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  • richardmitnick 2:08 pm on May 22, 2017 Permalink | Reply
    Tags: , , Genetics, In ‘Enormous Success’ Scientists Tie 52 Genes to Human Intelligence,   

    From NYT: “In ‘Enormous Success,’ Scientists Tie 52 Genes to Human Intelligence” 

    New York Times

    The New York Times

    MAY 22, 2017
    Carl Zimmer

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    Blood samples from some participants in a new study of genes linked to intelligence were held at the U.K. Biobank, above. Credit Wellcome Trust

    In a significant advance in the study of mental ability, a team of European and American scientists announced on Monday that they had identified 52 genes linked to intelligence in nearly 80,000 people.

    These genes do not determine intelligence, however. Their combined influence is minuscule, the researchers said [Nature Genetics], suggesting that thousands more are likely to be involved and still await discovery. Just as important, intelligence is profoundly shaped by the environment.

    Still, the findings could make it possible to begin new experiments into the biological basis of reasoning and problem-solving, experts said. They could even help researchers determine which interventions would be most effective for children struggling to learn.

    “This represents an enormous success,” said Paige Harden, a psychologist at the University of Texas, who was not involved in the study.

    For over a century, psychologists have studied intelligence by asking people questions. Their exams have evolved into batteries of tests, each probing a different mental ability, such as verbal reasoning or memorization.

    In a typical test, the tasks might include imagining an object rotating, picking out a shape to complete a figure, and then pressing a button as fast as possible whenever a particular type of word appears.

    Each test-taker may get varying scores for different abilities. But over all, these scores tend to hang together — people who score low on one measure tend to score low on the others, and vice versa. Psychologists sometimes refer to this similarity as general intelligence.

    It’s still not clear what in the brain accounts for intelligence. Neuroscientists have compared the brains of people with high and low test scores for clues, and they’ve found a few.

    Brain size explains a small part of the variation, for example, although there are plenty of people with small brains who score higher than others with bigger brains.

    Other studies hint that intelligence has something to do with how efficiently a brain can send signals from one region to another.

    Danielle Posthuma, a geneticist at Vrije University Amsterdam and senior author of the new paper, first became interested in the study of intelligence in the 1990s. “I’ve always been intrigued by how it works,” she said. “Is it a matter of connections in the brain, or neurotransmitters that aren’t sufficient?”

    Dr. Posthuma wanted to find the genes that influence intelligence. She started by studying identical twins who share the same DNA. Identical twins tended to have more similar intelligence test scores than fraternal twins, she and her colleagues found.

    Hundreds of other studies have come to the same conclusion, showing a clear genetic influence on intelligence [Nature Genetics]. But that doesn’t mean that intelligence is determined by genes alone.

    Our environment exerts its own effects, only some of which scientists understand well. Lead in drinking water, for instance, can drag down test scores. In places where food doesn’t contain iodine, giving supplements to children can raise scores.

    Advances in DNA sequencing technology raised the possibility that researchers could find individual genes underlying differences in intelligence test scores. Some candidates were identified in small populations, but their effects did not reappear in studies on larger groups.

    So scientists turned to what’s now called the genome-wide association study: They sequence bits of genetic material scattered across the DNA of many unrelated people, then look to see whether people who share a particular condition — say, a high intelligence test score — also share the same genetic marker.

    In 2014, Dr. Posthuma was part of a large-scale study of over 150,000 people that revealed 108 genes linked to schizophrenia. But she and her colleagues had less luck with intelligence, which has proved a hard nut to crack for a few reasons.

    Standard intelligence tests can take a long time to complete, making it hard to gather results on huge numbers of people. Scientists can try combining smaller studies, but they often have to merge different tests together, potentially masking the effects of genes.

    As a result, the first generation of genome-wide association studies on intelligence failed to find any genes. Later studies managed to turn up promising results, but when researchers turned to other groups of people, the effect of the genes again disappeared.

    But in the past couple of years, larger studies relying on new statistical methods finally have produced compelling evidence that particular genes really are involved in shaping human intelligence.

    “There’s a huge amount of real innovation going on,” said Stuart J. Ritchie, a geneticist at the University of Edinburgh who was not involved in the new study.

    Dr. Posthuma and other experts decided to merge data from 13 earlier studies, forming a vast database of genetic markers and intelligence test scores. After so many years of frustration, Dr. Posthuma was pessimistic it would work.

    “I thought, ‘Of course we’re not going to find anything,’” she said.

    She was wrong. To her surprise, 52 genes emerged with firm links to intelligence. A dozen had turned up in earlier studies, but 40 were entirely new.

    But all of these genes together account for just a small percentage of the variation in intelligence test scores, the researchers found; each variant raises or lowers I.Q. by only a small fraction of a point.

    “It means there’s a long way to go, and there are going to be a lot of other genes that are going to be important,” Dr. Posthuma said.

    Christopher F. Chabris, a co-author of the new study at Geisinger Health System in Danville, Pa., was optimistic that many of those missing genes would come to light, thanks to even larger studies involving hundreds of thousands, perhaps millions, of people.

    “It’s just like astronomy getting better with bigger telescopes,” he said.

    In the new study, Dr. Posthuma and her colleagues limited their research to people of European descent because that raised the odds of finding common genetic variants linked to intelligence.

    But other gene studies have shown that variants in one population can fail to predict what people are like in other populations. Different variants turn out to be important in different groups, and this may well be the case with intelligence.

    “If you try to predict height using the genes we’ve identified in Europeans in Africans, you’d predict all Africans are five inches shorter than Europeans, which isn’t true,” Dr. Posthuma said.

    Studies like the one published today don’t mean that intelligence is fixed by our genes, experts noted. “If we understand the biology of something, that doesn’t mean we’re putting it down to determinism,” Dr. Ritchie said.

    As an analogy, he noted that nearsightedness is strongly influenced by genes. But we can change the environment — in the form of eyeglasses — to improve people’s eyesight.

    Dr. Harden predicted that an emerging understanding of the genetics of intelligence would make it possible to find better ways to help children develop intellectually. Knowing people’s genetic variations would help scientists measure how effective different strategies are.

    Still, Dr. Harden said, we don’t have to wait for such studies to change people’s environments for the better. “We know that lead harms children’s intellectual abilities,” she said. “There’s low-hanging policy fruit here.”

    For her part, Dr. Posthuma wants to make sense of the 52 genes she and her colleagues discovered. There are intriguing overlaps between their influence on intelligence and on other traits.

    The genetic variants that raise intelligence also tend to pop up more frequently in people who have never smoked. Some of them also are found more often in people who take up smoking but quit successfully.

    As for what the genes actually do, Dr. Posthuma can’t say. Four of them are known to control the development of cells, for example, and three do an assortment of things inside neurons.

    To understand what makes these genes special, scientists may need to run experiments on brain cells. One possibility would be to take cells from people with variants that predict high and low intelligence.

    She and her colleagues might coax them to develop into neurons, which could then grow into “mini-brains” — clusters of neurons that exchange signals in the laboratory. Researchers could then see if their genetic differences made them behave differently.

    “We can’t do it overnight,” Dr. Posthuma said, “but it’s something I hope to be able to do in the future.”

    See the full article here .

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  • richardmitnick 2:33 pm on April 11, 2017 Permalink | Reply
    Tags: , , , Genetics, Molecular clocks track human evolution   

    From EarthSky: “Molecular clocks track human evolution” 

    1

    EarthSky

    April 9, 2017
    Bridget Alex, Harvard University
    Priya Moorjani, Columbia University

    1
    Our cells have a built-in genetic clock, tracking time… but how accurately?. Image via http://www.shutterstock.com

    DNA holds the story of our ancestry – how we’re related to the familiar faces at family reunions as well as more ancient affairs: how we’re related to our closest nonhuman relatives, chimpanzees; how Homo sapiens mated with Neanderthals; and how people migrated out of Africa, adapting to new environments and lifestyles along the way. And our DNA also holds clues about the timing of these key events in human evolution. The Conversation

    When scientists say that modern humans emerged in Africa about 200,000 years ago and began their global spread about 60,000 years ago, how do they come up with those dates? Traditionally researchers built timelines of human prehistory based on fossils and artifacts, which can be directly dated with methods such as radiocarbon dating and Potassium-argon dating. However, these methods require ancient remains to have certain elements or preservation conditions, and that is not always the case. Moreover, relevant fossils or artifacts have not been discovered for all milestones in human evolution.

    Analyzing DNA from present-day and ancient genomes provides a complementary approach for dating evolutionary events. Because certain genetic changes occur at a steady rate per generation, they provide an estimate of the time elapsed. These changes accrue like the ticks on a stopwatch, providing a “molecular clock.” By comparing DNA sequences, geneticists can not only reconstruct relationships between different populations or species but also infer evolutionary history over deep timescales.

    Molecular clocks are becoming more sophisticated, thanks to improved DNA sequencing, analytical tools and a better understanding of the biological processes behind genetic changes. By applying these methods to the ever-growing database of DNA from diverse populations (both present-day and ancient), geneticists are helping to build a more refined timeline of human evolution.

    How DNA accumulates changes

    Molecular clocks are based on two key biological processes that are the source of all heritable variation: mutation and recombination.

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    Mutations are changes to the DNA code, such as when one nucleotide base (A, T, G or C) is incorrectly subbed for another.. Image via http://www.shutterstock.com

    Mutations are changes to the letters of DNA’s genetic code – for instance, a nucleotide Guanine (G) becomes a Thymine (T). These changes will be inherited by future generations if they occur in eggs, sperm or their cellular precursors (the germline). Most result from mistakes when DNA copies itself during cell division, although other types of mutations occur spontaneously or from exposure to hazards like radiation and chemicals.

    In a single human genome, there are about 70 nucleotide changes per generation – minuscule in a genome made up of six billion letters. But in aggregate, over many generations, these changes lead to substantial evolutionary variation.

    Scientists can use mutations to estimate the timing of branches in our evolutionary tree. First they compare the DNA sequences of two individuals or species, counting the neutral differences that don’t alter one’s chances of survival and reproduction. Then, knowing the rate of these changes, they can calculate the time needed to accumulate that many differences. This tells them how long it’s been since the individuals shared ancestors.

    Comparison of DNA between you and your sibling would show relatively few mutational differences because you share ancestors – mom and dad – just one generation ago. However, there are millions of differences between humans and chimpanzees; our last common ancestor lived over six million years ago.

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    Bits of the chromosomes from your mom and your dad recombine as your DNA prepares to be passed on. Chromosomes image via http://www.shutterstock.com.

    Recombination, also known as crossing-over, is the other main way DNA accumulates changes over time. It leads to shuffling of the two copies of the genome (one from each parent), which are bundled into chromosomes. During recombination, the corresponding (homologous) chromosomes line up and exchange segments, so the genome you pass on to your children is a mosaic of your parents’ DNA.

    In humans, about 36 recombination events occur per generation, one or two per chromosome. As this happens every generation, segments inherited from a particular individual get broken into smaller and smaller chunks. Based on the size of these chunks and frequency of crossovers, geneticists can estimate how long ago that individual was your ancestor.

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    Gene flow between divergent populations leads to chromosomes with mosaic ancestry. As recombination occurs in each generation, the bits of Neanderthal ancestry in modern human genomes becomes smaller and smaller over time. Image via Bridget Alex.

    Building timelines based on changes

    Genetic changes from mutation and recombination provide two distinct clocks, each suited for dating different evolutionary events and timescales.

    Because mutations accumulate so slowly, this clock works better for very ancient events, like evolutionary splits between species. The recombination clock, on the other hand, ticks at a rate appropriate for dates within the last 100,000 years. These “recent” events (in evolutionary time) include gene flow between distinct human populations, the rise of beneficial adaptations or the emergence of genetic diseases.

    The case of Neanderthals illustrates how the mutation and recombination clocks can be used together to help us untangle complicated ancestral relationships. Geneticists estimate that there are 1.5-2 million mutational differences between Neanderthals and modern humans. Applying the mutation clock to this count suggests the groups initially split between 750,000 and 550,000 years ago.

    At that time, a population – the common ancestors of both human groups – separated geographically and genetically. Some individuals of the group migrated to Eurasia and over time evolved into Neanderthals. Those who stayed in Africa became anatomically modern humans.

    6
    An evolutionary tree displays the divergence and interbreeding dates that researchers estimated with molecular clock methods for these groups. Image via Bridget Alex.

    However, their interactions were not over: Modern humans eventually spread to Eurasia and mated with Neanderthals. Applying the recombination clock to Neanderthal DNA retained in present-day humans, researchers estimate that the groups interbred between 54,000 and 40,000 years ago. When scientists analyzed a Homo sapiens fossil, known as Oase 1, who lived around 40,000 years ago, they found large regions of Neanderthal ancestry embedded in the Oase genome, suggesting that Oase had a Neanderthal ancestor just four to six generations ago. In other words, Oase’s great-great-grandparent was a Neanderthal.

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    Comparing chromosome 6 from the 40,000-year-old Oase fossil to a present-day human. The blue bands represent segments of Neanderthal DNA from past interbreeding. Oase’s segments are longer because he had a Neanderthal ancestor just 4–6 generations before he lived, based on estimates using the recombination clock. Image via Bridget Alex.

    The challenges of unsteady clocks

    Molecular clocks are a mainstay of evolutionary calculations, not just for humans but for all forms of living organisms. But there are some complicating factors.

    The main challenge arises from the fact that mutation and recombination rates have not remained constant over human evolution. The rates themselves are evolving, so they vary over time and may differ between species and even across human populations, albeit fairly slowly. It’s like trying to measure time with a clock that ticks at different speeds under different conditions.

    One issue relates to a gene called Prdm9, which determines the location of those DNA crossover events. Variation in this gene in humans, chimpanzees and mice has been shown to alter recombination hotspots – short regions of high recombination rates. Due to the evolution of Prdm9 and hotspots, the fine-scale recombination rates differ between humans and chimps, and possibly also between Africans and Europeans. This implies that over different timescales and across populations, the recombination clock ticks at slightly different rates as hotspots evolve.

    Another issue is that mutation rates vary by sex and age. As fathers get older, they transmit a couple extra mutations to their offspring per year. The sperm of older fathers has undergone more rounds of cell division, so more opportunities for mutations. Mothers, on the other hand, transmit fewer mutations (about 0.25 per year) as a female’s eggs are mostly formed all at the same time, before her own birth. Mutation rates also depend on factors like onset of puberty, age at reproduction and rate of sperm production. These life history traits vary across living primates and probably also differed between extinct species of human ancestors.

    Consequently, over the course of human evolution, the average mutation rate seems to have slowed significantly. The average rate over millions of years since the split of humans and chimpanzees has been estimated as about 1×10?? mutations per site per year – or roughly six altered DNA letters per year. This rate is determined by dividing the number of nucleotide differences between humans and other apes by the date of their evolutionary splits, as inferred from fossils. It’s like calculating your driving speed by dividing distance traveled by time passed. But when geneticists directly measure nucleotide differences between living parents and children (using human pedigrees), the mutation rate is half the other estimate: about 0.5×10?? per site per year, or only about three mutations per year.

    For the divergence between Neanderthals and modern humans, the slower rate provides an estimate between 765,000-550,000 years ago. The faster rate, however, would suggest half that age, or 380,000-275,000 years ago: a big difference.

    To resolve the question of which rates to use when and on whom, researchers have been developing new molecular clock methods, which address the challenges of evolving mutation and recombination rates.

    New approaches for better dating

    One approach is to focus on mutations that arise at a steady rate regardless of sex, age and species. This may be the case for a special type of mutation that geneticists call CpG transitions by which the C nucelotides spontaneously become T’s. Because CpG transitions mostly do not result from DNA copying errors during cell division, their rates should be mainly independent of life history variables – and presumably more uniform over time.

    Focusing on CpG transitions, geneticists recently estimated the split between humans and chimps to have occurred between 9.3 and 6.5 million years ago, which agrees with the age expected from fossils. While in comparisons across species, these mutations seem to happen more like clockwork than other types, they are still not completely steady.

    Another approach is to develop models that adjust molecular clock rates based on sex and other life history traits. Using this method, researchers calculated a chimp-human divergence consistent with the CpG estimate and fossil dates. The drawback here is that, when it comes to ancestral species, we can’t be sure of life history traits, like age at puberty or generation length, leading to some uncertainty in the estimates.

    The most direct solution comes from analyses of ancient DNA recovered from fossils. Because the fossil specimens are independently dated by geologic methods, geneticists can use them to calibrate the molecular clocks for a given time period or population.

    This strategy recently resolved the debate over the timing of our divergence with Neanderthals. In 2016, geneticists extracted ancient DNA from 430,000-year-old fossils that were Neanderthal ancestors, after their lineage split from Homo sapiens. Knowing where these fossils belong in the evolutionary tree, geneticists could confirm that for this period of human evolution, the slower molecular clock rate of 0.5×10?? provides accurate dates. That puts the Neanderthal-modern human split between 765,000 to 550,000 years ago.

    As geneticists sort out the intricacies of molecular clocks and sequence more genomes, we’re poised to learn more than ever about human evolution, directly from our DNA.

    Bridget Alex, Postdoctoral College Fellow, Department of Human Evolutionary Biology, Harvard University and Priya Moorjani, Postdoctoral Research Fellow in Biological Sciences, Columbia University

    See the full article here .

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  • richardmitnick 11:33 am on March 5, 2017 Permalink | Reply
    Tags: , , , Biotechnology, , Genetics, Hamilton Smith, , Methylation, Restriction enzyme, The Man Who Kicked Off the Biotech Revolution   

    From Nautilus: “The Man Who Kicked Off the Biotech Revolution” Hamilton Smith 

    Nautilus

    Nautilus

    3.5.17
    Carl Zimmer

    It’s hard to tell precisely how big a role biotechnology plays in our economy, because it infiltrates so many parts of it. Genetically modified organisms such as microbes and plants now create medicine, food, fuel, and even fabrics. Recently, Robert Carlson, of the biotech firm Biodesic and the investment firm Bioeconomy Capital, decided to run the numbers and ended up with an eye-popping estimate. He concluded that in 2012, the last year for which good data are available, revenues from biotechnology in the United States alone were over $324 billion.

    “If we talk about mining or several manufacturing sectors, biotech is bigger than those,” said Carlson. “I don’t think people appreciate that.”

    1
    Matchmaker Biotech pioneer Hamilton Smith chose to study recombination in a species of bacteria called Haemophilus influenza (above), which can take up foreign DNA fragments and integrate them into its own DNA. Media for Medical/UIG via Getty Images

    What makes the scope of biotech so staggering is not just its size, but its youth. Manufacturing first exploded in the Industrial Revolution of the 19th century. But biotech is only about 40 years old. It burst into existence thanks largely to a discovery made in the late 1960s by Hamilton Smith, a microbiologist then at Johns Hopkins University, and his colleagues, that a protein called a restriction enzyme can slice DNA. Once Smith showed the world how restriction enzymes work, other scientists began using them as tools to alter genes.

    “And once you have the ability to start to manipulate the world with those tools,” said Carlson, “the world opens up.”

    The story of restriction enzymes is a textbook example of how basic research can ultimately have a huge impact on society. Smith had no such grand ambitions when he started his work. He just wanted to do some science. “I was just having a lot of fun, learning as I went,” Smith, now 85, said.

    In 1968, when Smith was a new assistant professor at Johns Hopkins University, he became curious about how cells cut DNA into pieces and shuffle them into new arrangements—a process known as recombination. “It’s a universal thing,” Smith said. “Every living thing has recombination systems. But at the time, no one was sure how it worked, mechanically.”

    Smith chose to study recombination in a species of bacteria called Haemophilus influenza. Like many other species, H. influenzae can take up foreign DNA, either sucking in loose fragments from the environment or gaining them from microbial donors. Somehow, the bacterium can then integrate these fragments into its own DNA.

    Bacteria gain useful genes in this way, endowing them with new traits such as resistance to antibiotics. But recombination also has a dark side for H. influenzae. Invading viruses can hijack the recombination machinery in bacteria. They then insert their own genes into their host’s DNA, so that the microbes make new copies of the virus.

    To understand recombination, Smith produced radioactive viruses by introducing viruses into bacteria that had been fed radioactive phosphorus. New viruses produced inside the bacteria ended up with radioactive phosphorus in their DNA. Smith and his colleagues could then unleash these radioactive viruses on other bacteria. The scientists expected that during the infection, the bacteria’s genes would become radioactive as the viruses inserted their genetic material into their host’s DNA.

    At least that was they thought would happen. When Smith’s graduate student Kent Wilcox infected bacteria with the radioactive viruses, the radioactivity never ended up in the bacteria’s own genome.

    Trying to make sense of the failure, Wilcox suggested to Smith that the bacteria were destroying the viral DNA. He based his suggestion on a hypothesis proposed a few years earlier by Werner Arber, a microbiologist at the University of Geneva. Arber speculated that enzymes could restrict the growth of viruses by chopping up their DNA, and dubbed these hypothetical molecules “restriction enzymes.”

    Arber recognized that if restriction enzymes went on an unchecked rampage, they could kill the bacteria themselves by chopping up their own DNA. He speculated that bacteria were shielding their own DNA from assault, and thus avoiding suicide, by covering their genes with carbon and hydrogen atoms—a process known as methylation. The restriction enzymes couldn’t attack methylated DNA, Arber proposed, but it could attack the unprotected DNA of invading viruses.

    The week before Wilcox had carried out his baffling experiment, Smith had assigned his lab a provocative new paper supporting Arber’s hypothesis. Matthew Meselson and Robert Yuan at Harvard University reported in the paper how they had discovered a protein in E. coli that cut up foreign DNA—in other words, an actual restriction enzyme. With that paper fresh in his mind, Wilcox suggested to Smith that they had just stumbled across another restriction enzyme in Haemophilus influenzae.

    Smith tested the idea with an elegant experiment. He poured viral DNA into a test tube, and DNA from H. influenza into another. To each of these tubes, he then added a soup of proteins from the bacteria. If indeed the bacteria made restriction enzymes, the enzymes in the soup would chop up the viral DNA into small pieces.

    Scientists were decades away from inventing the powerful sequencers that are used today to analyze DNA. But Smith came up with a simple way to investigate the DNA in his test tubes. A solution containing large pieces of DNA is more viscous—more syrupy, in effect—than one with small pieces. So Smith measured the solution in his two test tubes with a device called a viscometer. As he had predicted, the virus DNA quickly became far less viscous. Something—some H. influenzae protein, presumably—was cutting the virus DNA into little pieces.

    “So I immediately knew this had to be a restriction enzyme,” Smith said. “It was a wonderful result—five minutes, and you know you have a discovery.”

    That instant gratification was followed by months of tedium, as Smith and his colleagues sorted through the proteins in their cell extracts until at last they identified a restriction enzyme. They also discovered a methylation enzyme that protected H. influenzae’s own DNA from destruction by shielding it with carbon and hydrogen.

    Once Smith and his colleagues published the remarkable details of their restriction enzymes, other scientists began to investigate them as well. They didn’t just study the enzymes, though—they began employing them as a tool. In 1972, Paul Berg, a biologist at Stanford University, used restriction enzymes to make cuts in the DNA of SV40 viruses, and then used other enzymes to attach the DNA from another virus to those loose ends. Berg thus created a single piece of DNA made up of genetic material from two species.

    A pack of scientists followed Berg’s lead. They realized that they could use restriction enzymes to insert genes from many different species into bacteria, which could then churn out proteins from those genes. In effect, bacteria could be transformed into biological factories.

    In 1978, Hamilton Smith got a call from Stockholm. He learned that he was sharing that year’s Nobel Prize in Medicine with Werner Arber and Daniel Nathans, another Johns Hopkins scientist who had followed up on Smith’s enzyme research with experiments of his own. Smith was as flummoxed as he was delighted.

    “They caught me off-guard,” Smith said. “I always looked up to the Nobelists as being incredibly smart people who had accomplished some world-shaking thing. It just didn’t seem like I was in that league.”

    But already the full impact of his work was starting to become clear. Companies sprouted up that were dedicated to using restriction enzymes to modify DNA. The first commercial application of this technology came from Genentech, a company founded in 1976. Genentech scientists used restriction enzymes to create a strain of E. coli that carried the gene for human insulin. Previously, people with diabetes could only purchase insulin extracted from the pancreases of cows and pigs. Genentech sold insulin produced by swarms of bacteria reared in giant metal drums.

    Over the years, scientists have built on Smith’s initial successes by finding new tools for manipulating DNA. Yet even today, researchers make regular use of restriction enzymes to slice open genes. “They’re still absolutely crucial,” said Carlson. “If you want to put a specific sequence of DNA in another sequence, it’s still most often restriction enzymes that you use to do that.”

    And as Smith has watched restriction enzymes become powerful and versatile, he has slowly overcome his case of Nobel imposter syndrome. “It probably was okay to get it,” he admitted.

    See the full article here .

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    Welcome to Nautilus. We are delighted you joined us. We are here to tell you about science and its endless connections to our lives. Each month we choose a single topic. And each Thursday we publish a new chapter on that topic online. Each issue combines the sciences, culture and philosophy into a single story told by the world’s leading thinkers and writers. We follow the story wherever it leads us. Read our essays, investigative reports, and blogs. Fiction, too. Take in our games, videos, and graphic stories. Stop in for a minute, or an hour. Nautilus lets science spill over its usual borders. We are science, connected.

     
  • richardmitnick 8:35 am on January 10, 2017 Permalink | Reply
    Tags: , Genetics, , , , or TADs, , Syndactyly, topologically associating domains   

    From NYT: “A Family’s Shared Defect Sheds Light on the Human Genome” 

    New York Times

    The New York Times

    JAN. 9, 2017
    NATALIE ANGIER

    1
    Headcase Design

    They said it was their family curse: a rare congenital deformity called syndactyly, in which the thumb and index finger are fused together on one or both hands. Ten members of the extended clan were affected, and with each new birth, they told Stefan Mundlos of the Max Planck Institute for Molecular Genetics, the first question was always: “How are the baby’s hands? Are they normal?”

    Afflicted relatives described feeling like outcasts in their village, convinced that their “strange fingers” repulsed everybody they knew — including their unaffected kin. “One woman told me that she never received a hug from her father,” Dr. Mundlos said. “He avoided her.”

    The family, under promise of anonymity, is taking part in a study by Dr. Mundlos and his colleagues of the origin and development of limb malformations. And while the researchers cannot yet offer a way to prevent syndactyly, or to entirely correct it through surgery, Dr. Mundlos has sought to replace the notion of a family curse with “a rational answer for their condition,” he said — and maybe a touch of pioneers’ pride.

    The scientists have traced the family’s limb anomaly to a novel class of genetic defects unlike any seen before, a finding with profound implications for understanding a raft of heretofore mysterious diseases.

    The mutations affect a newly discovered design feature of the DNA molecule called topologically associating domains, or TADs. It turns out that the vast informational expanse of the genome is divvied up into a series of manageable, parochial and law-abiding neighborhoods with strict nucleic partitions between them — each one a TAD.

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    The hand of a woman with syndactyly, the congenital fusion of fingers. The deformity may range from a slight degree of webbing to almost complete fusion as shown here. Credit SPL/Science Source

    Breach a TAD barrier, and you end up with the molecular equivalent of that famous final scene in Mel Brooks’s comedy, “Blazing Saddles,” when the cowboy actors from one movie set burst through a wall and onto the rehearsal stage of a campy Fred Astaire-style musical. Soon fists, top hats and cream pies are flying.

    By studying TADs, researchers hope to better fathom the deep structure of the human genome, in real time and three dimensions, and to determine how a quivering, mucilaginous string of some three-billion chemical subunits that would measure more than six-feet long if stretched out nonetheless can be coiled and compressed down to four-10,000ths of an inch, the width of a cell nucleus — and still keep its operational wits about it.

    “DNA is a super-long molecule packed into a very small space, and it’s clear that it’s not packed randomly,” Dr. Mundlos said. “It follows a very intricate and controlled packing mechanism, and TADs are a major part of the folding protocol.”

    For much of the past 50 years, genetic research has focused on DNA as a kind of computer code, a sequence of genetic “letters” that inscribe instructions for piecing together amino acids into proteins, which in turn do the work of keeping us alive.

    Read Between the Folds

    Most of the genetic diseases deciphered to date have been linked to mishaps in one or another protein recipe. Scanning the DNA of patients with Duchenne muscular dystrophy, for example, scientists have identified telltale glitches in the gene that encodes dystrophin, a protein critical to muscle stability.

    At the root of Huntington’s disease, which killed the folk singer Woody Guthrie, are short, repeated bits of nucleic nonsense sullying the code for huntingtin, an important brain protein. The mutant product that results soon shatters into neurotoxic shards.

    Yet researchers soon realized there was much more to the genome than the protein codes it enfolded. “We were caught up in the idea of genetic information being linear and one-dimensional,” said Job Dekker, a biologist at the University of Massachusetts Medical School.

    For one thing, as the sequencing of the complete human genome revealed, the portions devoted to specifying the components of hemoglobin, collagen, pepsin and other proteins account for just a tiny fraction of the whole, maybe 3 percent of human DNA’s three billion chemical bases.

    And there was the restless physicality of the genome, the way it arranged itself during cell division into 23 spindly pairs of chromosomes that could be stained and studied under a microscope, and then somehow, when cell replication was through, merged back together into a baffling, ever-wriggling ball of chromatin — DNA wrapped in a protective packaging of histone proteins.

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    Stefan Mundlos of the Max Planck Institute for Molecular Genetics in Germany studies the origin and development of limb malformations, some of which are caused by a novel class of genetic defects. Credit Norbert Michalke/Max Planck Institute for Molecular Genetics, Berlin

    What was the link, scientists wondered, between the shape and animation of the DNA molecule at any given moment, in any given cell — and every cell has its own copy of the genome — and the relative mouthiness or muteness of the genetic information the DNA holds?

    “We realized that in order to understand how genetic information is controlled, we had to figure out how DNA was folded in space,” said Bing Ren of the University of California, San Diego.

    Using a breakthrough technology developed by Dr. Dekker and his colleagues called chromosome conformation capture, researchers lately have made progress in tracking the deep structure of DNA. In this approach, chromatin is chemically “frozen” in place, enzymatically chopped up and labeled, and then allowed to reassemble.

    The pieces that find each other again, scientists have determined, are those that were physically contiguous in the first place — only now all their positions and relationships are clearly marked.

    Through chromosome conformation studies and related research, scientists have discovered the genome is organized into about 2,000 jurisdictions, and they are beginning to understand how these TADs operate.

    As with city neighborhoods, TADs come in a range of sizes, from tiny walkable zones a few dozen DNA subunits long to TADs that sprawl over tens of thousands of bases and you’re better off taking the subway. TAD borders serve as folding instructions for DNA. “They’re like the dotted lines on a paper model kit,” Dr. Dekker said.

    TAD boundaries also dictate the rules of genetic engagement.

    Scientists have long known that protein codes are controlled by an assortment of genetic switches and enhancers — noncoding sequences designed to flick protein production on, pump it into high gear and muzzle it back down again. The new research indicates that switches and enhancers act only on those genes, those protein codes, stationed within their own precincts.

    Because TADs can be quite large, the way the Upper West Side of Manhattan comprises an area of about 250 square blocks, a genetic enhancer located at the equivalent of, say, Lincoln Center on West 65th Street, can amplify the activity of a gene positioned at the Cathedral of St. John the Divine, 45 blocks north.

    But under normal circumstances, one thing an Upper West Side enhancer will not do is reach across town to twiddle genes residing on the Upper East Side.

    4
    Scientists have learned that disruptions of the genome’s boundaries may cause syndactyly and other diseases, including some pediatric brain disorders that affect the brain’s white matter. Credit Living Art Enterprises, LLC/Science Source

    “Genes and regulatory elements are like people,” Dr. Dekker said. “They care about and communicate with those in their own domain, and they ignore everything else.”

    Breaking Boundaries

    What exactly do these boundaries consist of, that manage to both direct the proper folding of the DNA molecule and prevent cross talk between genes and gene switches in different domains? Scientists are not entirely sure, but preliminary results indicate that the boundaries are DNA sequences that attract the attention of sticky, roughly circular proteins called cohesin and CTCF, which adhere thickly to the boundary sequences like insulating tape.

    Between those boundary points, those clusters of insulating proteins, the chromatin strand can loop up and over like the ribbon in a birthday bow, allowing genetic elements distributed along the ribbon to touch and interact with one another. But the insulating proteins constrain the movement of each chromatin ribbon, said Richard A. Young of the Whitehead Institute for Biomedical Research, and keep it from getting entangled with neighboring loops — and the genes and regulatory elements located thereon.

    The best evidence for the importance of TADs is to see what happens when they break down. Researchers have lately linked a number of disorders to a loss of boundaries between genomic domains, including cancers of the colon, esophagus, brain and blood.

    In such cases, scientists have failed to find mutations in any of the protein-coding sequences commonly associated with the malignancies, but instead identified DNA damage that appeared to shuffle around or eliminate TAD boundaries. As a result, enhancers from neighboring estates suddenly had access to genes they were not meant to activate.

    Reporting in the journal Science, Dr. Young and his colleagues described a case of leukemia in which a binding site for insulator proteins had been altered not far from a gene called TAL1, which if improperly activated is known to cause leukemia. In this instance, disruption of the nearby binding site, Dr. Young said, “broke up the neighborhood and allowed an outside enhancer to push TAL1 to the point of tumorigenesis,” the production of tumors.

    Now that researchers know what to look for, he said, TAD disruptions may prove to be a common cause of cancer. The same may be true of developmental disorders — like syndactyly.

    In journals like Cell and Nature, Dr. Mundlos and his co-workers described their studies of congenital limb malformations in both humans and mice. The researchers have detected major TAD boundary disruptions that allowed the wrong control elements to stimulate muscle genes at the wrong time and in the wrong tissue.

    “If a muscle gene turns on in the cartilage of developing digits,” Dr. Mundlos said, “you get malformations.”

    Edith Heard, director of the genetics and developmental biology department at the Institut Curie in France, who with Dr. Dekker coined the term TAD, said that while researchers were just beginning to get a handle on the architecture of DNA, “suddenly a lot of things are falling into place. We’re coming into a renaissance time for understanding how the genome works.”

    See the full article here .

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  • richardmitnick 1:38 pm on January 9, 2017 Permalink | Reply
    Tags: , Genetics, Skeletal muscle mass,   

    U Aberdeen: “Gene could play role in body’s muscle mass” 

    U Aberdeen bloc

    University of Aberdeen

    09 January 2017
    Euan Wemyss
    e.wemyss@abdn.ac.uk

    1
    Scientists at the University of Aberdeen identify gene which could play role in determining muscle mass. No image credit.

    “Our research suggests this gene could play a role in regulating muscle mass and the fact that drugs have already been developed to target the gene gives us an obvious focus for further research”
    Dr Arimantas Lionikas

    Scientists have identified a gene they think could play a role in determining a person’s muscle mass – which is linked to a number of health factors, including how long someone lives.

    Previous studies have shown a link between muscle mass and life expectancy in elderly people.

    Muscle is the most abundant tissue in the body and enables many functions from allowing us to move around to allowing us to breathe.

    The amount of skeletal muscle mass each person has can vary significantly.

    Skeletal muscle mass can be increased if a person undertakes strength exercise but genetic factors play an equally important role in determining how much muscle mass a person can have.

    Now, scientists at the University of Aberdeen, led by Dr Arimantas Lionikas, have identified a gene that appears to affect muscle mass in mice. The findings have been published in Nature Genetics.

    The same gene has previously been linked with the spread of cancer and drugs have been developed to target it.

    The team hope to study these drugs further to understand their effects on muscle tissue. If there are different drugs targeting the same gene, the research could uncover which drug has the less negative effect on muscle mass.

    “Skeletal muscle mass is incredibly important in humans, especially as they get older. We have already seen in older adults that statistically, those with lower muscle mass are more likely to die at a younger age.

    “Our research suggests this gene could play a role in regulating muscle mass and the fact that drugs have already been developed to target the gene gives us an obvious focus for further research.”

    See the full article here .

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    U Aberdeen Campus

    Founded in 1495 by William Elphinstone, Bishop of Aberdeen and Chancellor of Scotland, the University of Aberdeen is Scotland’s third oldest and the UK’s fifth oldest university.

    William Elphinstone established King’s College to train doctors, teachers and clergy for the communities of northern Scotland, and lawyers and administrators to serve the Scottish Crown. Much of the King’s College still remains today, as do the traditions which the Bishop began.

    King’s College opened with 36 staff and students, and embraced all the known branches of learning: arts, theology, canon and civil law. In 1497 it was first in the English-speaking world to create a chair of medicine. Elphinstone’s college looked outward to Europe and beyond, taking the great European universities of Paris and Bologna as its model.
    Uniting the Rivals

    In 1593, a second, Post-Reformation University, was founded in the heart of the New Town of Aberdeen by George Keith, fourth Earl Marischal. King’s College and Marischal College were united to form the modern University of Aberdeen in 1860. At first, arts and divinity were taught at King’s and law and medicine at Marischal. A separate science faculty – also at Marischal – was established in 1892. All faculties were opened to women in 1892, and in 1894 the first 20 matriculated female students began their studies. Four women graduated in arts in 1898, and by the following year, women made up a quarter of the faculty.

    Into our Sixth Century

    Throughout the 20th century Aberdeen has consistently increased student recruitment, which now stands at 14,000. In recent years picturesque and historic Old Aberdeen, home of Bishop Elphinstone’s original foundation, has again become the main campus site.

    The University has also invested heavily in medical research, where time and again University staff have demonstrated their skills as world leaders in their field. The Institute of Medical Sciences, completed in 2002, was designed to provide state-of-the-art facilities for medical researchers and their students. This was followed in 2007 by the Health Sciences Building. The Foresterhill campus is now one of Europe’s major biomedical research centres. The Suttie Centre for Teaching and Learning in Healthcare, a £20m healthcare training facility, opened in 2009.

     
  • richardmitnick 2:55 pm on January 7, 2017 Permalink | Reply
    Tags: , Genetics, , ,   

    From Uncovering Genome Mysteries at WCG: “Big Data and Big Plans: Next Steps for Uncovering Genome Mysteries” 

    New WCG Logo

    WCGLarge

    World Community Grid (WCG)

    15 Dec 2016 [Under what rock have you been hiding?]
    Wim Degrave, Ph.D.
    Laboratório de Genômica Funcional e Bioinformática Instituto Oswaldo Cruz – Fiocruz

    Summary
    World Community Grid’s role in the Uncovering Genome Mysteries project has ended, but the research team’s work continues as they analyze the results of the calculations and prepare to apply the data to medical, agricultural, and other real-world applications.

    1
    A diver collects samples from seawood off the coast of Australia. Uncovering Genome Mysteries analyzed protein sequences from a wide variety of life forms in many environments such as the ocean.

    Background

    The Uncovering Genome Mysteries project began on World Community Grid in November 2014, with the aim of analyzing protein sequences to help understand how organisms function and interact with each other and the environment. The project began with 120 million predicted protein sequences from close to 150,000 organisms. These protein sequences and organisms represent a wide variety of known or uncharacterised life forms in our biosphere. They came from organisms in samples taken from a range of environments, including water and soil, as well as on and inside plants and animals. Additionally, 70 million sequences, derived from prospective analysis of genetic information from microbial marine ecosystems from Australia were added, with the objective to add to the identification of possible functionalities of these sequences. In July 2015, we added yet another 20 million newly predicted sequences of proteins.

    Thanks to the enthusiastic contributions of more than 76,000 World Community Grid volunteers, all of these protein sequences were analyzed in approximately 24 months.

    Uncovering Genome Mysteries has been a challenging and ambitious project. Analyzing all the predicted enzymes and other proteins encoded in the genetic information known thus far from of all the organisms and life forms from our biosphere is a large task. Due to the development of new sequencing technologies for fast and cheap determination of genetic code, additional basic information will become available at an accelerating rate, making it increasingly difficult [?]to perform such a complete comparative analysis in the future.

    Our daunting task of performing close to 100 quadrillion comparisons has now been completed. The resulting data is more than 30 terabytes of compressed information (more than 150 terabytes uncompressed), even though each comparison only resulted in a single line of numbers for only the very highest probability similarities between protein sequences.

    Results to Date and Plans for the Future

    So, what is next? The research team at Fiocruz has spent the last year designing and testing new algorithms to transform the output of the comparisons with distance calculations between the genomes of the organisms included. Scientific literature cites many different ways to do this, depending on the purpose of the analysis and the views on evolutionary biology.

    The results of the Uncovering Genome Mysteries can be summarized as follows:

    More complete and precise information is now available on the structure and function of proteins encoded by living organisms in our biosphere. More proteins are being studied and experimented with each day in the thousands of laboratories around the world, and by using results from the comparison performed through the project, functional parallels can be drawn for proteins that show structural similarity between organisms. This is particularly valuable when predicted protein fragments are compared from uncharacterised organisms, for example in environmental and ecology studies, such as those originated from the laboratory of co-investigator Dr. Torsten Thomas, and his team from the Centre for Marine Bio-Innovation & the School of Biological, Earth and Environmental Sciences at the University of New South Wales, Sydney, Australia. The resulting database with these functional annotations will be made publicly available as the next version of our protein comparison database, ProteinWorldDB, in the coming months.

    Through comparison, new protein functions are discovered that can have medical, agricultural, technological or industrial applications. These can be as new biopharmaceuticals, bioinsecticides, biodegradation of waste, or enzymes for production of chemicals, but especially when part of new biochemical pathways in cells, that help laboratories to develop new green chemistry or energy production, or biosynthesis and transformation of new drugs. This also adds to the growing knowledge of biotechnology and synthetic biology.

    The group at Fiocruz has developed new ways to compare genomes from different organisms. Traditionally, such analyses consider what is conserved between genomes, resulting in distance calculations that are used for phylogenetic studies and the estimation of evolutionary relationships between organisms. However, we feel that this is only part of the picture, and the Fiocruz team designed a new algorithm that also takes differences into account. This was coupled to a new visualization method for such comparisons, resulting in a markedly faster way to add new data to the picture. We hope that this method will enable us to keep track of data from new organisms that becomes available, adding results to the growing ProteinWorld DB database.

    Thank you to all World Community Grid volunteers who supported this project, and we plan to keep in touch as we have further news about our ongoing research.

    See the full article here.

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    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.
    BOINCLarge

    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.

    BOINC WallPaper

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

    MyBOINC

    “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-

    FightAIDS@home Phase II

    FAAH Phase II
    OpenZika

    Rutgers Open Zika

    Help Stop TB
    WCG Help Stop TB
    Outsmart Ebola together

    Outsmart Ebola Together

    Mapping Cancer Markers
    mappingcancermarkers2

    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding

    FightAIDS@Home

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
    ibm

    IBM – Smarter Planet
    sp

     
  • richardmitnick 1:04 pm on December 30, 2016 Permalink | Reply
    Tags: apolipoprotein E (ApoE) gene, , , , Genetics   

    From ASU via phys.org: “New study shows cognitive decline may be influenced by interaction of genetics and… worms” 

    ASU Bloc

    ASU

    phys.org

    phys.org

    1
    A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Credit: NHGRI

    You’ve likely heard about being in the right place at the wrong time, but what about having the right genes in the wrong environment? In other words, could a genetic mutation (or allele) that puts populations at risk for illnesses in one environmental setting manifest itself in positive ways in a different setting?

    That’s the question behind a recent paper published in The FASEB Journal by several researchers including lead author Ben Trumble, an assistant professor at Arizona State University’s School of Human Evolution and Social Change and ASU’s Center for Evolution and Medicine.

    These researchers examined how the apolipoprotein E (ApoE) gene might function differently in an infectious environment than in the urban industrialized settings where ApoE has mostly been examined. All ApoE proteins help mediate cholesterol metabolism, and assist in the crucial activity of transporting fatty acids to the brain. But in industrialized societies, ApoE4 variant carriers also face up to a four-fold higher risk for Alzheimer’s disease and other age-related cognitive declines, as well as a higher risk for cardiovascular disease.

    The goal of this study, Trumble explains, was to reexamine the potentially detrimental effects of the globally-present ApoE4 allele in environmental conditions more typical of those experienced throughout our species’ existence—in this case, a community of Amazonian forager-horticulturalists called the Tsimane.

    “For 99% of human evolution, we lived as hunter gatherers in small bands and the last 5,000-10,000 years—with plant and animal domestication and sedentary urban industrial life—is completely novel,” Trumble says. “I can drive to a fast-food restaurant to ‘hunt and gather’ 20,000 calories in a few minutes or go to the hospital if I’m sick, but this was not the case throughout most of human evolution.”

    Due to the tropical environment and a lack of sanitation, running water, or electricity, remote populations like the Tsimane face high exposure to parasites and pathogens, which cause their own damage to cognitive abilities when untreated.

    As a result, one might expect Tsimane ApoE4 carriers who also have a high parasite burden to experience faster and more severe mental decline in the presence of both these genetic and environmental risk factors.

    But when the Tsimane Health and Life History Project tested these individuals using a seven-part cognitive assessment and a medical exam, they discovered the exact opposite.

    In fact, Tsimane who both carried ApoE4 and had a high parasitic burden displayed steadier or even improved cognitive function in the assessment versus non-carriers with a similar level of parasitic exposure. The researchers controlled for other potential confounders like age and schooling, but the effect still remained strong. This indicated that the allele potentially played a role in maintaining cognitive function even when exposed to environmental-based health threats.

    For Tsimane ApoE4 carriers without high parasite burdens, the rates of cognitive decline were more similar to those seen in industrialized societies, where ApoE4 reduces cognitive performance.

    “It seems that some of the very genetic mutations that help us succeed in more hazardous time periods and environments may actually become mismatched in our relatively safe and sterile post-industrial lifestyles,” Trumble explains.

    Still, the ApoE4 variant appears to be much more than an evolutionary leftover gone bad, he adds. For example, several studies have shown potential benefits of ApoE4 in early childhood development, and ApoE4 has also been shown to eliminate some infections like giardia and hepatitis.

    “Alleles with harmful effects may remain in a population if such harm occurs late in life, and more so if those same alleles have other positive effects,” adds co-author Michael Gurven, professor of anthropology at University of California, Santa Barbara. “Exploring the effects of genes associated with chronic disease, such as ApoE4, in a broader range of environments under more infectious conditions is likely to provide much-needed insight into why such ‘bad genes’ persist.”

    The abstract and full research paper “Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden” can be viewed here in The FASEB Journal

    See the full article here .

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    ASU is the largest public university by enrollment in the United States.[11] Founded in 1885 as the Territorial Normal School at Tempe, the school underwent a series of changes in name and curriculum. In 1945 it was placed under control of the Arizona Board of Regents and was renamed Arizona State College.[12][13][14] A 1958 statewide ballot measure gave the university its present name.
    ASU is classified as a research university with very high research activity (RU/VH) by the Carnegie Classification of Institutions of Higher Education, one of 78 U.S. public universities with that designation. Since 2005 ASU has been ranked among the Top 50 research universities, public and private, in the U.S. based on research output, innovation, development, research expenditures, number of awarded patents and awarded research grant proposals. The Center for Measuring University Performance currently ranks ASU 31st among top U.S. public research universities.[15]

    ASU awards bachelor’s, master’s and doctoral degrees in 16 colleges and schools on five locations: the original Tempe campus, the West campus in northwest Phoenix, the Polytechnic campus in eastern Mesa, the Downtown Phoenix campus and the Colleges at Lake Havasu City. ASU’s “Online campus” offers 41 undergraduate degrees, 37 graduate degrees and 14 graduate or undergraduate certificates, earning ASU a Top 10 rating for Best Online Programs.[16] ASU also offers international academic program partnerships in Mexico, Europe and China. ASU is accredited as a single institution by The Higher Learning Commission.

    ASU Tempe Campus
    ASU Tempe Campus

     
  • richardmitnick 1:59 pm on December 17, 2016 Permalink | Reply
    Tags: , Boy in the bubble, Genetics, , ,   

    From UC Berkeley: “From a single genetic mutation, secrets of ‘boy in the bubble’ disease revealed” 

    UC Berkeley

    UC Berkeley

    December 15, 2016
    Brett Israel
    brett.israel@berkeley.edu

    UC Berkeley was part of an interdisciplinary, international research team that has identified the rare genetic mutation responsible for a unique case of “boy in the bubble” disease, known as severe combined immunodeficiency (SCID), a deadly immune system disorder. The researchers found that the cause was a mutated version of a gene called BCL11B, which also plays an unexpected role in the normal processes of immune system development.

    1
    World of his own: David Vetter (Photo: Courtesy Baylor College of Medicine Archives) http://i2.mirror.co.uk/incoming/article3196066.ece/ALTERNATES/s810/The-Boy-in-the-Bubble.jpg. Just a single case chosen at random from many.

    The discovery of this genetic mutation is the latest of several breakthroughs from this team, which has been accomplished by analyzing exomes — the roughly 2 percent of DNA that contains the instructions for building proteins — to identify the cause of mysterious immunological diseases in newborns.

    “This is a gene that had never been associated with SCID before, which required more advanced genome analysis techniques to discover,” said Berkeley computational biologist Steven Brenner, co-author of the study. “Moreover, unlike variants in every other known SCID gene, this mutation is dominant, which means you only need one copy of this mutation to disrupt multiple aspects of development.”

    The study was published Dec. 1 in the New England Journal of Medicine. The research article was accompanied by a perspective by Michael Lenardo, chief of the Molecular Development of the Immune System Section at the National Institute of Allergy and Infectious Diseases, commissioned by the journal. Lenardo wrote that the study is “an exciting example of recent achievements in the application of contemporary molecular genomics to clinical medicine, especially with regard to congenital diseases…This study reflects remarkable advances in molecular diagnosis.”

    The infant patient featured in the new study was identified through a population-based neonatal screening approach for SCID, which was developed in 2005 by Jennifer Puck, the study’s senior author and a UCSF professor of immunology and pediatrics. The screening indicated a severely compromised immune system, leaving the patient open to a likely fatal series of infections. However, UCSF doctors performed a bone marrow transplant, the standard of care for SCID, which provided the infant with a fully functional immune system.

    In addition to SCID, however, the infant was born with a constellation of abnormal features including craniofacial deformities, loose skin, excess body hair and neurological abnormalities, which suggested that a single rare genetic defect could underlie the patient’s disease.

    In part to determine whether the infant’s parents were carriers of a genetic mutation that could be passed on to future children, the research team set out to scan the genomes of both infant and parents for mutations that could be responsible for the disease. Researchers at UC Berkeley and UCSF built on their productive collaboration with researchers at Tata Consultancy Services to use next-generation exome sequencing to identify a single mutation present in the infant but not the parents — referred to as a de novo mutation — in the BCL11B gene, which had previously been associated primarily with lymphatic cancer. So finding the BLC11B mutation to be causative for SCID was a surprise.

    “We’re entering a new era of genomic medicine,” Puck said. “Our technology has progressed to the point that we can learn a great deal about a disease, and even learn important new facts about normal biology, from just a single patient. In this case we were able to unearth the potentially unique underlying genetic cause of one patient’s disease and come away with brand new understanding of how the immune system develops.”

    In order to understand the biological effects of the patient’s mutation, the researchers collaborated with the team of David Wiest at Fox Chase Cancer Center, in Philadelphia, to introduce the patient’s mutated form of BCL11B into zebrafish, whose immune systems are similar to those of humans. They found that the mutated form of BCL11B produced abnormalities in the zebrafish that mimicked those observed in the patient, including not only a disabled immune system but also similar craniofacial abnormalities. Blocking the mutated gene and replacing it with the normal human gene in embryonic zebrafish reversed all these symptoms, strongly suggesting that abnormal BCL11B was the cause of the symptoms seen in both zebrafish and the human patient.

    The normal BCL11B protein binds to DNA at sites across the genome to activate a wide variety of developmental genes in a precisely orchestrated sequence. Experiments revealed that the BCL11B gene mutation identified in the new study disrupts this protein’s ability to bind to DNA, thereby resulting in the wide array of immunological, neurological and craniofacial disruptions seen in both the human patient and in zebrafish.

    “In this case, however, a mutation in BCL11B turned the protein it produces into a monkey wrench that disrupted many different systems in the body,” Puck said.

    According to Puck, the findings illustrate the power of deeply studying rare diseases in individual patients: “We may never get another patient just like this one,” she said. “But as a result of studying this one case we were able to learn so much about a critical gene in a critical pathway that hadn’t been appreciated before.”

    The research was supported by the National Institutes of Health, Tata Consultancy Services, the Commonwealth of Pennsylvania, the M.D. Anderson Cancer Center, the Fox Chase Cancer Center, the Jeffrey Modell Foundation, the Lisa and Douglas Goldman Fund and the Michelle Platt-Ross Foundation.

    See the full article here .

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    Founded in the wake of the gold rush by leaders of the newly established 31st state, the University of California’s flagship campus at Berkeley has become one of the preeminent universities in the world. Its early guiding lights, charged with providing education (both “practical” and “classical”) for the state’s people, gradually established a distinguished faculty (with 22 Nobel laureates to date), a stellar research library, and more than 350 academic programs.

    UC Berkeley Seal

     
  • richardmitnick 9:08 am on August 3, 2016 Permalink | Reply
    Tags: , Genetics, ,   

    From UCLA: “Scientists develop new way to measure important chemical modification on RNA” 

    UCLA bloc

    UCLA

    August 02, 2016
    Mirabai Vogt-James

    A team of scientists including researchers from UCLA has developed an RNA sequencing technique that provides detailed information about a chemical modification that occurs on RNA and plays an important role in pluripotent stem cells’ ability to turn into other types of cells. The method could advance scientists’ use of stem cells in regenerative medicine, since pluripotent stem cells can turn into any cell type in the body.

    The study, published in the journal Nature Methods, outlines the new sequencing technique, which measures the percentage of RNA that is methylated, or chemically modified, for each gene in the genome.

    RNA serves an important purpose inside cells; it carries genetic messages from DNA. These messages direct cells to make the proteins that play many critical roles in the body, but errors in how those messages are produced or regulated can lead to a variety of diseases, including cancer and neurological disorders.

    Until recently, little was known about how RNA activity is regulated by methylation of the RNA molecules. The new study looks at a specific type of RNA methylation known as m6A or N6-methyladenosine, which is a chemical modification that has a variety of functions, such as controlling how long the RNA will live in the cell and how much protein it will produce. The m6A modification is the most abundant type of RNA methylation on protein-producing RNAs.

    The data analyses were led by co-senior author Yi Xing, a professor of microbiology, immunology and molecular genetics in the UCLA College and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. Dr. Cosmas Giallourakis, co-senior author and an assistant professor of medicine at Harvard Medical School and Massachusetts General Hospital, led the development of the new sequencing technique. First authors were Benoit Molinie at Harvard Medical School and Jinkai Wang, a UCLA postdoctoral fellow.

    “Previously, we were only able to determine the location of m6A on the RNA, but not the amount,” said Xing, who is also a member of the UCLA Institute for Quantitative and Computational Biosciences and director of UCLA’s bioinformatics doctoral program.

    The ability to determine the percentage of m6A on RNA gives researchers information that could potentially help detect disease, Xing said, since m6A levels on RNA may be different in diseased cells than in healthy cells. Researchers can also use information about m6A levels to gain insights into a pluripotent stem cell’s ability to turn into other types of cells.

    Pluripotent stem cells have two unique abilities. They can turn into any specialized cell in the body, such as skin, bone, blood or brain cells; this process is called “differentiation.” They can also create copies of themselves. These abilities hold great promise for advances in regenerative medicine. But scientists are particularly interested in understanding how to control the process through which pluripotent stem cells differentiate into specialized cell types that are safe and fully capable of regenerating aging or diseased tissue. Another challenge is maintaining pluripotent stem cells in the lab, since they have a tendency to spontaneously differentiate, at which point scientists lose the ability to control the cell’s fate.

    Previous research by a team led by Xing and Giallourakis showed that blocking m6A prevents pluripotent stem cells from differentiating into specialized cell types, while allowing them to retain their critical pluripotent flexibility.

    The new sequencing technique, called m6A-LAIC-seq, is a novel method that scientists can use to obtain valuable data about RNA methylation using specialized machines that produce hundreds of millions of RNA sequences and provide insights into the molecular signature of a cell.

    “We are very excited about the promising data and the new tool that is now available to study m6A in a wide range of cell types including pluripotent stem cells,” Xing said. “We anticipate that our research will improve the understanding and use of pluripotent stem cells in regenerative medicine.”

    The study was supported by grants from Massachusetts General Hospital, the National Institutes of Health (GM088342, DK090122, ES002109 and ES024615) and the National Science Foundation (CHE-1308839); an Alfred Sloan Research Fellowship; the National Research Foundation of Singapore through the Singapore–MIT Alliance for Research and Technology; and by the UCLA Broad Stem Cell Research Center–Rose Hills Foundation Research Award.

    See the full article here .

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    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

     
  • richardmitnick 7:33 am on July 20, 2016 Permalink | Reply
    Tags: , , Genetics,   

    From Princeton: “Role for enhancers in bursts of gene activity (Cell)” 

    Princeton University
    Princeton University

    July 19, 2016
    Marisa Sanders for the Office of the Dean for Research

    A new study by researchers at Princeton University suggests that sporadic bursts of gene activity may be important features of genetic regulation rather than just occasional mishaps. The researchers found that snippets of DNA called enhancers can boost the frequency of bursts, suggesting that these bursts play a role in gene control.

    The researchers analyzed videos of Drosophila fly embryos undergoing DNA transcription, the first step in the activation of genes to make proteins. In a study published on July 14 in the journal Cell, the researchers found that placing enhancers in different positions relative to their target genes resulted in dramatic changes in the frequency of the bursts.

    “The importance of transcriptional bursts is controversial,” said Michael Levine, Princeton’s Anthony B. Evnin ’62 Professor in Genomics and director of the Lewis-Sigler Institute for Integrative Genomics. “While our study doesn’t prove that all genes undergo transcriptional bursting, we did find that every gene we looked at showed bursting, and these are the critical genes that define what the embryo is going to become. If we see bursting here, the odds are we are going to see it elsewhere.”

    The transcription of DNA occurs when an enzyme known as RNA polymerase converts the DNA code into a corresponding RNA code, which is later translated into a protein. Researchers were puzzled to find about ten years ago that transcription can be sporadic and variable rather than smooth and continuous.

    In the current study, Takashi Fukaya, a postdoctoral research fellow, and Bomyi Lim, a postdoctoral research associate, both working with Levine, explored the role of enhancers on transcriptional bursting. Enhancers are recognized by DNA-binding proteins to augment or diminish transcription rates, but the exact mechanisms are poorly understood.

    Until recently, visualizing transcription in living embryos was impossible due to limits in the sensitivity and resolution of light microscopes. A new method developed three years ago has now made that possible. The technique, developed by two separate research groups, one at Princeton led by Thomas Gregor, associate professor of physics and the Lewis-Sigler Institute for Integrative Genomics, and the other led by Nathalie Dostatni at the Curie Institute in Paris, involves placing fluorescent tags on RNA molecules to make them visible under the microscope.

    The researchers used this live-imaging technique to study fly embryos at a key stage in their development, approximately two hours after the onset of embryonic life where the genes undergo fast and furious transcription for about one hour. During this period, the researchers observed a significant ramping up of bursting, in which the RNA polymerase enzymes cranked out a newly transcribed segment of RNA every 10 or 15 seconds over a period of perhaps 4 or 5 minutes per burst. The genes then relaxed for a few minutes, followed by another episode of bursting.

    The team then looked at whether the location of the enhancer – either upstream from the gene or downstream – influenced the amount of bursting. In two different experiments, Fukaya placed the enhancer either upstream of the gene’s promoter, or downstream of the gene and saw that the different enhancer positions resulted in distinct responses. When the researchers positioned the enhancer downstream of the gene, they observed periodic bursts of transcription. However when they positioned the enhancer upstream of the gene, the researchers saw some fluctuations but no discrete bursts. They found that the closer the enhancer is to the promoter, the more frequent the bursting.

    To confirm their observations, Lim applied further data analysis methods to tally the amount of bursting that they saw in the videos. The team found that the frequency of the bursts was related to the strength of the enhancer in upregulating gene expression. Strong enhancers produced more bursts than weak enhancers. The team also showed that inserting a segment of DNA called an insulator reduced the number of bursts and dampened gene expression.

    In a second series of experiments, Fukaya showed that a single enhancer can activate simultaneously two genes that are located some distance apart on the genome and have separate promoters. It was originally thought that such an enhancer would facilitate bursting at one promoter at a time—that is, it would arrive at a promoter, linger, produce a burst, and come off. Then, it would randomly select one of the two genes for another round of bursting. However, what was instead observed was bursting occurring simultaneously at both genes.

    “We were surprised by this result,” Levine said. “Back to the drawing board! This means that traditional models for enhancer-promoter looping interactions are just not quite correct,” Levine said. “It may be that the promoters can move to the enhancer due to the formation of chromosomal loops. That is the next area to explore in the future.”

    The study was funded by grants from the National Institutes of Health (U01EB021239 and GM46638).

    Access the paper here:

    Takashi Fukaya, Bomyi Lim & Michael Levine. Enhancer Control of Transcriptional Bursting, Cell (2016), Published July 14. EPub ahead of print June 9. http://dx.doi.org/10.1016/j.cell.2016.05.025

    See the full article here .

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