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  • richardmitnick 4:50 pm on January 22, 2016 Permalink | Reply
    Tags: , , , Genetics   

    From Broad Institute: “The beauty of imbalance” 

    Broad Institute

    Broad Institute

    January 21st, 2016
    Angela Page

    Temp 1
    Broad researchers have found that asymmetrical mutational patterns on the two strands of the double helix could be implicated in cancer. Image by Madeleine Price Ball/Lauren Solomon

    Every day, every cell in the body picks up one or two genetic mutations. Luckily, cells have a whole battery of strategies for fixing these errors. But most of the time, even if a mutation doesn’t get fixed — or doesn’t get fixed properly — there are no obvious functional implications. That is, the mutation isn’t known to impair the function of the cell. Some mutations, however — called “driver” mutations — do impair the cell, leading to cancer, aging, or other types of diseases.

    Identifying new driver mutations (a few hundred genes that carry driver mutations are known so far) is a huge focus for most labs that study cancer, including that of Broad Cancer Genome Computational Analysis group director Gad Getz. But in new research recently published in Cell, Getz and computational biology group leader Michael Lawrence wanted to look at all those other mutations: the “passengers” that may or may not cause cancer. Doing so, they surmised, would not only help them understand the fundamental biology of cells, but may also point them toward new mechanisms for causing mutations associated with cancer.

    And that’s exactly what happened. The new work reveals the mechanism behind cancers associated with a family of enzymes called APOBEC, which had been rather enigmatic until now. The original purpose of APOBEC enzymes, according to Lawrence, was probably to fight viruses. But recent studies from Getz’s lab and others have shown that many cancers are enriched for genetic mutations caused by these enzymes.

    “Something that most cervical and bladder cancers, some breast cancers, many head and neck cancers, and a scattering of many other tumor types, all have in common is over-activity of APOBEC enzymes,” Lawrence said. People had been studying APOBEC cancers for years, trying to figure out what exactly was going wrong, but they had so far met with little success.

    One thing that had interested Lawrence and Getz about APOBEC was that while it introduces dozens of mutations all across the genome, it always affects the cytosine bases — the “Cs” in the famous DNA alphabet which also contains As, Ts, and Gs. This was interesting because it played right into a hypothesis about asymmetry that Getz and Lawrence had already begun to explore.

    “Every cell has two DNA strands that wrap around each other in a double helix. Both carry the same information, so each double helix has two copies of the information,” Lawrence said. “When damage happens to the DNA it might happen on just one strand.” Identifying the strand on which the damage originally occurred could give researchers clues about the mechanisms behind cancer mutations.

    “But because the cell so carefully maintains the matching of the two strands, a misplaced base on one strand quickly leads to a complementary misplaced base on the other,” said Nicholas Haradhvala, co-first author on the paper together with Paz Polak, both associated scientists at Broad and members of Getz’s lab at MGH. “By the time DNA sequencing is performed, it is impossible to tell which strand originally was damaged.”

    In order to identify the strand originally damaged, Haradhvala and his colleagues looked at asymmetrical processes such as DNA transcription and replication. DNA transcription is the first step in gene expression, whereby the genetic blueprints contained in the gene are read and translated into proteins. DNA replication is the process by which DNA is copied when cells divide. In transcription, a variety of cellular apparatuses unzip the two DNA strands and then make a mirror image copy of one of them. The other strand hangs out like a vulnerable flag in the wind, waiting for the process to complete, potentially getting blown over with mutations in the meantime. The strand that is being read is further protected from mutation because the process includes a step in which another apparatus comes in with the specific job of repairing any damage it finds. The non-transcribed strand — that vulnerable flag — doesn’t benefit from such a perk.

    After analyzing the mutational patterns of 590 tumors across 14 different cancer types, the team discovered that liver cancers seem to be riddled with mutations that stem from transcription-coupled damage. That is, mutations tend to pile up on the non-transcribed strand more frequently in liver tumors than expected. This is a novel phenomenon that is first described in this work.

    In replication, both strands are copied simultaneously, but since the machinery that does so only works in one direction, copying the strand with the opposite orientation is a bit of a stilted process. The copying apparatus, a protein called a polymerase, takes a step forward, copies everything behind it, and then moves another step forward and copies backwards again. The other strand is just happily copied in a continuous, (literally) straightforward manner. And since the backwards strand is so often hanging out alone, it is more vulnerable to damage just like the non-transcribed strand described above.

    So in both transcription and replication, cellular processes treat the two strands of DNA in an asymmetrical fashion. This asymmetry is what allowed Getz, Lawrence, and their colleagues to figure out the mechanism behind APOBEC cancers. It turns out, according to the team’s painstaking analysis of millions of data points, that the APOBEC enzyme most often introduces mutations to the lagging (or “backward”) strand during DNA replication.

    Both the liver and APOBEC findings are big news. After all, it’s not every day that a new mechanism for generating mutations comes along. But more importantly, they also offer insight into how DNA transcription and replication work from the perspective of mutations — findings that could have implications in understanding even more cancer types in the future.
    “It’s like having a computational microscope,” said Getz. “It allows us to see what’s going on inside the cell, where the action is happening while the DNA is being transcribed or replicated. That’s the beauty of this work.”

    Going forward, Getz, Lawrence, and their colleagues have big plans for their asymmetry work. They are already in the process of collaborating with dozens of labs around the globe to collect and analyze whole genome sequences of 2,800 tumors. Part of that work will include asymmetry analyses like those described here, to try to understand whether these processes have mechanistic implications for other cancer types as well. In the meantime, they are also collaborating with their benchtop biologist colleagues to carry out functional studies as follow up to the computational work done for this study, trying to recreate in a live setting what they saw in that computational microscope.

    Other Broad Researchers:

    Julian Hess, Esther Rheinbay, Jaegil Kim, Yosef Maruvka, Lior Braunstein, Atanas Kamburov, and Amnon Koren.

    Papers cited:

    Burns, et al. Evidence for APOBEC3B mutagenesis in multiple human cancers Nature Genetics. Online July 14, 2013. DOI: 10.1038/ng.2701

    Haradhvala, et al. Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair. Cell. Online January 21, 2016. DOI: 10.1016/j.cell.2015.12.050

    Roberts, et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nature Genetics. January 28, 2013. DOI: 10.1038/ng.2702

    See the full article here .

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    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
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    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

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  • richardmitnick 3:16 pm on January 20, 2016 Permalink | Reply
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    From Berkeley: “Advance improves cutting and pasting with CRISPR-Cas9 gene editing” 

    UC Berkeley

    UC Berkeley

    January 20, 2016
    Robert Sanders

    Temp 1
    A view of the Cas9 protein (red and blue) bound to a double strand of DNA (purple and grey). After both strands are cut, one DNA strand (purple dots) is free and able to bind with a piece of DNA to be inserted at the break.This behavior can be utilized to significantly boost the efficiency of gene editing. Image by Christopher Richardson, UC Berkeley, based on structure solved by Martin Jinek’s lab.

    UC Berkeley researchers have made a major improvement in CRISPR-Cas9 technology that achieves an unprecedented success rate of 60 percent when replacing a short stretch of DNA with another.

    The improved technique is especially useful when trying to repair genetic mutations that cause hereditary diseases, such as sickle cell disease or severe combined immune deficiency. The technique allows researchers to patch an abnormal section of DNA with the normal sequence and potentially correct the defect and is already working in cell culture to improve ongoing efforts to repair defective genes.

    “The exciting thing about CRISPR-Cas9 is the promise of fixing genes in place in our genome, but the efficiency for that can be very low,” said Jacob Corn, scientific director of the Innovative Genomics Initiative at UC Berkeley, a group that focuses on next-generation genome editing and gene regulation for lab and clinical application. “If you think of gene editing as a word processor, we know how to cut, but we need a more efficient way to paste and glue a new piece of DNA where we make the cut.”

    “In cases where you want to change very small regions of DNA, up to 30 base pairs, this technique would be extremely effective,” said first author Christopher Richardson, an IGI postdoc.

    Problems in short sections of DNA, including single base-pair mutations, are typical of many genetic diseases. Base pairs are the individual building blocks of DNA, strung end-to-end in a strand that coils around a complementary strand to make the well-known helical, double-stranded DNA molecule.

    Richardson, Corn and their IGI colleagues describe the new technique in the Jan. 21 issue of the journal Nature Biotechnology.

    Grabbing onto a loose strand

    Richardson invented the new approach after finding that the Cas9 protein, which does the actual DNA cutting, remains attached to the chromosome for up to six hours, long after it has sliced through the double-stranded DNA. Richardson looked closely at the Cas9 protein bound to the two strands of DNA and discovered that while the protein hangs onto three of the cut ends, one of the ends remains free.

    Jennifer Doudna explains how CRISPR-Cas9 edits genes. Video by Roxanne Makasdjian and Stephen McNally, UC Berkeley.
    Watch/download mp4 video here .

    When Cas9 cuts DNA, repair systems in the cell can grab a piece of complementary DNA, called a template, to repair the cut. Researchers can add templates containing changes that alter existing sequences in the genome — for example, correcting a disease-causing mutation.

    Richardson reasoned that bringing the substitute template directly to the site of the cut would improve the patching efficiency, and constructed a piece of DNA that matches the free DNA end and carries the genetic sequence to be inserted at the other end. The technique worked extremely well, allowing successful repair of a mutation with up to 60 percent efficiency.

    “Our data indicate that Cas9 breaks could be different at a molecular level from breaks generated by other targeted nucleases, such as TALENS and zinc-finger nucleases, which suggests that strategies like the ones we are using can give you more efficient repair of Cas9 breaks,” Richardson said.

    The researchers also showed that variants of the Cas9 protein that bind DNA but do not cut also can successfully paste a new DNA sequence at the binding site, possibly by forming a “bubble” structure on the target DNA that also acts to attract the repair template. Gene editing using Cas9 without genome cutting could be safer than typical gene editing by removing the danger of off-target cutting in the genome, Corn said.

    Co-authors with Richardson and Corn are IGI researchers Jordan Ray, Mark DeWitt and Gemma Curie. The work was funded by the Li Ka Shing Foundation.

    See the full article here .

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  • richardmitnick 8:06 am on January 18, 2016 Permalink | Reply
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    From New scientist: “The Society of Genes: Time for a subtler picture of evolution” 


    New Scientist

    13 January 2016
    Bob Holmes

    Temp 1
    Image: Alexander Nemenov/AFP/Getty Images

    FORTY years ago, Richard Dawkins’ book The Selfish Gene popularised the notion that the gene, rather than the individual, was the true unit of evolution. That view has dominated evolutionary genetics ever since. But in The Society of Genes, biologists Itai Yanai and Martin Lercher say that it’s time to replace the selfish-gene metaphor with a new one that focuses on relationships.

    “We are not the simple sum of our genes,” they write. “The members of the society of genes do not live in isolation. Working together, forming rivalries and partnerships, is the only way they can form a human body that can sustain them for a few decades and propel them into the next generation of humanity.”

    Their book is not a dry academic argument. Instead, Yanai and Lercher use the idea of a society of genes as a vantage point from which to reintroduce the entire field of evolutionary genetics. It is analogous to modern society, which is full of cooperative and competitive interactions. As in any industry, some genes are workers and builders, while others manage the operation as a whole. This helps us understand the complex genetic networks regulating metabolism and development, where many genes work together and each has multiple functions.

    The authors also hope this will give non-specialist readers a more secure grasp of the intricate and often surprising adaptations undergone by living organisms.

    Cancer – to take a familiar example – is best understood as a disease of the genome: a breakdown of the usual checks and balances among genes that keep cells from dividing more than they should. No single malfunctioning gene causes cancer. Instead, several members of the society of genes need to fail in order for a tumour to form.

    Other chapters apply this to the genetics of immune systems, the evolutionary benefits of sexual reproduction, genetic differences among human populations, the origin of life and more. Many of these insights will be familiar to readers with a good background in evolutionary biology. But even experienced readers are likely to encounter perspectives that are unexpected enough to make the book worth their effort.

    For example, the authors speculate why so many elite athletes are of African descent. Because early humans evolved on that continent, Africa still has more genetic diversity than all other continents combined. So, to the extent that genes determine performance, the best genes for any given skill – sprinting, throwing – are likely to be found in Africa. Since genes also affect intelligence, the best chess players ought someday also to come from African ancestry, they suggest. And – although they don’t say it outright – the brightest scientists, too.

    The idea of genes working together is nothing new, of course. Four decades ago, Dawkins himself acknowledged that the selfishness of individual genes is tempered by their need to cooperate to keep their carrier organism alive and well. What Yanai and Lercher’s metaphor shift does is revalue those networks of competition and cooperation. They are no longer afterthoughts: rather, they are the centrepiece of our understanding.

    Yanai and Lercher take care to assume no prior knowledge, explaining even elementary concepts such as the gene, natural selection and heredity. Readers meeting biology for the first time will be well served by this richer, more nuanced, way of viewing genetics, while those with a deeper background will find plenty of interest, notably in the vivid clarity of the explanations.

    See the full article here .

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  • richardmitnick 2:31 pm on January 13, 2016 Permalink | Reply
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    From MIT Tech Review: “CRISPR Dispute to Be Decided by Patent Office” 

    MIT Technology Review
    M.I.T Technology Review

    January 12, 2016
    Jacob S. Sherkow

    A “patent interference” proceeding will determine who controls foundational patents on gene editing.

    As this magazine and others have detailed, CRISPR-Cas9—the powerful gene-editing technology being hailed as molecular biology’s “holy grail”—is the subject of a contentious dispute between the widely celebrated Jennifer Doudna at the University of California, Berkeley, and wunderkind Feng Zhang at the Broad Institute and MIT.

    The central question: who invented it first?

    Yesterday, that dispute became official in the eyes of the U.S. Patent and Trademark Office when an administrative patent judge officially declared an “interference” between Doudna’s pending patent application and a dozen of Zhang’s already issued patents. The interference proceeding sets up a legal showdown that may strip Zhang of his patents and see the two scientists deposed under oath.

    Even among patent attorneys—generally, friends of the arcane and hypertechnical—interference proceedings are famous for their complexity. The U.S. patent office now grants patents on a “first to file” basis. But before 2013 this was not the case. Historically, U.S. patent law instead recognized that patent rights should go to whoever could prove they were “first to invent” an idea. Because there is a lag between when patent applications are filed and when they are issued—roughly, three years—this gave rise to the possibility that a later inventor could be awarded a patent before the patent office had time to process an earlier inventor’s application. In that circumstance, the later inventor’s patent “interferes” with the earlier inventor’s ability to rightfully obtain theirs.

    This is precisely what occurred between Doudna and Zhang, whose patents are covered by the older rule. Doudna, with colleagues in Europe, filed a provisional patent application on her early iteration of the CRISPR editing technology on May 25, 2012; Zhang did the same on December 12, 2012. But Zhang’s attorneys requested that the patent office expedite its review of his application under a procedure—funnily named a Petition to Make Special—that allows inventors a quick up-or-down vote on simplified patent applications. As a result, Zhang was awarded his first patent on April 15, 2014, while Doudna’s patent application remained in limbo. Shortly thereafter, Zhang was awarded over a dozen patents on various forms of the technology.

    Perhaps fearing that they were losing the great biotech patent race of the century, Doudna’s attorneys amended her application in order to directly conflict with Zhang’s patents. Specifically, Doudna’s attorneys claimed that her patent application covered gene-editing in mammalian cells—including humans—even though her original filing didn’t detail that aspect of the technology. Yesterday, to the delight of watchers of patent dockets everywhere, an administrative patent judge with a PhD in molecular biology, Judge Deborah Katz, officially declared the interference.

    Despite these seemingly dry technicalities, the CRISPR patent dispute has been spiced with intrigue. During the examination of Doudna’s patent application, several unidentified third parties filed papers with the patent office seeking to block it, arguing that she was not the first to invent her CRISPR technique, while the Broad Institute unleashed its own volley of legal papers, lab notebooks, even copies of private e-mails between scientists. If Doudna’s original application did not command the focus of patent office supervisors when it was filed, it sure does now.

    What comes next? A panel of three patent judges will get to decide who gets the patent rights to CRISPR-Cas9 editing in animal cells. Their decision is likely to center on a few core issues. One is whether Doudna’s original patent application really covered working with human cells. Another is the earliest date either scientist can prove they performed their breakthrough work.

    Yesterday’s declaration of an interference proceeding already provides a few hints. First, it lists Doudna as the “senior party” and Zhang as the “junior party”—an initial determination that the administrative patent judge agrees that Doudna was the first inventor. This means that the burden of proof rests on Zhang, much like how, in a criminal trial, the government—not a criminal defendant—must prove its case beyond a reasonable doubt. Second, the declaration puts at issue all of the patent claims; none are left out. This suggests that the interference proceeding—assuming it retains its current scope—will be an all-or-nothing affair: Zhang will either get to keep all of his patents or lose all of them. This may mean that there is little room, legally, for the patent office to keep both sides happy. But as the dispute has shown us thus far, there is always room for surprises.

    See the full article here .

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  • richardmitnick 11:51 am on December 22, 2015 Permalink | Reply
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    From New Scientist: “CRISPR will make 2016 the year of gene-edited organisms” 


    New Scientist

    15 December 2015
    Next year preview
    Michael Le Page

    Image credit: Dr Yorgos Nikas/Science Photo Library

    Will the first gene-edited baby be born in 2016? Let’s hope not. It is far from clear it can be done safely – although technically it is now possible. Gene editing with the new method known as CRISPR is so cheap, easy and effective that a few scientists with the appropriate expertise could tweak one or more genes in a human embryo before it is implanted in a woman’s womb.

    What 2016 will undoubtedly bring is a lot more gene-edited organisms. CRISPR works well in everything from butterflies to monkeys. It has already been used to create extra-muscular beagle dogs and sheep; long-haired goats; and pigs immune to common diseases. Next up could be hypoallergenic pet dogs and cats, cattle resistant to TB, or chickens that don’t get bird flu.

    But whether any of these make it out of the lab in the next 12 months depends on the regulators. Gene editing can add new pieces of DNA, as in conventional genetic engineering, so any living thing altered in this way is bound in many countries by strict regulations on genetically modified organisms. Getting approval to sell modified animals takes a lot of time and money.

    But gene editing can also be used to make changes to existing genes – tweaks that are indistinguishable from naturally occurring gene variants. The mutation that made the beagles more muscly already exists in dog breeds like the bully whippet.

    In theory, this kind of gene editing should be exempt from regulation. If the regulators agree, this could be the year that people start eating, drinking or wearing products from gene-edited farm animals and plants, or buy the first gene-edited pets.

    See the full article here .

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  • richardmitnick 11:10 am on November 12, 2015 Permalink | Reply
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    From AAAS: “The 3230 genes you can’t do without” 



    11 November 2015
    Elizabeth Pennisi

    By comparing sets of genes from tens of thousands of people, researchers have found some that the body can’t seem to live without. Jane Ades/NHGRI

    Fiddle just a little bit with any one of about 3200 genes in the human body and you could be toast. That’s the conclusion of a new study, which finds that about 15% of our 20,000 genes are so critical to our livelihood that even minor mutations can kill us before we’re born. The findings should help researchers better track down the genes that cause human disease.

    Given how useful any insights into gene function are for understanding the genetic basis of disease, the data are “priceless,” says Kári Stephánsson, a geneticist at deCODE in Reykjavík.

    The new study, which was recently posted to a preprint repository but has not yet been published in a peer-reviewed publication, was the result of researchers comparing the parts of the genome known as exomes, which code for proteins, from 60,000 people—10 times more than had ever been attempted. Researchers led by Daniel MacArthur, a geneticist at the Broad Institute of the Massachussetts Institute of Technology and Harvard University in Cambridge, Massachusetts, achieved this feat by reaching out to teams around the world who had collected their own sets of exomes. Among all those genes, the researchers found 10 million variants—places within genes that varied from person to person.

    MacArthur’s team calculated how many variants each gene should have if those changes arise by chance. Then they compared that to the number of variants actually found for each gene. The result: 3230 genes that had either no observed variation, or compared to what was expected, much, much less of the kind of changes that could lead to a malfunction of the gene.

    Such data suggests that, whenever one of these genes mutates, the embryo usually dies or the person is too sick to reproduce—so the variation disappears. ”Genes that displayed no variants should be essential or play crucial biological functions,” says Ping Xu, a molecular microbiologist at Virginia Commonwealth University in Richmond.

    Ping and others have similarly found such essential genes in bacteria or in mice. And many of the highlighted human genes are associated with the same critical cellular operations, such as the cell’s protein-building factories, as in those species, MacArthur’s group reports. About 20% of the human genes uncovered by the analysis are already associated with diseases, but many are not—yet. They are the first places David Goldstein, a geneticist at Columbia University in New York City who was not involved with the work, says he will look for connections to medical conditions. And because they seem vital “these genes can be specifically monitored during drug development for potential side effects and cytotoxicity,” Xu says.

    The key to the success of MacArthur’s team, say other researchers, was gathering so much DNA data. (MacArthur declined to comment since the paper isn’t officially published yet.) “They do a really nice job of showing that you get a lot more information by studying an order of magnitude more people,” says Joshua Akey, a population geneticist at the University of Washington in Seattle.

    Even so, Goldstein is quick to point out that 3230 is not the complete set of essential genes in the human body and that only by studying more exomes will researchers be able to refine that number. Furthermore, exomes don’t cover DNA in between genes, which help regulate gene activity, and variation there can also be important. Finally, what researchers really want to know is what specific part of each gene is essential. Bottom line, Goldstein says: “This is another step on a very long road that we are on to understand what does and doesn’t happen in the human genome.”

    See the full article here .

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  • richardmitnick 7:59 am on October 26, 2015 Permalink | Reply
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    From U Washington: “New UW model helps zero in on harmful genetic mutations” 

    U Washington

    University of Washington

    October 22, 2015
    Jennifer Langston

    A new UW model can help narrow down which genetic mutations affect how genes splice and contribute to disease. In this illustration, the cell’s splicing machinery is trying to pick which “cutting” sites (pictured as white flags) it should use. Jennifer Sunami

    Between any two people, there are likely to be at least 10 million differences in the genetic sequence that makes up their DNA.

    Most of these differences don’t alter the way cells behave or cause health problems. But some genetic variations greatly increase the likelihood that a person will develop cancer, diabetes, colorblindness or a host of other diseases.

    Despite rapid advances in our ability to map an individual’s genome — the precise coding that makes up his or her genes — we know much less about which mutations or anomalies actually cause disease.

    Now, a new model and publicly available Web tool developed by University of Washington researchers can more accurately and quantitatively predict which genetic mutations significantly change how genes splice and may warrant increased attention from disease researchers and drug developers.

    The model — the first to train a machine learning algorithm on vast amounts of genetic data created with synthetic biology techniques — is outlined in a paper published in the Oct. 22 issue of Cell.

    “Some people have variations in a particular gene, but what you really want to know is whether those matter or not,” said lead author Alexander Rosenberg, a UW electrical engineering doctoral student. “This model can help you narrow down the universe — hugely — of the mutations that might be most likely to cause disease.”

    In particular, the model predicts how these genetic sequence variations affect alternative splicing — a critical process that enables a single gene to create many different forms of proteins by including or excluding snippets of RNA.

    “This is an avenue that’s unexplored to a large extent,” said Rosenberg. “It’s fairly easy to look at how mutations affect proteins directly, but people have not been able to look at how mutations affect proteins through splicing.”

    For example, a scientist studying the genetic underpinnings of lung cancer or depression or a particular birth defect could type the most commonly shared DNA sequence in a particular gene into the Web tool, as well as multiple variations. The model will tell the scientist which mutations cause outsized differences in how the gene splices — which could be a sign of trouble — and which have little or no effect.

    The researcher would still need to investigate whether a particular genetic sequence causes harmful changes, but the online tool can help rule out the many variations that aren’t likely to be of interest to health researchers. To validate the model’s predictive powers, the UW team tested it on a handful of well-understood mutations such as those in the BRCA2 gene that have been linked to breast and ovarian cancer.

    Compared to previously published models, the UW approach is roughly three times more accurate at predicting the extent to which a mutation will cause genetic material to be included or excluded in the protein-making process — which can change how those proteins function and cause biological processes to go awry.

    The UW team used synthetic biology and DNA sequencing techniques to create a massive library of genetic data. By training a machine learning algorithm on that large synthetic dataset, the UW model can make accurate predictions about the human genome.University of Washington

    That’s because the UW team used a new approach that combines synthetic biology and machine learning techniques to create the model.

    Machine learning algorithms — which enable computers to infer rules and “learn” from vast amounts of data — become more accurate the more data they’re exposed to. But the human genome only has roughly 25,000 genes that create proteins.

    Using common molecular biology techniques, the UW team created a library of over 2 million synthetic “mini-genes” by including random DNA sequences. Then they determined how each random sequence element affected where genes spliced and what types of RNA were produced — which ultimately determines which proteins get made.

    That larger library of synthetic data essentially teaches the model to become smarter, said lead author Georg Seelig, a UW assistant professor of electrical engineering and of computer science & engineering.

    “Our algorithm works super well because it was trained on these synthetic datasets. And the reason it works so well is because that synthetic dataset is orders of magnitude larger than the training set you get from the actual human genome,” said Seelig.

    “It is remarkable that a model trained entirely on synthetic data can outperform models trained directly on the human genome on the task of predicting the impact of mutations in people,” he said.

    Next research steps include expanding the approach beyond alternative splicing to other processes that determine how genes are expressed.

    In the meantime, by making the Web tool free and publicly available, the team hopes other scientists will use their alternative splicing model — and ultimately make progress in narrowing down which natural genetic variations are most meaningful when it comes to health and disease.

    “Other research groups and companies can use our model to rank the areas of interest to them,” Seelig said. “We hope other people will take this further to more clinical applications.”

    Co-authors include former UW doctoral student Rupali P. Patwardhan and associate professor Jay Shendure in the UW Department of Genome Sciences.

    For more information, contact Seelig at gseelig@uw.edu.

    See the full article here .

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  • richardmitnick 3:24 am on October 16, 2015 Permalink | Reply
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    From EPFL: “The future of farming depends on local breeds” 

    EPFL bloc

    Ecole Polytechnique Federale Lausanne

    Jan Overney

    The dwindling genetic diversity of farm animals is increasingly becoming a threat to livestock production. Although new DNA technologies can help us address this problem, changing habits to preserve local lineages may prove to be challenging. No image credit.

    It is hard to overestimate the importance of global livestock production to society and the economy. It constitutes the main source of income for 1.3 billion farmers, providing vital food for 800 million subsistence farmers, and making up 40% of global agricultural GDP. But overbreeding and dwindling genetic diversity could limit the ability of livestock populations to adapt the environmental changes, such as global warming and related new diseases. Currently on the sidelines, lesser-known livestock breeds and the DNA they carry could become key to securing the future of livestock farming.

    For four years leading up to 2014, a European research project chaired by EPFL took stock of the past, present, and future of farm animal genetic resources and outlined the questions of highest priority for research, infrastructure and policy development for the coming decade. A selection of the project’s scientific output has now been published by the open access journal Frontiers in Genetics and is available online in the form of 31 research papers.

    A shrinking genetic reservoir

    Over the past 100 years, many local breeds have gone extinct, as more productive industrial breeds have taken over. Even within these breeds, the genetic diversity between individuals is shrinking. So why does this matter? “A reduction of genetic diversity goes hand with hand with a reduction of the species’ capacity to adapt to new diseases, warmer temperatures, or new food sources,” says Stéphane Joost, the project’s chair.

    “Studying 1,200 sheep from 32 old, native breeds from around the world, we previously identified a specific gene involved in regulating their metabolism, whose presence correlated strongly with the amount of incident solar radiation – a genetic trait that made them better adapted to their environment than cosmopolitan breeds that are more productive in the short term,” says Joost. If breeds carrying such specific adaptations disappear, so too will the coping strategies they acquired throughout evolution.

    The better choice?

    Joost’s advice to farmers: “Farmers should keep their local, well adapted breeds,” he urges. They may be less productive than their industrially bred cousins, but in developing countries with extreme climates sticking to them is often the wiser choice – a lesson that many farmers learn the hard way. After investing their savings to crossbreed a species of cow local to West Africa with an industrial breed, farmers in Burkina Faso first reaped the fruits of their investment, until they realized that all of the mixed breed’s offspring were poorly adapted to their climate and eventually died. “Only local breeds are adapted to resist to such harsh environments and withstand diseases such as trypanosomiasis, spread by the tsetse fly,” says Joost.

    An archive of adaptation

    Understanding the genetic history of today’s breeds could help us find ways of adapting in the future, says Joost. “What ancestral animals conferred the species with a specific trait? And what can we do today to recover that same trait?” he asks. Knowing, for example, exactly which native species were crossbred to produce today’s breeds could help pinpoint certain well-adapted genes present in the native species that may have been lost. In the same way, well-adapted local breeds that were abandoned to the point of extinction could be recreated by cross-breeding the ancestral species they emerged from.

    To ensure that the research carried out in this project finds its way into the agricultural community, the 31 studies will be compiled into an e-book, which will also be made available in print and distributed to stakeholders in developing countries by the FAO. But changing habits will be an uphill battle, as it involves sacrificing short-term profits for long-term sustainability – a problem that Joost and the co-organizers of the research project are well aware of. “Throughout this project, we emphasized the need to work with social scientists to effectively influence the habits of the breeders associations and other stakeholders. This is one front on which we still have much to do,” he concludes.

    See the full article here .

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    EPFL is Europe’s most cosmopolitan technical university. It receives students, professors and staff from over 120 nationalities. With both a Swiss and international calling, it is therefore guided by a constant wish to open up; its missions of teaching, research and partnership impact various circles: universities and engineering schools, developing and emerging countries, secondary schools and gymnasiums, industry and economy, political circles and the general public.

  • richardmitnick 6:58 am on October 10, 2015 Permalink | Reply
    Tags: , Genetics,   

    From Nature: “Gene-editing record smashed in pigs” 

    Nature Mag

    06 October 2015
    Sara Reardon

    Researchers modify more than 60 genes in effort to enable organ transplants into humans.

    Geneticist George Church has co-founded a company that is developing genetically modified pigs to grow organs for human transplant. Jessica Rinaldi/Reuters

    For decades, scientists and doctors have dreamed of creating a steady supply of human organs for transplantation by growing them in pigs. But concerns about rejection by the human immune system and infection by viruses embedded in the pig genome have stymied research. Now, by modifying more than 60 genes in pig embryos — ten times more than have been edited in any other animal — researchers believe they may have produced a suitable non-human organ donor.

    The work was presented on 5 October at a meeting of the US National Academy of Sciences (NAS) in Washington DC on human gene editing. Geneticist George Church of Harvard Medical School in Boston, Massachusetts, announced that he and colleagues had used the CRISPR/Cas9 gene-editing technology to inactivate 62 porcine endogenous retroviruses (PERVs) in pig embryos. These viruses are embedded in all pigs’ genomes and cannot be treated or neutralized. It is feared that they could cause disease in human transplant recipients.

    The gene-edited pigs will be raised in isolation from pathogens. ableimages / Alamy Stock Photo

    Church’s group also modified more than 20 genes in a separate set of pig embryos, including genes that encode proteins that sit on the surface of pig cells and are known to trigger a human immune response or cause blood clotting. Church declined to reveal the exact genes, however, because the work is as yet unpublished. Eventually, pigs intended for organ transplants would need both these modifications and the PERV deletions.

    Preparing for implantation

    “This is something I’ve been wanting to do for almost a decade,” Church says. A biotech company that he co-founded to produce pigs for organ transplantation, eGenesis in Boston, is now trying to make the process as cheap as possible.

    Church released few details about how his team managed to remove so many pig genes. But he says that both sets of edited pig embryos are almost ready to implant into mother pigs. eGenesis has procured a facility at Harvard Medical School where the pigs will be implanted and raised in isolation from pathogens.

    Jennifer Doudna, a biochemist at University of California, Berkeley, who was one of the inventors of CRISPR/Cas9 technology, is impressed by the number of edited genes. If the work holds up, she says, it could be useful for synthetic-biology applications where genes can be switched on and off. In microorganisms, creating these circuits requires the insertion or modification of multiple genes that regulate one another.

    Cutting multiple genes will also be useful for human therapies, says George Daley, a stem-cell biologist at Harvard Medical School, because many diseases with a genetic component involve more than one gene.

    Nature doi:10.1038/nature.2015.18525

    See the full article here .

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    Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions. Nature also provides rapid, authoritative, insightful and arresting news and interpretation of topical and coming trends affecting science, scientists and the wider public.

  • richardmitnick 2:33 pm on September 25, 2015 Permalink | Reply
    Tags: , , , Genetics,   

    From MIT: “New system for human genome editing has potential to increase power and precision of DNA engineering” 

    MIT News

    September 25, 2015
    Broad Institute

    CRISPR systems are found in many different bacterial species, and have evolved to protect host cells against infection by viruses. Image courtesy of Broad Institute/Science Photo Images

    CRISPR-Cpf1 offers simpler approach to editing DNA; technology could disrupt scientific and commercial landscape.

    A team including the scientist who first harnessed the CRISPR-Cas9 system for mammalian genome editing has now identified a different CRISPR system with the potential for even simpler and more precise genome engineering.

    In a study published today in Cell, Feng Zhang and his colleagues at the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT, with co-authors Eugene Koonin at the National Institutes of Health, Aviv Regev of the Broad Institute and the MIT Department of Biology, and John van der Oost at Wageningen University, describe the unexpected biological features of this new system and demonstrate that it can be engineered to edit the genomes of human cells.

    “This has dramatic potential to advance genetic engineering,” says Eric Lander, director of the Broad Institute. “The paper not only reveals the function of a previously uncharacterized CRISPR system, but also shows that Cpf1 can be harnessed for human genome editing and has remarkable and powerful features. The Cpf1 system represents a new generation of genome editing technology.”

    CRISPR sequences were first described in 1987, and their natural biological function was initially described in 2010 and 2011. The application of the CRISPR-Cas9 system for mammalian genome editing was first reported in 2013, by Zhang and separately by George Church at Harvard University.

    In the new study, Zhang and his collaborators searched through hundreds of CRISPR systems in different types of bacteria, searching for enzymes with useful properties that could be engineered for use in human cells. Two promising candidates were the Cpf1 enzymes from bacterial species Acidaminococcus and Lachnospiraceae, which Zhang and his colleagues then showed can target genomic loci in human cells.

    “We were thrilled to discover completely different CRISPR enzymes that can be harnessed for advancing research and human health,” says Zhang, the W.M. Keck Assistant Professor in Biomedical Engineering in MIT’s Department of Brain and Cognitive Sciences.

    The newly described Cpf1 system differs in several important ways from the previously described Cas9, with significant implications for research and therapeutics, as well as for business and intellectual property:

    First: In its natural form, the DNA-cutting enzyme Cas9 forms a complex with two small RNAs, both of which are required for the cutting activity. The Cpf1 system is simpler in that it requires only a single RNA. The Cpf1 enzyme is also smaller than the standard SpCas9, making it easier to deliver into cells and tissues.

    Second, and perhaps most significantly: Cpf1 cuts DNA in a different manner than Cas9. When the Cas9 complex cuts DNA, it cuts both strands at the same place, leaving “blunt ends” that often undergo mutations as they are rejoined. With the Cpf1 complex the cuts in the two strands are offset, leaving short overhangs on the exposed ends. This is expected to help with precise insertion, allowing researchers to integrate a piece of DNA more efficiently and accurately.

    Third: Cpf1 cuts far away from the recognition site, meaning that even if the targeted gene becomes mutated at the cut site, it can likely still be recut, allowing multiple opportunities for correct editing to occur.

    Fourth: The Cpf1 system provides new flexibility in choosing target sites. Like Cas9, the Cpf1 complex must first attach to a short sequence known as a PAM, and targets must be chosen that are adjacent to naturally occurring PAM sequences. The Cpf1 complex recognizes very different PAM sequences from those of Cas9. This could be an advantage in targeting some genomes, such as in the malaria parasite as well as in humans.

    “The unexpected properties of Cpf1 and more precise editing open the door to all sorts of applications, including in cancer research,” says Levi Garraway, an institute member of the Broad Institute, and the inaugural director of the Joint Center for Cancer Precision Medicine at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and the Broad Institute. Garraway was not involved in the research.

    An open approach to empower research

    Zhang, along with the Broad Institute and MIT, plan to share the Cpf1 system widely. As with earlier Cas9 tools, these groups will make this technology freely available for academic research via the Zhang lab’s page on the plasmid-sharing website Addgene, through which the Zhang lab has already shared Cas9 reagents more than 23,000 times with researchers worldwide to accelerate research. The Zhang lab also offers free online tools and resources for researchers through its website.

    The Broad Institute and MIT plan to offer nonexclusive licenses to enable commercial tool and service providers to add this enzyme to their CRISPR pipeline and services, further ensuring availability of this new enzyme to empower research. These groups plan to offer licenses that best support rapid and safe development for appropriate and important therapeutic uses.

    “We are committed to making the CRISPR-Cpf1 technology widely accessible,” Zhang says. “Our goal is to develop tools that can accelerate research and eventually lead to new therapeutic applications. We see much more to come, even beyond Cpf1 and Cas9, with other enzymes that may be repurposed for further genome editing advances.”

    See the full article here .

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    The mission of MIT is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the MIT community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

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