequencing the genome of a Neanderthal, a human-like creature who lived until about 40,000 years ago. Pääbo’s tale is part hero’s journey and part guidebook to shattering scientific paradigms. He began dreaming about the ancients on a childhood trip to Egypt from his native Sweden. When he grew up, he attended medical school and studied molecular biology, but the romance of the past never faded. As a young researcher, he tried to mummify a calf liver in a lab oven and then extract DNA from it. Most of Pääbo’s advisors saw ancient DNA as a “quaint hobby,” but he persisted through years of disappointing results, patiently awaiting technological innovation that would make the work fruitful. All the while, Pääbo became adept at recruiting researchers, luring funding, generating publicity, and finding ancient bones.

    Eventually, his determination paid off: in 1996, he led the effort to sequence part of the Neanderthal mitochondrial genome. (Mitochondria, which serve as cells’ energy packs, appear to be remnants of an ancient single-celled organism, and they have their own DNA, which children inherit from their mothers. This DNA is simpler to read than the full human genome.) Finally, in 2010, Pääbo and his colleagues published the full Neanderthal genome.

    That may have been one of the greatest feats of modern biology, yet it is also part of a much bigger story about the extraordinary utility of DNA. For a long time, we have seen the genome as a tool for predicting the future. Do we have the mutation for Huntington’s? Are we predisposed to diabetes? But it may have even more to tell us about the past: about distant events and about the network of lives, loves, and decisions that connects them.


    Long before research on ancient DNA took off, Luigi Cavalli-Sforza made the first attempt to rebuild the history of the world by comparing the distribution of traits in different living populations. He started with blood types; much later, his popular 2001 book Genes, Peoples, and Languages explored demographic history via languages and genes. Big historical arcs can also be inferred from the DNA of living people, such as the fact that all non-Africans descend from a small band of humans that left Africa 60,000 years ago. The current distribution across Eurasia of a certain Y chromosome—which fathers pass to their sons—rather neatly traces the outline of the Mongolian Empire, leading researchers to propose that it comes from Genghis Khan, who pillaged and raped his way across the continent in the 13th century.

    But in the last few years, geneticists have found ways to explore not just big events but also the dynamics of populations through time. A 2014 study used the DNA of ancient farmers and hunter-gatherers from Europe to investigate an old question: Did farming sweep across Europe and become adopted by the resident hunter-gatherers, or did farmers sweep across the continent and replace the hunter-gatherers? The researchers sampled ancient individuals who were identified as either farmers or hunters, depending on how they were buried and what goods were buried with them. A significant difference between the DNA of the two groups was found, suggesting that even though there may have been some flow of hunter-­gatherer DNA into the farmers’ gene pool, for the most part the farmers replaced the hunter-gatherers.

    Looking at more recent history, Peter Ralph and Graham Coop compared small segments of the genome across Europe and found that any two modern Europeans who lived in neighboring populations, such as Belgium and Germany, shared between two and 12 ancestors over the previous 1,500 years. They identified tantalizing variations as well. Most of the common ancestors of Italians seem to have lived around 2,500 years ago, dating to the time of the Roman Republic, which preceded the Roman Empire. Though modern Italians share ancestors within the last 2,500 years, they share far fewer of them than other Europeans share with their own countrymen. In fact, Italians from different regions of Italy today have about the same number of ancestors in common with one another as they have with people from other countries. The genome reflects the fact that until the 19th century Italy was a group of small states, not the larger country we know today.

    In a very short amount of time, the genomes of ancient people have ­facilitated a new kind of population genetics. It reveals phenomena that we have no other way of knowing about.

    Significant events in British history suggest that the genetics of Wales and some remote parts of Scotland should be different from genetics in the rest of Britain, and indeed, a standard population analysis on British people separates these groups out. But this year scientists led by Peter Donnelly at Oxford uncovered a more fine-grained relationship between genetics and history. By tracking subtle patterns across the genomes of modern Britons whose ancestors lived in particular rural areas, they found at least 17 distinct clusters that probably reflect different groups in the historic population of Britain. This work could help explain what happened during the Dark Ages, when no written records were made—for example, how much ancient British DNA was swamped by the invading Saxons of the fifth century.

    The distribution of certain genes in modern populations tells us about cultural events and choices, too: after some groups decided to drink the milk of other mammals, they evolved the ability to tolerate lactose. The descendants of groups that didn’t make this choice don’t tolerate lactose well even today.


    Analyzing the DNA of the living is much easier than analyzing ancient DNA, which is always vulnerable to contamination. The first analyses of Neanderthal mitochondrial DNA were performed in an isolated lab that was irradiated with UV light each night to destroy DNA carried in on dust. Researchers wore face shields, sterile gloves, and other gear, and if they entered another lab, Pääbo would not allow them back that day. Still, controlling contamination only took Pääbo’s team to the starting line. The real revolution in analysis of ancient DNA came in the late 1990s, with ­second-generation DNA sequencing techniques. Pääbo replaced Sanger sequencing, invented in the 1970s, with a technique called pyrosequencing, which meant that instead of sequencing 96 fragments of ancient DNA at a time, he could sequence hundreds of thousands.

    Such breakthroughs made it possible to answer one of the longest-running questions about Neanderthals: did they mate with humans? There was scant evidence that they had, and Pääbo himself believed such a union was unlikely because he had found no trace of Neanderthal genetics in human mitochondrial DNA. He suspected that humans and Neanderthals were biologically incompatible. But now that the full Neanderthal genome has been sequenced, we can see that 1 to 3 percent of the genome of non-Africans living today contains variations, known as alleles, that apparently originated with Neanderthals. That indicates that humans and Neanderthals mated and had children, and that those children’s children eventually led to many of us. The fact that sub-Saharan Africans do not carry the same Neanderthal DNA suggests that Neanderthal-human hybrids were born just as humans were expanding out of Africa 60,000 years ago and before they colonized the rest of the world. In addition, the way Neanderthal alleles are distributed in the human genome tells us about the forces that shaped lives long ago, perhaps helping the earliest non-Africans adapt to colder, darker regions. Some parts of the genome with a high frequency of Neanderthal variants affect hair and skin color, and the variants probably made the first Eurasians lighter-skinned than their African ancestors.

    Ancient DNA will almost certainly complicate other hypotheses, like the ­African-origin story, with its single migratory human band. Ancient DNA also reveals phenomena that we have no other way of knowing about. When Pääbo and colleagues extracted DNA from a few tiny bones and a couple of teeth found in a cave in the Altai Mountains in Siberia, they discovered an entirely new sister group, the Denisovans. Indigenous Australians, Melanesians, and some groups in Asia may have up to 5 percent Denisovan DNA, in addition to their Neanderthal DNA.

    In a very short amount of time, a number of ancients have been sequenced by teams all over the world, and the growing library of their genomes has facilitated a new kind of population genetics. What is it that DNA won’t be able to tell us about the past? It may all come down to what happened in the first moments or days after someone’s death. If, for some reason, cells dry out quickly—if you die in a desert or a dry cave, if you are frozen or mummified—post-mortem damage to DNA can be halted, but it may never be possible to sequence DNA from remains found in wet, tropical climates. Still, even working with only the scattered remains that we have found so far, we keep gaining insights into ancient history. One of the remaining mysteries, Pääbo observes, is why modern humans, unlike their archaic cousins, spread all over the globe and dramatically reshaped the environment. What made us different? The answer, he believes, lies waiting in the ancient genomes we have already sequenced.

    There is some irony in the fact that Pääbo’s answer will have to wait until we get more skillful at reading our own genome. We are at the very beginning stages of understanding how the human genome works, and it is only once we know ourselves better that we will be able to see what we had in common with Neanderthals and what is truly different.

    See the full article here.

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  • richardmitnick 6:45 pm on March 24, 2014 Permalink | Reply
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    From Berkeley Lab: “New Technique for Identifying Gene-Enhancers” 

    Berkeley Lab

    Berkeley Lab-Led Research Team Unveils Powerful New Tool for Studying DNA Elements that Regulate Genes

    March 24, 2014
    Lynn Yarris (510) 486-5375 lcyarris@lbl.gov

    An international team led by researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) has developed a new technique for identifying gene enhancers – sequences of DNA that act to amplify the expression of a specific gene – in the genomes of humans and other mammals. Called SIF-seq, for site-specific integration fluorescence-activated cell sorting followed by sequencing, this new technique complements existing genomic tools, such as ChIP-seq (chromatin immunoprecipitation followed by sequencing), and offers some additional benefits.

    “While ChIP-seq is very powerful in that it can query an entire genome for characteristics associated with enhancer activity in a single experiment, it can fail to identify some enhancers and identify some sites as being enhancers when they really aren’t,” says Diane Dickel, a geneticist with Berkeley Lab’s Genomics Division and member of the SIF-seq development team. “SIF-seq is currently capable of testing only hundreds to a few thousand sites for enhancer activity in a single experiment, but can determine enhancer activity more accurately than ChIP-seq and is therefore a very good validation assay for assessing ChIP-seq results.”

    Dickel is the lead author of a paper in Nature Methods describing this new technique. The paper is titled Function-based identification of mammalian enhancers using site-specific integration. The corresponding authors are Axel Visel and Len Pennacchio, also geneticists with Berkeley Lab’s Genomics Division. (See below for a complete list of authors.)

    With the increasing awareness of the important role that gene enhancers play in normal cell development as well as in disease, there is strong scientific interest in identifying and characterizing these enhancers. This is a challenging task because an enhancer does not have to be located directly adjacent to the gene whose expression it regulates, but can instead be located hundreds of thousands of DNA base pairs away. The challenge is made even more difficult because the activity of many enhancers is restricted to specific tissues or cell types.

    Diane Dickel is the lead author of Nature Methods paper describing a new technique for identifying gene enhancers in the genomes of humans and other mammals. (Photo by Roy Kaltschmidt)

    “For example, brain enhancers will not typically work in heart cells, which means that you must test your enhancer sequence in the correct cell type,” Dickel says.

    Currently, enhancers can be identified through chromatin-based assays, such as ChIP-seq, which predict enhancer elements indirectly based on the enhancer’s association with specific epigenomic marks, such as transcription factors or molecular tags on DNA-associated histone proteins. Visel, Pennacchio, Dickel and their colleagues developed SIF-seq in response to the need for a higher-throughput functional enhancer assay that can be used in a wide variety of cell types and developmental contexts.

    “We’ve shown that SIF-seq can be used to identify enhancers active in cardiomyocytes, neural progenitor cells, and embryonic stem cells, and we think that it has the potential to be expanded for use in a much wider variety of cell types,” Dickel says. “This means that many more types of enhancers could potentially be tested in vitro in cell culture.”

    In SIF-seq, hundreds or thousands of DNA fragments to be tested for enhancer activity are coupled to a reporter gene and targeted into a single, reproducible site in embryonic cell genomes. Every embryonic cell will have exactly one potential enhancer-reporter. Fluorescence-activated sorting is then used to identify and retrieve from this mix only those cells that display strong reporter gene expression, which represent the cells with the most active enhancers.

    “Unlike previous enhancer assays for mammals, SIF-seq includes the integration of putative enhancers into a single genomic locus,” says Visel. “Therefore, the activity of enhancers is assessed in a reproducible chromosomal context rather than from a transiently expressed plasmid. Furthermore, by making use of embryonic stem cells and in vitro differentiation, SIF-seq can be used to assess enhancer activity in a wide variety of disease-relevant cell types.”

    Berkeley Lab’s Len Pennacchio (left) and Axel Visel led the development of a new technique for identifying gene enhancers called SIF-seq, for site-specific integration fluorescence-activated cell sorting followed by sequencing. (Photo by Roy Kaltschmidt)

    Adds Pennacchio, “The range of biologically or disease-relevant enhancers that SIF-seq can be used to identify is limited only by currently available stem cell differentiation methods. Although we did not explicitly test the activity of species-specific enhancers, such as those derived from certain classes of repetitive elements, our results strongly suggest that SIF-seq can be used to identify enhancers from other mammalian genomes where desired cell types are difficult or impossible to obtain.”

    The ability of SIF-seq to use reporter assays in mouse embryonic stem cells to identify human embryonic stem cell enhancers that are not present in the mouse genome opens the door to intriguing research possibilities as Dickel explains.

    “Human and chimpanzee genes differ very little, so one hypothesis in evolutionary genomics holds that humans and chimpanzees are so phenotypically different because of differences in the way they regulate gene expression. It is very difficult to carry out enhancer identification through ChIP-seq that would be useful in studying this hypothesis,” she says. “However, because SIF-seq only requires DNA sequence from a mammal and can be used in a variety of cell types, it should be possible to compare the neuronal enhancers present in a large genomic region from human to the neuronal enhancers present in the orthologous chimpanzee region. This could potentially tell us interesting things about the genetic differences that differentiate human brain development from that of other primates.”

    In addition to Dickel, Pennacchio and Visel, other co-authors of the Nature Methods paper were Yiwen Zhu, Alex Nord, John Wylie, Jennifer Akiyama, Veena Afzal, Ingrid Plajzer-Frick, Aileen Kirkpatrick, Berthold Göttgens and Benoit Bruneau.

    This research was primarily supported by the National Institutes of Health.

    See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California

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  • richardmitnick 1:58 pm on March 17, 2014 Permalink | Reply
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    From Berkeley Lab: “Vast Gene-Expression Map Yields Neurological and Environmental Stress Insights” 

    Berkeley Lab

    March 16, 2014
    Dan Krotz 510-486-4019 dakrotz@lbl.gov

    A consortium led by scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) has conducted the largest survey yet of how information encoded in an animal genome is processed in different organs, stages of development, and environmental conditions. Their findings paint a new picture of how genes function in the nervous system and in response to environmental stress.

    They report their research this week in the Advance Online Publication of the journal Nature.

    The scientists studied the fruit fly, an important model organism in genetics research. Seventy percent of known human disease genes have closely related genes in the fly, yet the fly genome is one-thirtieth the size of ours. Previous fruit fly research has provided insights on cancer, birth defects, addictive behavior, and neurological diseases. It has also advanced our understanding of processes common to all animals such as body patterning and synaptic transmission.

    The remarkable complexity of the fruit fly transcriptome comes to life in this fruit fly embryo. Blue dye indicates the presence of RNA molecules in the brain from a previously uncharacterized gene (CG42748) that encodes hundreds of different proteins. No image credit.

    In the latest scientific fruit from the fruit fly, the consortium, led by Susan Celniker of Berkeley Lab’s Life Sciences Division, generated the most comprehensive map of gene expression in any animal to date. Scientists from the University of California at Berkeley, Indiana University at Bloomington, the University of Connecticut Health Center, and several other institutions contributed to the research.

    In all organisms, the information encoded in genomes is transcribed into RNA molecules that are either translated into proteins, or utilized to perform functions in the cell. The collection of RNA molecules expressed in a cell is known as its transcriptome, which can be thought of as the “read out” of the genome.

    While the genome is essentially the same in every cell in our bodies, the transcriptome is different in each cell type and constantly changing. Cells in cardiac tissue are radically different from those in the gut or the brain, for example.

    The transcriptome also changes rapidly in response to environmental challenges. These dynamics in gene expression allow our bodies to adapt to changes such as temperature or exposure to chemicals.

    The broad range of genes that respond to environmental stress is evident in this genome-wide map of genes that are up or down-regulated when fruit flies are exposed to the heavy metal cadmium. Labeled genes are those that showed a 20-fold change in response. No image credit.

    To map the transcriptome, the scientists used deep sequencing technology to generate 1.2 trillion bases of RNA sequence data. They analyzed RNA in 29 fruit fly tissue types, 25 cell lines, and “environmental challenge” scenarios including heat, cold, heavy metal poisoning, and acute exposure to pesticides.

    The combination of extremely deep sequencing and a diverse array of tissues and conditions resulted in a full-body map of RNA activity, which revealed new genes and rare RNAs that are expressed in only one tissue type. Among the discoveries are the unexpected complexity and diversity of the RNAs present in tissues of the nervous system, and previously unknown genes implicated in stress response.

    In samples of the fly’s nervous system, the scientists found about 100 genes that can encode hundreds or even thousands of different types of proteins. Many of these proteins are made in the developing embryo during the early formation of the nervous system. This hints at a previously unknown source of the complexity of the brain, given that most genes express five or fewer types of transcripts, and half encode just one protein.

    “Our study indicates that the total information output of an animal transcriptome is heavily weighted by the needs of the developing nervous system,” says Ben Brown, a Berkeley Lab staff scientist in the Life Sciences Division who led the data analysis team.

    The scientists also discovered a much broader response to stress than previously recognized. Exposure to heavy metals like cadmium resulted in the activation of known stress-response pathways that prevent damage to DNA and proteins. It also revealed several new genes of completely unknown function.

    “To better understand how cells fight stress, we have to figure out what these mysterious genes do,” says Celniker.

    The research was funded by the National Human Genome Research Institute modENCODE Project.

    Other institutions involved in this research include the Sloan-Kettering Institute, Japan’s RIKEN Yokohama Institute, Cold Spring Harbor Laboratory, and Harvard Medical School.

    See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California

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  • richardmitnick 6:19 pm on February 6, 2014 Permalink | Reply
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    From Berkeley Lab: “New Insight into an Emerging Genome-Editing Tool” 

    Berkeley Lab

    Berkeley Researchers Show Expanded Role for Guide RNA in Cas9 Interactions with DNA

    February 06, 2014
    Lynn Yarris (510) 486-5375 lcyarris@lbl.gov

    The potential is there for bacteria and other microbes to be genetically engineered to perform a cornucopia of valuable goods and services, from the production of safer, more effective medicines and clean, green, sustainable fuels, to the clean-up and restoration of our air, water and land. Cells from eukaryotic organisms can also be modified for research or to fight disease. To achieve these and other worthy goals, the ability to precisely edit the instructions contained within a target’s genome is a must. A powerful new tool for genome editing and gene regulation has emerged in the form of a family of enzymes known as Cas9, which plays a critical role in the bacterial immune system. Cas9 should become an even more valuable tool with the creation of the first detailed picture of its three-dimensional shape by researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley.

    The crystal structure of SpyCas9 features a nuclease domain lobe (red) and an alpha-helical lobe (gray) each with a nucleic acid binding cleft that becomes functionalized when Cas9 binds to guide RNA.

    Upon binding with guide RNA, the two structural lobes of Cas9 reorient so that the two nucleic acid binding clefts face each other, forming a central channel that interfaces with target DNA.

    Biochemist Jennifer Doudna and biophysicist Eva Nogales, both of whom hold appointments with Berkeley Lab, UC Berkeley, and the Howard Hughes Medical Institute (HHMI), led an international collaboration that used x-ray crystallography to produce 2.6 and 2.2 angstrom (Å) resolution crystal structure images of two major types of Cas9 enzymes. The collaboration then used single-particle electron microscopy to reveal how Cas9 partners with its guide RNA to interact with target DNA. The results point the way to the rational design of new and improved versions of Cas9 enzymes for basic research and genetic engineering.

    “The combination of x-ray protein crystallography and electron microscopy single-particle analysis showed us something that was not anticipated,” says Nogales. “The Cas9 protein, on its own, exists in an inactive state, but upon binding to the guide RNA, the Cas9 protein undergoes a radical change in its three-dimensional structure that enables it to engage with the target DNA.”

    “Because we now have high-resolution structures of the two major types of Cas9 proteins, we can start to see how this family of bacterial enzymes has evolved,” Doudna says. “We see that the two structures are quite different from each other outside of their catalytic domains, suggesting an interesting structural plasticity that could explain how Cas9 is able to use different kinds of guide RNAs. Also, the differences in the two structures suggest that it may be possible to engineer smaller Cas9 variants and still retain function, an important goal for some genome engineering applications.”

    Eva Nogales (left) and Jennifer Doudna led a study that produced the first detailed look at the 3D structure of the Cas9 enzyme and how it partners with guide RNA. (Photo by Roy Kaltschmidt)

    Doudna and Nogales are the corresponding authors, along with Martin Jinek of the University of Zurich, of a paper in Science that describes this research. The paper is titled Structures of Cas9 endonucleases reveal RNA-mediated conformational activation. Co-authors are Fuguo Jiang, David Taylor, Samuel Sternberg, Emine Kaya, Enbo Ma, Carolin Anders, Michael Hauer, Kaihong Zhou, Steven Lin, Mattias Kaplan, Anthony Iavarone and Emmanuelle Charpentier.

    See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California

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  • richardmitnick 9:09 pm on July 18, 2013 Permalink | Reply
    Tags: , Genomics,   

    From Berkeley Lab: “Boldly Illuminating Biology’s ‘Dark Matter'” 

    Berkeley Lab

    July 18, 2013
    Massie Ballon 925-927-2541 mlballon@lbl.gov

    “Is space really the final frontier, or are the greatest mysteries closer to home? In cosmology, dark matter is said to account for the majority of mass in the universe, however its presence is inferred by indirect effects rather than detected through telescopes. The biological equivalent is ‘microbial dark matter,’ that pervasive yet practically invisible infrastructure of life on the planet, which can have profound influences on the most significant environmental processes from plant growth and health, to nutrient cycles in terrestrial and marine environments, the global carbon cycle, and possibly even climate processes. By employing next generation DNA sequencing of genomes isolated from single cells, great strides are being made in the monumental task of systematically bringing to light and filling in uncharted branches in the bacterial and archaeal tree of life. In an international collaboration led by the U.S. Department of Energy Joint Genome Institute (DOE JGI), managed by Berkeley Lab, the most recent findings from exploring microbial dark matter were published online July 14, 2013 in the journal Nature.

    There are more microbes in, on and around the Earth than there are stars in the sky, and we only know about a small fraction of the microbial diversity around us. In an effort to learn more about the ‘microbial dark matter,’ researchers are sequencing and analyzing samples collected from around the world. (Composition by Zosia Rostomian, Berkeley Lab)

    ‘Instead of wondering through the starkness of space, this achievement is more like the 21st Century equivalent of Lewis and Clark’s expedition to open the American West,’ said Eddy Rubin, DOE JGI Director. ‘This is a powerful example of how the DOE JGI pioneers discovery, in that we can take a high throughput approach to isolating and characterizing single genomes from complex environmental samples of millions of cells, to provide a profound leap of understanding the microbial evolution on our planet. This is really the next great frontier.’”

    See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California

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  • richardmitnick 2:57 pm on March 28, 2013 Permalink | Reply
    Tags: , , , Genomics   

    From Brookhaven Lab: “Researchers Find Surprising Similarities Between Genetic and Computer Codes” 

    Brookhaven Lab

    March 28, 2013
    Contacts: Chelsea Whyte, (631) 344-8671 or Peter Genzer, (631) 344-3174

    “The term ‘survival of the fittest’ refers to natural selection in biological systems, but Darwin’s theory may apply more broadly than that. New research from the U.S. Department of Energy’s Brookhaven National Laboratory shows that this evolutionary theory also applies to technological systems.

    Sergei Maslov

    Computational biologist Sergei Maslov of Brookhaven National Laboratory worked with graduate student Tin Yau Pang from Stony Brook University to compare the frequency with which components ‘survive’ in two complex systems: bacterial genomes and operating systems on Linux computers. Their work is published in the Proceedings of the National Academy of Sciences.

    Linux Mascot Tux

    Maslov and Pang set out to determine not only why some specialized genes or computer programs are very common while others are fairly rare, but to see how many components in any system are so important that they can’t be eliminated. ‘If a bacteria genome doesn’t have a particular gene, it will be dead on arrival,’ Maslov said. ‘How many of those genes are there? The same goes for large software systems. They have multiple components that work together and the systems require just the right components working together to thrive.’

    Using data from the massive sequencing of bacterial genomes, now a part of the DOE Systems Biology Knowledgebase (KBase), Maslov and Pang examined the frequency of usage of crucial bits of genetic code in the metabolic processes of 500 bacterial species and found a surprising similarity with the frequency of installation of 200,000 Linux packages on more than 2 million individual computers. Linux is an open source software collaboration that allows designers to modify source code to create programs for public use.

    The most frequently used components in both the biological and computer systems are those that allow for the most descendants. That is, the more a component is relied upon by others, the more likely it is to be required for full functionality of a system.

    It may seem logical, but the surprising part of this finding is how universal it is. ‘It is almost expected that the frequency of usage of any component is correlated with how many other components depend on it,’ said Maslov. ‘But we found that we can determine the number of crucial components – those without which other components couldn’t function – by a simple calculation that holds true both in biological systems and computer systems.'”

    See the full article here.

    One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world.Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.

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  • richardmitnick 8:16 pm on June 28, 2012 Permalink | Reply
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    From Berkeley Lab: “Programmable DNA Scissors Found for Bacterial Immune System” 

    Berkeley Lab

    Discovery Could Lead to Editing Tool for Genomes

    June 28, 2012
    Lynn Yarris

    “Genetic engineers and genomics researchers should welcome the news from the Lawrence Berkeley National Laboratory (Berkeley Lab) where an international team of scientists has discovered a new and possibly more effective means of editing genomes. This discovery holds potentially big implications for advanced biofuels and therapeutic drugs, as genetically modified microorganisms, such as bacteria and fungi, are expected to play a key role in the green chemistry production of these and other valuable chemical products.

    Programmable DNA scissors: A double-RNA structure in the bacterial immune system has been discovered that directs Cas9 protein to cleave and destroy invading DNA at specific nucleotide sequences. This same dual RNA structure should be programmable for genome editing. (Image by H. Adam Steinberg, artforscience.com)

    Jennifer Doudna, a biochemist with Berkeley Lab’s Physical Biosciences Division and professor at the University of California (UC) Berkeley, helped lead the team that identified a double-RNA structure responsible for directing a bacterial protein to cleave foreign DNA at specific nucleotide sequences. Furthermore, the research team found that it is possible to program the protein with a single RNA to enable cleavage of essentially any DNA sequence.

    ‘We’ve discovered the mechanism behind the RNA-guided cleavage of double-stranded DNA that is central to the bacterial acquired immunity system,’ says Doudna, who holds appointments with UC Berkeley’s Department of Molecular and Cell Biology and Department of Chemistry, and is an investigator with the Howard Hughes Medical Institute (HHMI).

    See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California


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