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  • richardmitnick 11:39 am on September 16, 2014 Permalink | Reply
    Tags: , , Genetics,   

    From M.I.T.: “Neuroscientists identify key role of language gene” 

    MIT News

    September 15, 2014
    Anne Trafton | MIT News Office

    Neuroscientists have found that a gene mutation that arose more than half a million years ago may be key to humans’ unique ability to produce and understand speech.


    Researchers from MIT and several European universities have shown that the human version of a gene called Foxp2 makes it easier to transform new experiences into routine procedures. When they engineered mice to express humanized Foxp2, the mice learned to run a maze much more quickly than normal mice.

    The findings suggest that Foxp2 may help humans with a key component of learning language — transforming experiences, such as hearing the word “glass” when we are shown a glass of water, into a nearly automatic association of that word with objects that look and function like glasses, says Ann Graybiel, an MIT Institute Professor, member of MIT’s McGovern Institute for Brain Research, and a senior author of the study.

    “This really is an important brick in the wall saying that the form of the gene that allowed us to speak may have something to do with a special kind of learning, which takes us from having to make conscious associations in order to act to a nearly automatic-pilot way of acting based on the cues around us,” Graybiel says.

    Wolfgang Enard, a professor of anthropology and human genetics at Ludwig-Maximilians University in Germany, is also a senior author of the study, which appears in the Proceedings of the National Academy of Sciences this week. The paper’s lead authors are Christiane Schreiweis, a former visiting graduate student at MIT, and Ulrich Bornschein of the Max Planck Institute for Evolutionary Anthropology in Germany.

    All animal species communicate with each other, but humans have a unique ability to generate and comprehend language. Foxp2 is one of several genes that scientists believe may have contributed to the development of these linguistic skills. The gene was first identified in a group of family members who had severe difficulties in speaking and understanding speech, and who were found to carry a mutated version of the Foxp2 gene.

    In 2009, Svante Pääbo, director of the Max Planck Institute for Evolutionary Anthropology, and his team engineered mice to express the human form of the Foxp2 gene, which encodes a protein that differs from the mouse version by only two amino acids. His team found that these mice had longer dendrites — the slender extensions that neurons use to communicate with each other — in the striatum, a part of the brain implicated in habit formation. They were also better at forming new synapses, or connections between neurons.

    Pääbo, who is also an author of the new PNAS paper, and Enard enlisted Graybiel, an expert in the striatum, to help study the behavioral effects of replacing Foxp2. They found that the mice with humanized Foxp2 were better at learning to run a T-shaped maze, in which the mice must decide whether to turn left or right at a T-shaped junction, based on the texture of the maze floor, to earn a food reward.

    The first phase of this type of learning requires using declarative memory, or memory for events and places. Over time, these memory cues become embedded as habits and are encoded through procedural memory — the type of memory necessary for routine tasks, such as driving to work every day or hitting a tennis forehand after thousands of practice strokes.

    Using another type of maze called a cross-maze, Schreiweis and her MIT colleagues were able to test the mice’s ability in each of type of memory alone, as well as the interaction of the two types. They found that the mice with humanized Foxp2 performed the same as normal mice when just one type of memory was needed, but their performance was superior when the learning task required them to convert declarative memories into habitual routines. The key finding was therefore that the humanized Foxp2 gene makes it easier to turn mindful actions into behavioral routines.

    The protein produced by Foxp2 is a transcription factor, meaning that it turns other genes on and off. In this study, the researchers found that Foxp2 appears to turn on genes involved in the regulation of synaptic connections between neurons. They also found enhanced dopamine activity in a part of the striatum that is involved in forming procedures. In addition, the neurons of some striatal regions could be turned off for longer periods in response to prolonged activation — a phenomenon known as long-term depression, which is necessary for learning new tasks and forming memories.

    Together, these changes help to “tune” the brain differently to adapt it to speech and language acquisition, the researchers believe. They are now further investigating how Foxp2 may interact with other genes to produce its effects on learning and language.

    This study “provides new ways to think about the evolution of Foxp2 function in the brain,” says Genevieve Konopka, an assistant professor of neuroscience at the University of Texas Southwestern Medical Center who was not involved in the research. “It suggests that human Foxp2 facilitates learning that has been conducive for the emergence of speech and language in humans. The observed differences in dopamine levels and long-term depression in a region-specific manner are also striking and begin to provide mechanistic details of how the molecular evolution of one gene might lead to alterations in behavior.”

    The research was funded by the Nancy Lurie Marks Family Foundation, the Simons Foundation Autism Research Initiative, the National Institutes of Health, the Wellcome Trust, the Fondation pour la Recherche Médicale, and the Max Planck Society.

    See the full article here.

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  • richardmitnick 9:43 am on September 14, 2014 Permalink | Reply
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    From M.I.T Tech Review: “Gene-Silencing Drugs Finally Show Promise” 

    MIT Technology Review
    M.I.T Technology Review

    September 14, 2014
    Kevin Bullis

    After more than a decade of disappointment, a startup leads the development of a powerful new class of drugs based on a Nobel-winning idea.

    The disease starts with a feeling of increased clumsiness. Spilling a cup of coffee. Stumbling on the stairs. Having accidents that are easy to dismiss—everyone trips now and then.

    But it inevitably gets worse. Known as familial amyloid polyneuropathy, or FAP, it can go misdiagnosed for years as patients lose the ability to walk or perform delicate tasks with their hands. Most patients die within 10 to 15 years of the first symptoms.

    There is no cure. The disease is caused by malformed proteins produced in the liver, so one treatment is a liver transplant. But few patients can get one—and it only slows the disease down.

    Now, after years of false starts and disappointment, it looks like an audacious idea for helping these patients finally could work.

    In 1998, researchers at the Carnegie Institution and the University of Massachusetts made a surprising discovery about how cells regulate which proteins they produce. They found that certain kinds of RNA—which is what DNA makes to create proteins—can turn off specific genes. The finding, called RNA interference (RNAi), was exciting because it suggested a way to shut down the production of any protein in the body, including those connected with diseases that couldn’t be touched with ordinary drugs. It was so promising that its discoverers won the Nobel Prize just eight years later.

    Inspired by the discovery, another group of researchers—including the former thesis supervisor of one of the Nobel laureates—founded Alnylam in Cambridge, Massachusetts, in 2002. Their goal: fight diseases like FAP by using RNAi to eliminate bad proteins (see “The Prize of RNAi” and “Prescription RNA”). Never mind that no one knew how to make a drug that could trigger RNAi. In fact, that challenge would bedevil the researchers for the better part of a decade. Along the way, the company lost the support of major drug companies that had signed on in a first wave of enthusiasm. At one point the idea of RNAi therapy was on the verge of being discredited.

    But now Alnylam is testing a drug to treat FAP in advanced human trials. It’s the last hurdle before the company will seek regulatory approval to put the drug on the market. Although it’s too early to tell how well the drug will alleviate symptoms, it’s doing what the researchers hoped it would: it can decrease the production of the protein that causes FAP by more than 80 percent.

    This could be just the beginning for RNAi. Alnylam has more than 11 drugs, including ones for hemophilia, hepatitis B, and even high cholesterol, in its development pipeline, and has three in human trials —progress that led the pharmaceutical company Sanofi to make a $700 million investment in the company last winter. Last month, the pharmaceutical giant Roche, an early Alnylam supporter that had given up on RNAi, reversed its opinion of the technology as well, announcing a $450 million deal to acquire the RNAi startup Santaris. All told, there are about 15 RNAi-based drugs in clinical trials from several research groups and companies.

    “The world went from believing RNAi would change everything to thinking it wouldn’t work, to now thinking it will,” says Robert Langer, a professor at MIT, and one of Alnylam’s advisors.

    Delivering Drugs

    Alnylam started with high hopes. Its founders, among them the Nobel laureate and MIT biologist Philip Sharp, had solved one of the biggest challenges facing the idea of RNAi therapies. When RNAi was discovered, the process was triggered by introducing a type of RNA, called double stranded RNA, into cells. This worked well in worms and fruit flies. But the immune system in mammals reacted violently to the RNA, causing cells to die and making the approach useless except as a research tool. The Alnylam founders figured out that shorter strands, called siRNA, could slip into mammalian cells without triggering an immune reaction, suggesting a way around this problem.

    Yet another huge problem remained. RNA interference depends upon delivering RNA to cells, tricking the cells into allowing it through the protective cell membrane, and then getting the cells to incorporate it into molecular machinery that regulates proteins. Scientists could do this in petri dishes but not in animals.

    Alnylam looked everywhere for solutions, scouring the scientific literature, collaborating with other companies, considering novel approaches of its own. It focused on two options. One was encasing RNA in bubbles of fat-like nanoparticles of lipids. They are made with the same materials that make up cell membranes—the thought was that the cell would respond well to the familiar substance. The other approach was attaching a molecule to the RNA that cells like to ingest, tricking the cell into eating it.

    And both approaches worked, sort of. Researchers were able to block protein production in lab animals. But getting the delivery system right wasn’t easy. The early mechanisms were too toxic at the doses required to be used as drugs.

    As a result, delivering RNA through the bloodstream like a conventional drug seemed a far-off prospect. The company tried a shortcut of injecting chemically modified RNA directly into diseased tissue —for example, into the retina to treat eye diseases. That approach even got to clinical trials. But it was shelved because it didn’t perform as well as up-and-coming drugs from other companies.

    By 2010, some of the major drug companies that were working with and investing in Alnylam lost patience. Novartis decided not to extend a partnership with Alnylam; Roche gave up on RNAi altogether. Alnylam laid off about a quarter of its workers, and by mid-2011, its stock price had plunged by 80 percent from its peak.

    But Alnylam and partner companies, notably the Canadian startup Tekmira, were making steady progress in the lab. Researchers identified one part of the lipid nanoparticles that was keeping them from delivering its cargo of RNA to the right part of a cell. That was “the real eureka moment,” says Rachel Meyers, Alnylam’s vice president of research. Better nanoparticles improved the potency of a drug a hundredfold and its safety by about five times, clearing the way for clinical trials for FAP—a crucial event that kept the company alive.

    Even with that progress, Alnylam needed more. The nanoparticle delivery mechanism is costly to make and requires frequent visits to the hospital for hour-long IV infusions—something patients desperate to stay alive will put up with, but likely not millions of people with high cholesterol.

    So Alnylam turned to its second delivery approach—attaching molecules to RNA to trick cells into ingesting it. Researchers found just the right inducement—attaching a type of sugar molecule. This approach allows for the drug to be administered with a simple injection that patients could give themselves at home.

    In addition to being easier to administer, the new sugar-based drugs are potentially cheaper to make. The combination of low cost and ease-of-use is allowing Alnylam to go after more common diseases—not just the rare ones that patients will go to great lengths to treat. “Because we’ve made incredible improvements in the delivery strategy,” Meyers says, “we can now go after big diseases where we can treat millions of patients potentially.”

    The Next Frontier

    In a sixth-floor lab on the MIT campus, postdoctoral researcher James Dahlman takes down boxes from a high shelf. They contain hundreds of vials, each containing a unique type of nanoparticle that Dahlman synthesized painstakingly, one at a time. “It turns out we have a robot in the lab that can do that,” he says. “But I didn’t know about it at the time.”

    Dahlman doesn’t work for Alnylam; he had been searching for the next great delivery mechanism, one that could greatly expand the diseases that can be treated by RNAi. Some of the materials look like clear liquids. Some are waxy, some like salt crystals. He points to a gap in the rows of vials, where a vial is conspicuously missing. “That’s the one that worked. That’s the miracle material,” he says.

    For all of their benefits, the drug delivery mechanisms Alnylam uses have one flaw—they’re effective only for delivering drugs to liver cells. For a number of reasons, the liver is a relatively easy target—that’s where all kinds of nanoparticles tend to end up. Alnylam sees the potential for billions of dollars in revenue from liver-related diseases. Yet most diseases involve other tissues in the body.

    Dahlman and his colleagues at MIT are some of the leaders in the next generation of RNAi delivery—targeting delivery to places throughout the body. Last month, in two separate articles, they published the results of studies showing that Dahlman’s new nanoparticles are a powerful way to deliver RNAi to blood vessel cells, which are associated with a wide variety of diseases. The studies showed that the method could be used to reduce tumor growth in lung cancer, for example.

    Treating cancer is one area where RNAi’s particular advantages are expected to shine. Conventional chemotherapy affects more than just the target cancer cells—it also hurts healthy tissue, which is why it makes people feel miserable. But RNAi can be extremely precise, potentially shutting down only proteins found in cancer cells. And Dahlman’s latest delivery system makes it possible to simultaneously target up to 10 proteins at once, which could make cancer treatments far more effective. Lab work like this is far from fruition, but if it maintains its momentum, the drugs currently in clinical trials could represent just a small portion of the benefits of the discovery of RNAi.

    See the full article here.

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  • richardmitnick 7:37 am on September 10, 2014 Permalink | Reply
    Tags: , , Genetics   

    From Astrobiology: “A single evolutionary road may lead to Rome” 

    Astrobiology Magazine

    Astrobiology Magazine

    Sep 10, 2014
    Contact(s): Layne Cameron Media Communications office: (517) 353-8819 cell: (765) 748-4827 Layne.Cameron@cabs.msu.edu , Jason Gallant Zoology office: (517) 884-7756 jgallant@msu.edu, Michigan State University

    A well-known biologist once theorized that many roads led to Rome when it comes to two distantly related organisms evolving a similar trait. A new paper, published in Nature Communications, suggests that when it comes to evolving some traits – especially simple ones – there may be a shared gene, one road, that’s the source.

    Jason Gallant, MSU zoologist, shows that a single evolutionary road may lead to Rome. Photo by G.L. Kohuth – See more at: http://www.astrobio.net/topic/origins/origin-and-evolution-of-life/single-evolutionary-road-may-lead-rome/#sthash.d9t39bd2.dpuf

    Jason Gallant, MSU zoologist and the paper’s first author, focused on butterflies to illustrate his metaphorical roadmap on evolutionary traits. Butterfly wings are important biological models. While some butterflies are poisonous and notify their predators via colorful wing markings, others are nontoxic but have evolved similar color patterns to avoid being eaten.

    Many scientists, including the famed Ernst Mayr, favored the “many roads” theory. This was largely attributed to being unable to identify a shared gene for such traits. Gallant, Sean Mullen, co-author and Boston University biologist, and their collaborators, however, were able to pinpoint the single gene responsible for two different families of butterflies’ flashy markings.

    The North American and South American species last had a common ancestor more than 65 million years ago. So, rather than evolve these traits independently using two unique mechanisms, the genetic control of particular butterfly markings can be traced to a single gene present in their ancient ancestors, said Gallant, who also teamed with Arnaud Martin and Bob Reed from Cornell University, and Marcus Kronforst from the University of Chicago.

    “This result represents the culmination of a decade’s worth of effort, but we identified the mechanism for a single aspect of wing patterns in a lineage,” Gallant said. “Is this the rule or the exception? For simple traits, it’s beginning to look like it could be the rule. The jury is still out on complicated traits, but there may be fewer roads leading to Rome than we once thought.”

    The decade-long journey began as a butterfly mapping study and later involved the 30,000 genes that comprise white admiral butterflies and red-spotted purple butterflies in North America. They are the same species of butterflies, but to a common observer, they look completely unrelated.

    Jason Gallant, MSU zoologist, studied butterflies to illustrate his metaphorical roadmap on evolutionary traits. Photo by G.L. Kohuth

    In the southern United States, the red-spotted purples [Limenitis arthemis] have dark-blue wings that mimic the poisonous pipevine swallowtail. The white admirals [also Limenitis arthemis], with distinctive white bands on their wings, reside in northern climes where the swallowtail is not found. A hybrid of the two can be found in a region near Pennsylvania.

    Red Spotted Purple

    White admiral

    Out of the 30,000 genes, Gallant, Mullen and their team narrowed the candidates to three. In one of these genes, WntA, they discovered the presence of a retrotransposon, a DNA virus of sorts, which appears to cause the deviations in wing pattern.

    “It’s the same type of DNA ‘virus’ that causes random-colored kernels in Indian corn,” Gallant said. “It was present in 100 percent of the red-spotted purples, 50 percent of the hybrids and zero percent of the white admirals; I’ve never seen such clean data like this – ever.”

    For comparison, a different species of South American butterflies, studied by researchers from Cornell and the University of Chicago, were folded into the experiment. This species is separated by a mountain range rather than a continent, but the genetic patterns were the same. The group with dark wing markings had a deletion in the WntA gene in the same spot that the retrotransposon occurred in the North American butterflies.

    When asked to comment on the significance of the work, Mullen stated the main goal of evolutionary biology is to understand the origin and maintenance of biodiversity. Within this context, a major unanswered question is whether or not evolution is predictable, and, if so, over what evolutionary time scales?

    “We addressed this question by identifying the specific genetic changes responsible for the repeated evolution of similar color pattern traits in two butterfly lineages that last shared a common ancestor some 65 million years ago,” he said. “Surprisingly, we found that changes in the expression of the same gene during development were responsible in both cases. This result implies an unprecedented level of predictability in the evolutionary process over deep time.”

    Since this evolutionary trait was triggered, perhaps somewhat accidentally, it stirs questions as to what other changes are taking place before our eyes.

    “Copying errors and genomic viruses directly lead to the wing patterns of these beautiful butterflies,” Gallant said. “It’s these accidents that allow the evolutionary process to move forward. When I look over a field of butterflies, it makes me wonder what types of ‘mistakes’ are happening right now that may lead to important evolutionary changes years from now? What evolutionary processes will we someday be able to predict?”

    See the full article here.


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  • richardmitnick 8:06 pm on August 27, 2014 Permalink | Reply
    Tags: , , Genetics, ,   

    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 4:57 pm on August 25, 2014 Permalink | Reply
    Tags: , , Genetics   

    From Astrobiology: “Alternate mechanism of species formation picks up support, thanks to a South American ant” 

    Astrobiology Magazine

    Astrobiology Magazine

    Aug 25, 2014
    Source: University of Rochester

    A newly-discovered species of ant supports a controversial theory of species formation. The ant, only found in a single patch of eucalyptus trees on the São Paulo State University campus in Brazil, branched off from its original species while living in the same colony, something thought rare in current models of evolutionary development.

    “Most new species come about in geographic isolation,” said Christian Rabeling, assistant professor of biology at the University of Rochester. “We now have evidence that speciation can take place within a single colony.”

    The findings by Rabeling and the research team were published today in the journal Current Biology.

    In discovering the parasitic Mycocepurus castrator, Rabeling and his colleagues uncovered an example of a still-controversial theory known as sympatric speciation, which occurs when a new species develops while sharing the same geographic area with its parent species, yet reproducing on its own.“While sympatric speciation is more difficult to prove,” said Rabeling, “we believe we are in the process of actually documenting a particular kind of evolution-in-progress.”

    New species are formed when its members are no longer able to reproduce with members of the parent species. The commonly-accepted mechanism is called allopatric speciation, in which geographic barriers—such as mountains—separate members of a group, causing them to evolve independently.

    “Since [Charles] Darwin’s Origin of Species, evolutionary biologists have long debated whether two species can evolve from a common ancestor without being geographically isolated from each other,” said Ted Schultz, curator of ants at the Smithsonian’s National Museum of Natural History and co-author of the study. “With this study, we offer a compelling case for sympatric evolution that will open new conversations in the debate about speciation in these ants, social insects and evolutionary biology more generally.”

    A queen ant of the parasitic species Mycocepurus castrator. Credit: Christian Rabeling/University of Rochester

    M. castrator is not simply another ant in the colony; it’s a parasite that lives with—and off of—its host, Mycocepurus goeldii. The host is a fungus-growing ant that cultivates fungus for its nutritional value, both for itself and, indirectly, for its parasite, which does not participate in the work of growing the fungus garden.

    That led the researchers to study the genetic relationships of all fungus-growing ants in South America, including all five known and six newly discovered species of the genus Mycocepurus, to determine whether the parasite did evolve from its presumed host. They found that the parasitic ants were, indeed, genetically very close to M. goeldii, but not to the other ant species.

    They also determined that the parasitic ants were no longer reproductively compatible with the host ants—making them a unique species—and had stopped reproducing with their host a mere 37,000 years ago—a very short period on the evolutionary scale.

    A big clue for the research team was found by comparing the ants’ genes, both in the cell’s nucleus as well as in the mitochondria—the energy-producing structures in the cells. Genes are made of units called nucleotides, and Rabeling found that the sequencing of those nucleotides in the mitochondria is beginning to look different from what is found in the host ants, but that the genes in the nucleus still have traces of the relationship between host and parasite, leading him to conclude that M. castrator has begun to evolve away from its host.

    Rabeling explained that just comparing some nuclear and mitochondrial genes may not be enough to demonstrate that the parasitic ants are a completely new species. “We are now sequencing the entire mitochondrial and nuclear genomes of these parasitic ants and their host in an effort to confirm speciation and the underlying genetic mechanism.”

    The parasitic ants need to exercise discretion because taking advantage of the host species is considered taboo in ant society. Offending ants have been known to be killed by worker mobs. As a result, the parasitic queen of the new species has evolved into a smaller size, making them difficult to distinguish from a host worker.

    Host queens and males reproduce in an aerial ceremony, in the wet tropics only during a particular season when it begins to rain. Rabeling found that the parasitic queens and males, needing to be more discreet about their reproductive activities, diverge from the host’s mating pattern. By needing to hide their parasitic identity, M. castrator males and females lost their special adaptations that allowed them to reproduce in flight, and mate inside the host nest, making it impossible for them to sexually interact with their host species.

    See the full article here.


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  • richardmitnick 2:25 pm on August 21, 2014 Permalink | Reply
    Tags: Genetics,   

    From Quanta: “I Contain Multitudes” 

    Quanta Magazine
    Quanta Magazine

    August 21, 2014
    Kat McGowan

    Your DNA is supposed to be your blueprint, your unique master code, identical in every one of your tens of trillions of cells. It is why you are you, indivisible and whole, consistent from tip to toe.


    But that’s really just a biological fairy tale. In reality, you are an assemblage of genetically distinctive cells, some of which have radically different operating instructions. This fact has only become clear in the last decade. Even though each of your cells supposedly contains a replica of the DNA in the fertilized egg that began your life, mutations, copying errors and editing mistakes began modifying that code as soon as your zygote self began to divide. In your adult body, your DNA is peppered by pinpoint mutations, riddled with repeated or rearranged or missing information, even lacking huge chromosome-sized chunks. Your data is hopelessly corrupt.

    Most genome scientists assume that this DNA diversity, called “somatic mutation” or “structural variation,” is bad. Mutations and other genetic changes can alter the function of the cell, usually for the worse. Disorderly DNA is a hallmark of cancers, and genomic variation can cause a suite of brain disorders and malformations. It makes sense: Cells working off garbled information probably don’t function very well.

    Most research to date has focused on how aberrant DNA drives disease, but even healthy bodies harbor genetic disorder. In the last few years, some researchers report that anywhere from 10 to 40 percent of brain cells and between 30 and 90 percent of human liver cells are aneuploid, meaning that one entire chromosome is either missing or duplicated. Copy number variations, in which chunks of DNA between 100 and a few million letters in length are multiplied or eliminated, also seem to be widespread in healthy people.

    Our vulnerabilities and our resilience are all bound up together, two sides of one coin.

    The exact extent of cell-to-cell diversity is still unclear and a matter of some debate. It’s only in the last two years that scientists have been able to look carefully at just one genome at a time, with the advent of new methods of single-cell DNA sequencing. (Earlier methods averaged the results of thousands or millions of cells and could only detect huge aberrations or relatively common ones.) Because this work is so new, each study includes surprises: A single-cell genome sequencing study of 97 neurons from healthy brains, published today by Christopher Walsh, a neurologist at Boston Children’s Hospital and Howard Hughes Medical Institute, and the postdoctoral researcher Xuyu Cai found few that were aneuploid — less than 5 percent. But most had at least one good-sized copy number variation.

    Walsh’s findings and others mark a third phase in human genomics. When the complete DNA of one human being was first sequenced in 2000, it was considered to be “the” human genome. Soon after, researchers began to explore the differences between individuals, launching the era of the “personal genome.” Now science is entering the age of the microgenome, in which research begins to explore the worlds within us, examining our inherent imperfections and contradictions, the multitudes we contain.

    With that third phase comes a deeper question. What do our genetic contradictions mean? Do they play an important role in our biology? At this point, just about every genome scientist has a slightly different take. One surprising theory suggests that DNA diversity might be good for you. It’s a feature, not a bug.

    Courtesy of Fred Gage

    Our genetically diverse brains might be one reason we are all so different, suspects Salk Institute neurobiologist Fred Gage.

    According to this idea, genetic heterogeneity allows bodies to be more adaptive and resilient. The logic comes from evolutionary biology. Genetic diversity is clearly beneficial for a population or species, because a few individuals will likely be randomly equipped to survive unpredictable environmental changes, such as a drought or an epidemic. Along similar lines, some biologists have proposed that genetic diversity might also be beneficial within the individual. If new conditions demand new abilities or functions, such as surviving an environmental toxin or learning a new skill, genetic heterogeneity increases the odds that at least some cells will be able to thrive in this new situation. “I think of the body as a population of cells, similar to the population of human organisms walking this earth,” said James Lupski, a geneticist at Baylor College of Medicine, who studies how DNA alterations shape human traits. In any such population, “there’s a lot to be said for generating variation, and allowing the most fit variation to be selected out.”

    The most radical version of this argument comes from Fred Gage, a Salk Institute neurobiologist best known for pioneering studies in neuroplasticity,

    Contrary to conventional thought as expressed in this diagram, brain functions are not confined to certain fixed locations

    the adult brain’s ability to adapt. His team has found several types of genetic variation to be common in normal adult human brains, and he thinks this diversity could help explain the organ’s amazingly complex structure and remarkable flexibility. “We can’t predict what will happen to us in our 80 years of life,” he said. “We have to build in mechanisms of diversity that will help us adapt to the things that happen to us.” Experts in liver biology propose a similar idea. They even have preliminary evidence that genetic diversity actually can make the organ more resilient.

    The outcome of this research could also have practical consequences. If somatic mutations are common in healthy bodies, then biomedical researchers can no longer assume that DNA aberrations point toward the causes of disease. Doctors won’t be able to trust that the DNA found in a blood or saliva sample actually reflects the gene sequences in the heart or the liver. Should somatic variation turn out to be not just common but also good for you, it will undermine the longstanding presumption that the healthiest genome gets replicated with perfect fidelity. The most highly functional bodies may be the ones that permit a little mutation, that encourage a certain amount of genetic wildness and disorder within.

    A Patchwork Brain

    In the immune system, DNA diversity is without a doubt essential to health — it’s how our bodies recognize infectious invaders even if we’ve never encountered them before. Our immune cells produce hundreds of millions of unique and distinctive receptors, a vast library that can detect and combat just about any possible foreign agent. Amazingly, this variety is generated from just a handful of immunoglobulin genes, which are reshuffled and recombined randomly in each immune cell. Every unique mix of these gene fragments results in a slightly different receptor, a discovery that earned Susumu Tonegawa a Nobel Prize in 1987. “It was necessary to our survival as a species to randomly generate millions of types of variations to make us enough antibodies,” said Lupski. “I wouldn’t call that pathology; I’d call it normal biology.”

    A normal cell is supposed to have two copies of each chromosome, but this brain cell from an embryonic mouse has three copies of chromosome 2 and only one of 15 and 17.
    National Academy of Sciences

    But the immune system was thought to be just one fluky exception, and DNA variation elsewhere in the body was written off as error, the unfortunate result of imperfections in the copying machinery. Enzymes involved in copying and editing DNA during cell division may snip out, reinsert or make too many copies of stretches of the genome, creating copy number variations. Aneuploidies are the result of a different type of mistake. They occur when duplicated chromosomes are divvied up unevenly between two dividing cells.

    Such mutations are termed “somatic” because they aren’t inherited; instead, they spontaneously appear in non-reproductive cells. If a somatic mutation happens during development in a rapidly dividing tissue, it may be present in hundreds or millions of cells. By contrast, germline mutations are usually inherited: They were already in the egg or sperm at the moment of conception, which means they affect every cell in the body.

    Some researchers suspected that something like what was happening with the immune system might be going on in the brain. Here, too, a limited set of genes somehow codes for a great diversity of cells — perhaps as many as 10,000 different types. “The brain is extraordinarily interesting, and people are always looking for elegant ways to explain how you get these amazing levels of diversity,” said Ira Hall, a molecular geneticist at the Washington University School of Medicine in St. Louis, who has studied mechanisms of DNA rearrangement for many years.

    In 2001, neuroscientist Jerold Chun and other researchers at the University of California San Diego made the surprising discovery that about a third of the immature cells that give rise to neurons in an embryonic mouse brain were aneuploid. “People thought we were nuts,” said Chun, now a neuroscientist at Scripps Research Institute in San Diego. In follow-up papers, Chun and others found that full-grown aneuploid neurons were common in adult mouse brains, even forming circuits with other cells. They showed up in humans too: In people who had died from causes unrelated to the brain, roughly 10 percent of their brain cells were found to be aneuploid.

    Jerold Chun of the Scripps Research Institute discovered in 2001 that a third of the cells in an embryonic mouse brain had the wrong number of chromosomes.

    If each brain harbored a subpopulation of idiosyncratic, genetically freakish neurons, some of which might respond in weird ways to stimulation or to injury, that might begin to account for the incredible variation between brains and individuals, Chun reasoned. “It gives you the ability to create a nervous system that’s almost infinitely diverse,” said Chun. “On top of the genetic diversity we have as a species, neural diversity places orders of magnitude more possibilities into the system.”

    Along similar lines, Gage’s group found that tiny chunks of DNA, called mobile elements, could trigger small genetic changes to newly born neurons in the adult human brain. These insertions are too small to easily locate on a genome-wide basis, so his group looked for larger copy number variations (CNVs) in 110 neurons from postmortem brains. Gage teamed up with Hall, who has expertise in single-cell sequencing, and they reported last fall that 13 to 41 percent of adult human neurons had at least one major CNV, and some had ten or more.

    Gage proposes that the mobile elements and the CNVs exist for the same reason: They promote dynamic flexibility in the brain, which could turn out to be essential during times of rapid change. “You are provided with added diversity, which is preparation for unexpected changes. It may give you some adaptability that a stagnant, univalent genome would not.” The cells that provide advantages survive and make connections with other cells. Those that don’t, die off. It’s survival of the fittest, right there in our brains.

    Bursting With Chromosomes

    Whether other parts of the body are as riddled with genomic glitches is unclear. “It’s still very early,” said Hall. Outside of the brain, the best-documented genomic variability in healthy people is in the liver. More than a hundred years ago, biologists noticed that some hepatocytes (liver cells) were huge, swollen with two or more nuclei and bursting with chromosomes. Modern estimates are that in humans, about half of all hepatocytes are polyploid, meaning that instead of having the usual two copies of each chromosome, they have four, eight, even 16.

    One theory is that the extra DNA serve as backup copies. The liver is like a waste processing plant: It deactivates and disposes of toxic substances, and its cells are constantly exposed to DNA-damaging chemicals. If an important gene on one chromosome in a liver cell gets knocked out by a DNA-disrupting poison, the extra copies of the chromosome will ensure that gene still functions.

    Liver cells. Andy Duncan, Nature

    This dividing liver cell apparently didn’t read the textbook: It has multiple extra copies of its DNA (blue regions), and it is preparing to split into thirds.

    But Andrew Duncan, a cell biologist at the University of Pittsburgh, and colleagues noticed that when polyploid cells split, the daughter cells are often aneuploid, with oddball sets of chromosomes rather than the usual pairs: Some chromosomes are solitary, some come in threes. About half of all human hepatocytes are aneuploid, indicating that the backup-copy theory can’t be the whole story. Duncan thinks that the liver, like the brain, benefits from genomic diversity for similar reasons. The liver has the ability to regenerate itself, should it become damaged by toxins or diseases like cirrhosis or hepatitis. A genetically diverse pool of cells means that some might be better equipped to survive. Those outliers will multiply, outcompete other cells and reconstruct the organ.

    Duncan even has some proof this can happen, at least in a lab mouse. Mice that have been genetically modified to develop hereditary tyrosinemia, a human liver disease, will resist the disease if they also lose another gene on chromosome 16 called homogentisic acid dioxygenase. Duncan found in 2012 that the livers of the sickly mice were selectively rebuilt by aneuploid cells that had randomly lost a copy of chromosome 16. “This genetic trick allowed them to resist the disease,” he said.

    He is now hoping to show that something similar can happen in other mouse models of human liver diseases, and is also looking for evidence that aneuploid cells can rebuild the livers of sick humans as well. “It’s becoming something people at least consider, that maybe these chromosomal variations could be playing a role” in disease recovery, he said. “It’s up to us and others to figure out what that role is.”

    A Good Thing?

    Meanwhile, not everyone is convinced that large-scale genetic aberrations are all that common in healthy bodies. Much of that doubt is related to technological shortcomings: The traditional method of identifying aneuploidy, fluorescent in situ hybridization, isn’t ideally suited to survey all 23 pairs of chromosomes, and deciding that one chromosome is aneuploid can be somewhat subjective. The newer single-cell sequencing methods can directly audit one entire genome, but they require the DNA to be chemically amplified, skewing results. Getting deep enough “coverage” of the genome (repeating the sequencing enough to correct most errors) is still time-consuming and expensive, so studies are done at low coverage. Even large CNVs are hard to detect, and the smaller ones are currently almost impossible to survey systematically.

    For all these reasons, genome biologist Angelika Amon at MIT (and also a Howard Hughes scholar), whose research focuses on aneuploidy in cancer and aging, thinks that major genetic variation in healthy bodies has been overestimated. That’s in part because she thinks it is biologically implausible: Her studies shown that aneuploidy makes cells grow slowly and show signs of metabolic stress. “Everything we’ve studied about aneuploidy in yeast, mouse and humans shows us that having the wrong chromosome number is not a good thing,” she said.

    Christopher Walsh of Harvard Medical School recently found that many cells in healthy brains have at least one big chunk of DNA missing or out of place.Stuart Cahill, The Boston Herald

    Walsh thinks that the more plausible range of aneuploidy in the brain is less than 5 percent (in line with what’s seen in most other tissues, like skin), as opposed to Chun’s estimate of around 10 percent. (Amon believes it is closer to 2 percent.) With megabase-sized CNVs, the picture is even murkier. While Amon also suspects that current CNV estimates have been overinflated by the statistical methods used to analyze variation, Walsh’s most recent study is more or less consistent with the lower range of what Chun and Gage have found — that very roughly speaking, most brain cells have at least one substantial CNV. “CNV is pretty common, even in the normal developing brain,” said Walsh. “I was impressed with that.”

    These questions of where and how much will likely be resolved as the technology and methods to analyze genomes continue to improve. Whether somatic mutations are largely beneficial, or even an essential source of human diversity and adaptability, will be harder to answer. For now, the idea “is very theoretical, not based on real data,” admitted Gage.

    Another study from Walsh’s group published today reveals that CNVs in even a small number of cells can result in severe brain malformations, such as brains that have two cortexes, or are smooth as an egg. “As few as 10 percent of cells being mutated can give you all kinds of problems — seizures, intellectual disabilities,” said Walsh. In his eyes, the downsides of somatic mutation in the brain are obvious, and any potential benefit is yet to be proven. Likewise, while Lupski thinks that somatic variation is significant, he is not yet convinced that it’s helpful. More experiments like Duncan’s are needed to prove that genetically diverse brains or livers have measurable advantages over homogenous ones.

    But even the skeptics appreciate the deep appeal of the idea that genomic diversity could be helpful. “People are excited about it, because it could provide an explanation for human variability,” said Amon. We possess a bewildering variety of habits and behaviors and a capacity to adjust to just about anything life throws at us. It’s compelling because it reflects a truth about human nature, that our vulnerabilities and our resilience are all bound up together, two sides of one coin. It just seems to fit with who we are.

    See the full article here.

    Formerly known as Simons Science News, Quanta Magazine is an editorially independent online publication launched by the Simons Foundation to enhance public understanding of science. Why Quanta? Albert Einstein called photons “quanta of light.” Our goal is to “illuminate science.” At Quanta Magazine, scientific accuracy is every bit as important as telling a good story. All of our articles are meticulously researched, reported, edited, copy-edited and fact-checked.

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  • richardmitnick 2:41 pm on August 20, 2014 Permalink | Reply
    Tags: , , , Genetics   

    From Caltech: “Programmed to Fold: RNA Origami” 

    Caltech Logo

    Katie Neith

    Researchers from Aarhus University in Denmark and Caltech have developed a new method for organizing molecules on the nanoscale. Inspired by techniques used for folding DNA origami—first invented by Paul Rothemund, a senior research associate in computation and neural systems in the Division of Engineering and Applied Science at Caltech—the team, which includes Rothemund, has fabricated complicated shapes from DNA’s close chemical cousin, RNA.

    Unlike DNA origami, whose components are chemically synthesized and then folded in an artificial heating and cooling process, RNA origami are synthesized enzymatically and fold up as they are being synthesized, which takes place under more natural conditions compatible with living cells. These features of RNA origami may allow designer RNA structures to be grown within living cells, where they might be used to organize cellular enzymes into biochemical factories.

    “The parts for a DNA origami cannot easily be written into the genome of an organism. An RNA origami, on the other hand, can be represented as a DNA gene, which in cells is transcribed into RNA by a protein machine called RNA polymerase,” explains Rothemund.

    So far, the researchers have demonstrated their method by designing RNA molecules that fold into rectangles and then further assemble themselves into larger honeycomb patterns. This approach was taken to make the shapes recognizable using an atomic force microscope, but many other shapes should be realizable.

    This illustration is an artist’s impression of RNA nanostructures that fold up while they are being synthesized by polymerase enzymes, which read instructions from DNA templates. Once formed, the RNAs assemble into honeycomb-shaped lattices on the mica surface below. Credit: Cody Geary

    A paper describing the research appears in the August 15 issue of the journal Science.

    “What is unique about the method is that the folding recipe is encoded into the molecule itself, through its sequence.” explains first author Cody Geary, a postdoctoral scholar at Aarhus University.

    In other words, the sequence of the RNAs defines both the final shape, and the order in which different parts of the shape fold. The particular RNA sequences that were folded in the experiment were designed using software called NUPACK, created in the laboratory of Caltech professor Niles Pierce. Both the Rothemund and Pierce labs are funded by a National Science Foundation. Molecular Programming Project (MPP) Expeditions in Computing grant.

    “Our latest research is an excellent example of how tools developed by one part of the MPP are being used by another,” says Rothemund.

    “RNA has a richer structural and functional repertoire than DNA, and so I am especially interested in how complex biological motifs with special 3-D geometries or protein-binding regions can be added to the basic architecture of RNA origami,” says Geary, who completed his BS in chemistry at Caltech in 2003.

    The project began with an extended visit by Geary and corresponding author Ebbe Andersen, also from Aarhus University, to Rothemund’s Caltech lab.

    “RNA origami is still in its infancy,” says Rothemund. “Nevertheless, I believe that RNA origami, because of their potential to be manufactured by cells, and because of the extra functionality possible with RNA, will have at least as big an impact as DNA origami.”

    Rothemund (BS ’94) reported the original method for DNA origami in 2006 in the journal Nature. Since then, the work has been cited over 6,000 times and DNA origami have been made in over 50 labs worldwide for potential applications such as drug delivery vehicles and molecular computing.

    “The payoff is that unlike DNA origami, which are expensive and have to be made outside of cells, RNA origami should be able to be grown cheaply in large quantities, simply by growing bacteria with genes for them,” he adds. “Genes and bacteria cost essentially nothing to share, and so RNA origami will be easily exchanged between scientists.”

    See the full article here.

    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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  • richardmitnick 8:01 am on August 19, 2014 Permalink | Reply
    Tags: , Genetics, ,   

    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 7:24 am on August 14, 2014 Permalink | Reply
    Tags: , , Genetics, , , Suicide   

    From M.I.T.: “Could a Genetic Test Predict the Risk for Suicide?” 

    MIT News

    August 13, 2014
    Antonio Regalado

    Scientists are hunting for the genetic basis of suicide and developing suicide DNA tests.

    No one could have predicted that Oscar-winning comedian Robin Williams would kill himself.

    Or could they?

    When someone commits suicide, the reaction is often the same. It’s disbelief, mixed with a recognition that the signs were all there. Depression. Maybe talk of ending one’s life.

    Now, by studying people who think about committing suicide, as well as brains of people who actually did, two groups of genome researchers in the U.S. and Europe are claiming they can use DNA tests to actually predict who will attempt suicide.

    While claims for a suicide test remain preliminary, and controversial, a “suicide gene” is not as fanciful as it sounds. The chance that a person takes his or her own life is in fact heritable, and many scientific teams are now involved in broad expeditions across the human genome to locate suicide’s biological causes.

    Based on such gene research, one startup company, Sundance Diagnostics, based in Boulder, Colorado, says it will begin offering a suicide risk test to doctors next month, but only in connection with patients taking antidepressant drugs like Prozac and Zoloft.

    The Sundance test rests on research findings reported by the Max Planck Institute of Psychiatry in 2012. The German researchers, based in Munich, scanned the genes of 898 people taking antidepressants and identified 79 genetic markers they claimed together had a 91 percent probability of correctly predicting “suicidal ideation,” or imagining the act of suicide.

    It’s well known that after going on antidepressants, some people do begin thinking about killing themselves. The risk is large enough that a decade ago the U.S. Food and Drug Administration slapped a warnings on antidepressant pills, saying they “increased the risk … of suicidal thinking and behavior” in children and young adults.

    “The number of completed suicides is not large, but none of us want our loved one to be at risk. You wouldn’t play roulette if it was your child,” says Sundance CEO Kim Bechthold, who licensed the test idea from Max Planck. She says the DNA tests will be carried out on a saliva sample.

    Given how many people take antidepressants, the market for a suicide test could be big. In the U.S., about 11 percent of Americans 12 years and older take antidepressants, according to a 2011 estimate by the U.S. Centers for Disease Control and Prevention.

    For now, however, experts say there are good reasons to view any suicide test with skepticism. Genome studies often turn up apparent connections that later are found not to mean much. Dozens of genes have been linked to suicide, but none in a truly definitive fashion.

    “I don’t think there are any credible genomic tests for suicide risk or prevention,” says Muin J. Khoury, head of the Office of Public Health Genomics at the U.S. Centers for Disease Control and Prevention. According to the CDC, suicide is the 10th most common cause of death in the U.S., accounting for 39,518 deaths in 2011.

    What is certain, says the CDC’s Khoury, is that suicide runs in families. On its list of suicide risk factors, the CDC lists family history as the most important, followed by mistreatment of children, prior suicide attempts, and depression.

    That family connection is what makes scientists certain that genes are involved. In 2013, for instance, Danish researchers looked at 221 adopted children who later in life committed suicide. They found that their biological siblings, raised in different households, were five times as likely to also commit suicide as other people. Identical twins are also more likely to both kill themselves than are two non-identical twins.

    Altogether, epidemiologists believe that 30 percent to 55 percent of the risk that someone takes their own life is inherited, and the risk isn’t linked to any specific mental illness, like depression or schizophrenia.

    That means suicide probably has its own unique genetic causes, says Stella Dracheva, a pathologist who studies the brains of suicide victims at Memorial Sloan Kettering in New York.”Suicide is a very complex condition, but there is a lot of evidence that it has a biological base,” she says. “There is something different in people who commit suicide.”

    In her view, that means it’s worth searching for suicide genes and that a DNA test is also theoretically plausible. She says a test would be particularly useful among veterans or other groups at unusually high risk of harming themselves.

    A person’s life history still has more to do with whether it ends in suicide than genes do. Virginia Willour, a geneticist at the University of Iowa who studies suicidal thinking among bipolar patients, says environmental factors are especially important in preventing suicide. Getting medical treatment, an involved family, and religious beliefs all cut the chance of suicide dramatically.

    Willour’s grandfather was bipolar and killed himself. “I chose to research suicidal behavior because I knew the impact. His suicide was a constant reminder and presence in my childhood,” she says.

    The pain and disbelief surrounding suicide only raises the stakes for scientists claiming they can predict it. The latest report of a possible suicide test came in July from Johns Hopkins University, in Baltimore, where geneticists published a report saying that the presence of alterations to a single gene could predict who will attempt suicide with 80 percent accuracy.

    Johns Hopkins has filed a patent on a suicide test, and the university is attempting to license it.

    That research, carried out by Zachary Kaminsky, an assistant professor of psychiatry at Johns Hopkins, began on a collection of a small number of brains of suicide victims held by the National Institutes of Health. Instead of looking just at DNA, they studied patterns of methylation, a type of chemical block on genes that can lower their activity. They found that one gene, SKA2, seemed to be blocked often in the suicide brains. They later found the same gene block was common when they tested the blood of a larger number of people having suicidal thoughts.

    “We seem to be able to predict suicidal behavior and attempts, based on seeing these epigenetic changes in the blood,” says Kaminsky. “The caveat is that we have small sample sizes.”

    Kaminsky says that following the report, his e-mail inbox was immediately flooded by people wanting the test. “They wanted to know, if my dad died from suicide, is my son at risk?” he says. They didn’t understand that the type of DNA change he identified probably isn’t the inherited kind, but instead may be the result of stress or some other environmental factor.

    Kaminsky’s publication has drawn some criticism from scientists who say his conclusions were based on thin evidence. They say more data is needed. “It’s a striking finding, but as always, when you look at complex genetics, you need replication. Time will tell if it [stands up],” says Willour.

    The bigger problem, says Dracheva, is that there are simply not enough brains of suicide victims to study. Unlike studies of diabetes or schizophrenia, where scientists can call on thousands or tens of thousands of patients, suicide studies remain small, and their findings much more tentative.

    It’s because they don’t have DNA from enough people who committed suicide that researchers, including those at Hopkins and Max Planck, have had to try connecting the dots between DNA and whether or not people have suicidal thoughts. Yet there’s no straight line between the contemplation of suicide and actually doing it.

    “Who doesn’t think about killing themselves?” says Dracheva.

    See the full article here.

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  • richardmitnick 6:45 pm on August 6, 2014 Permalink | Reply
    Tags: , , , Genetics, ,   

    From M.I.T.: “A new way to model cancer” 

    MIT News

    August 6, 2014
    Anne Trafton | MIT News Office

    Sequencing the genomes of tumor cells has revealed thousands of mutations associated with cancer. One way to discover the role of these mutations is to breed a strain of mice that carry the genetic flaw — but breeding such mice is an expensive, time-consuming process.

    Now, MIT researchers have found an alternative: They have shown that a gene-editing system called CRISPR can introduce cancer-causing mutations into the livers of adult mice, enabling scientists to screen these mutations much more quickly.

    Image: Thinkstock

    In a study appearing in the Aug. 6 issue of Nature, the researchers generated liver tumors in adult mice by disrupting the tumor suppressor genes p53 and pten. They are now working on ways to deliver the necessary CRISPR components to other organs, allowing them to investigate mutations found in other types of cancer.

    “The sequencing of human tumors has revealed hundreds of oncogenes and tumor suppressor genes in different combinations. The flexibility of this technology, as delivery gets better in the future, will give you a way to pretty rapidly test those combinations,” says Institute Professor Phillip Sharp, an author of the paper.

    Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the David H. Koch Professor of Biology, is the paper’s senior author. The lead authors are Koch Institute postdocs Wen Xue, Sidi Chen, and Hao Yin.

    Gene disruption

    CRISPR relies on cellular machinery that bacteria use to defend themselves from viral infection. Researchers have copied this bacterial system to create gene-editing complexes that include a DNA-cutting enzyme called Cas9 bound to a short RNA guide strand that is programmed to bind to a specific genome sequence, telling Cas9 where to make its cut.

    In some cases, the researchers simply snip out part of a gene to disrupt its function; in others, they also introduce a DNA template strand that encodes a new sequence to replace the deleted DNA.

    To investigate the potential usefulness of CRISPR for creating mouse models of cancer, the researchers first used it to knock out p53 and pten, which protect cells from becoming cancerous by regulating cell growth. Previous studies have shown that genetically engineered mice with mutations in both of those genes will develop cancer within a few months.

    Studies of such genetically engineered mice have yielded many important discoveries, but the process, which requires introducing mutations into embryonic stem cells, can take more than a year and costs hundreds of thousands of dollars. “It’s a very long process, and the more genes you’re working with, the longer and more complicated it becomes,” Jacks says.

    Using Cas enzymes targeted to cut snippets of p53 and pten, the researchers were able to disrupt those two genes in about 3 percent of liver cells, enough to produce liver tumors within three months.

    Many models possible

    The researchers also used CRISPR to create a mouse model with an oncogene called beta catenin, which makes cells more likely to become cancerous if additional mutations occur later on. To create this model, the researchers had to cut out the normal version of the gene and replace it with an overactive form, which was successful in about 0.5 percent of hepatocytes (the cells that make up most of the liver).

    The ability to not only delete genes, but also to replace them with altered versions “really opens up all sorts of new possibilities when you think about the kinds of genes that you would want to mutate in the future,” Jacks says. “Both loss of function and gain of function are possible.”

    Using CRISPR to generate tumors should allow scientists to more rapidly study how different genetic mutations interact to produce cancers, as well as the effects of potential drugs on tumors with a specific genetic profile.

    “This is a game-changer for the production of engineered strains of human cancer,” says Ronald DePinho, director of the University of Texas MD Anderson Cancer Center, who was not part of the research team. “CRISPR/Cas9 offers the ability to totally ablate gene function in adult mice. Enhanced potential of this powerful technology will be realized with improved delivery methods, the testing of CRISPR/Cas9 efficiency in other organs and tissues, and the use of CRISPR/Cas9 in tumor-prone backgrounds.”

    In this study, the researchers delivered the genes necessary for CRISPR through injections into veins in the tails of the mice. While this is an effective way to get genetic material to the liver, it would not work for other organs of interest. However, nanoparticles and other delivery methods now being developed for DNA and RNA could prove more effective in targeting other organs, Sharp says.

    The research was funded by the National Institutes of Health and the National Cancer Institute.

    See the full article here.

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