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  • richardmitnick 8:45 am on May 19, 2016 Permalink | Reply
    Tags: , Genetics, Mapping gene networks to better understand disease, , Swiss Institute of Bioinformatics (SIB), University of Lausanne   

    From Science Node: “Mapping gene networks to better understand disease” 

    Science Node bloc
    Science Node

    18 May, 2016
    Phoebe Baldwin

    Lung cancer cells invade surrounding tissues. Image courtesy Scott Wilkinson and Adam Marcus.

    The risk of a person developing a complex disease such as cancer is influenced by their genes. Advances in genome-sequencing technologies have enabled researchers to compare the genetic variations between people with a given condition, and people without. However, the mechanisms by which these genetic variations impact upon disease processes remain largely unknown.

    Research spearheaded by the University of Lausanne and the Swiss Institute of Bioinformatics (SIB) used innovative software to construct gene network maps that will increase understanding of how diseases start and progress. The findings were recently published* in Nature Methods.

    The researchers used data from the Functional Annotation of the Mammalian Genome (FANTOM) consortium. They examined almost 400 different human cell and tissue types — the most ever analyzed at one time — to determine the networks in which genes interact for a given disorder. To analyze this data they developed a new software tool called Magnum, which they have made freely downloadable.

    Using Magnum, the team was able to map networks of interacting genes with unprecedented resolution. Then, using genetic associations from public data, the researchers were able to relate the genes to 37 different psychiatric, neurodegenerative, and immune-related diseases.

    Their results showed that genes that are associated with a given disorder tend to cluster in groups. In this way they are connected in networks, and specifically in networks of tissues that are relevant for that disease.

    “What I hoped we would see was enrichment in neural tissues for psychiatric diseases and so forth, as has been observed in other studies that looked at gene expression,” says project leader Daniel Marbach. “Our results turned out so fine-grained, that even within the different neural tissues or immune cells, the most relevant ones came up. That was surprising to everybody.”

    In cases of schizophrenia, for example, the strongest clustering of disease-associated genes was observed in networks of brain tissues and in structures that are known to be targeted by current medical treatments.

    The network-based approach is promising because of this clustering of genes in relevant tissues. Each network acts as a ‘control system’ for the cells or tissues by outlining hundreds of thousands of regulatory interactions among genes.

    “We propagate information in these networks about diseases,” says Marbach. “If we have one diseased gene that interacts with another gene, then that other gene has an increased likelihood of being involved in the same disease process.”

    Studies like this could drive progress toward better diagnostic tests and targeted treatments that will be more successful and have fewer side effects. Observing individual genes and groups of interacting genes further could give a better understanding of disease processes and mechanisms.

    “In the future we would like to identify specific pathways or disease mechanisms in these tissues,” says Marbach. “It was good to see the known biology repeated in a new way, and add new hypotheses for some diseases that another cell type or tissue may be involved.”

    *Science paper:
    Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases

    See the full article here .

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  • richardmitnick 4:40 pm on May 10, 2016 Permalink | Reply
    Tags: , Genetics, , New approach to genetic analysis yields markers linked to complex diseases   

    From MIT: “New approach to genetic analysis yields markers linked to complex diseases” 

    MIT News
    MIT News
    MIT Widget

    May 10, 2016
    Anne Trafton

    “This approach overcomes a major hurdle in the human genetics field and addresses an important question surrounding the hidden heritability of many complex traits,” Laurie Boyer says. Image: Christine Daniloff/MIT

    Study identifies new gene variants that may be targets for treating arrhythmia.

    Many diseases, such as cancer, diabetes, and schizophrenia, tend to be passed down through families. After researchers sequenced the human genome about 15 years ago, they had high hopes that this trove of information would reveal the genes that underlie these strongly heritable diseases.

    However, around 2010, scientists began to realize that this wasn’t panning out. For one, there just weren’t enough patients: In order to unearth a statistically significant genetic marker, researchers would need groups of patients much larger than what they had been able to assemble so far. Furthermore, many of the variants that these studies turned up were found outside the regions of DNA that encode proteins, making it much more difficult to figure out how they might cause disease.

    A new study* from MIT addresses both of those problems. By combining information on gene-disease associations with maps of chemical modifications known as epigenomic marks, which control what genes are turned on, the researchers were able to identify additional genetic contributors to a heritable cardiac disorder that makes people more susceptible to heart failure.

    “This approach overcomes a major hurdle in the human genetics field and addresses an important question surrounding the hidden heritability of many complex traits,” says Laurie Boyer, the Irwin and Helen Sizer Career Development Associate Professor of Biology and Biological Engineering at MIT and one of the senior authors of the study.

    This strategy could also shed light on many other inherited diseases, the researchers say.

    “The exciting part is that we’ve applied this to one trait in one tissue, but we can apply this now to basically every disease,” says Xinchen Wang, an MIT graduate student and the paper’s lead author. “The new direction for us now is to target some of the bigger diseases like cholesterol-related heart disease and Alzheimer’s.”

    Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory and of the Broad Institute, is also a senior author of the paper, which appears in the May 10 issue of the journal eLife.

    Finding patterns

    Since the human genome project was completed, scientists have compared the genetic make-up of thousands of people, in search of genetic differences associated with particular diseases. These studies, known as genome-wide association studies (GWAS), have revealed genetic markers linked with type 2 diabetes, Parkinson’s disease, obesity, and Crohn’s disease, among others.

    However, in order for a variant to be considered significant, it must meet stringent statistical criteria based on how frequently it appears in patients and how much of an effect it has on the disease. Until now, the only way to yield more significant “hits” for a given variant would be to double or triple the number of people in the studies, which is difficult and expensive.

    The MIT team took an alternative approach, which was to try to identify variants that don’t occur often enough to reach genome-wide significance in the smaller studies but still have an impact on a particular disease.

    “Below this genome-wide significance threshold lies a large number of markers that perhaps we should be paying attention to,” Kellis says. “If we can successfully prioritize new disease genes in these subthreshold loci, we can have a head start in developing new therapeutics that target these genes.”

    To test the usefulness of this strategy, the researchers focused on a cardiac trait known as the QT interval, which is a measure of how long it takes for electrical impulses to flow through the heart as it contracts. Variations in this interval are a risk factor for arrhythmia and heart failure, which is one of the leading causes of death in the United States.

    Genome-wide association studies had already yielded about 60 genetic markers linked with variations in QT interval length. The MIT team created a computer algorithm that first analyzes these known markers to discover common epigenomic properties among them, and then uses these properties to pick out subthreshold genetic markers with similar properties that make these markers likely contributors to the disease trait.

    This analysis revealed that many of the known, significant genetic variants were located in parts of the genome known as enhancers, which control gene activity from a distance. Enhancers where these variants were found were also active specifically in heart tissue, tended to be located in DNA regions that are more likely to be regulatory, and were found in regions that are similar across primate species.

    The researchers then analyzed the variants that were only weakly associated with QT interval and found approximately 60 additional locations that shared most of these properties, potentially doubling the number of candidate regions previously identified using genetic evidence alone.

    Next, the researchers sought to predict the target genes that these genetic variants affect. To do so, they analyzed models of the three-dimensional structure of chromosomes to predict the long-distance contacts between enhancer regions harboring subthreshold variants and their potential target genes. They selected about two dozen of those genes for further study, and from their own experiments combined with an analysis of previous gene knockout studies, they found that many of the predicted new target genes did have an effect on the heart’s ability to conduct electrical impulses.

    “This is the smoking gun we were looking for,” Kellis says. “We now have genetic evidence from humans, epigenomic evidence from heart cells, and experimental data from mice, together showing that the genetic differences in subthreshold enhancers influence heart function.”

    Skipping ahead

    Boyer’s lab now plans to apply this approach to learning more about congenital heart defects.

    “We know very little about the genetic etiology of congenital heart defects. Every 15 minutes a baby is born with a congenital heart defect, and it’s a devastating set of defects,” she says. “We could now go back to some of these genomic and epigenomic studies to improve our understanding of the biology of these different defects.”

    This approach developed by the MIT team is general and should allow researchers working on many traits to identify genetic markers that are invisible when using genome-wide association studies alone. This can speed up the development of new therapies, especially for rare diseases, where gathering sufficiently large groups of patients can be very difficult and sometimes impossible.

    “Instead of waiting for years until subthreshold variants are elucidated with genetics, we can skip ahead and begin characterizing the prioritized regions and genes immediately,” Boyer says.

    “We expect that an expanded set of candidate drug targets can shorten the path to new therapeutics by decades for many devastating disorders, and help translate these insights into tangible improvements in human health,” Kellis says.

    The research was funded by the National Institutes of Health and the National Health, Lung, and Blood Institute Bench to Bassinet Program.

    Other institutions contributing to this study include Massachusetts General Hospital, and the Hubrecht Institute and the University of Groningen, both in the Netherlands.

    *Science paper:
    Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures in eLife

    See the full article here .

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  • richardmitnick 8:20 am on March 31, 2016 Permalink | Reply
    Tags: , , Genetics,   

    From AAAS: “Cause of rare immune disease identified” 



    Mar. 30, 2016
    Mitch Leslie

    A newly discovered disease found in a Belgian family may cause illness by inappropriately activating the inflammasome, a cellular structure that triggers inflammation. Chris Bickel/Science

    The Belgian family had puzzled doctors for more than a decade. Beginning when they were children, some members were prone to bouts of fever that could last for months. Their muscles and joints ached, their blood vessels were inflamed, and their skin erupted with sores that ranged from severe acne to abscesses and ulcers. One patient’s heart was so badly damaged that he needed a transplant at the age of 20.

    Now, researchers have figured out why the family members became ill, revealing that they suffer from a previously undiscovered genetic disease that unleashes a protein that normally helps protect us from microbes. Armed with the findings, doctors might be able to recognize other people with similar symptoms who have gone undiagnosed and offer treatment. In addition, the researchers say, the results might provide insight into more common diseases such as inflammatory bowel disease, where inflammation is out of control.

    “The paper beautifully works out the biochemistry” of how the mutation that causes the new disease alters a key immune protein, says geneticist Daniel Kastner of the National Human Genome Research Institute in Bethesda, Maryland, who wasn’t connected to the research.

    Scientists have already identified several rare but painful diseases in which the immune system triggers inappropriate inflammation in various parts of the body. These conditions differ from autoimmune diseases like rheumatoid arthritis and type I diabetes because a different branch of the immune system, which includes the body’s first responders to foreign invaders, malfunctions. Some of the Belgian family’s symptoms resembled the symptoms of one of these so-called autoinflammatory diseases, familial Mediterranean fever (FMF), but they were much worse. In FMF, for instance, fever lasts for a few days, not months.

    FMF results from mutations in the gene for pyrin, a protein inside many immune cells that detects infections by certain microbes. One attempt to track down the genetic flaw in the Belgian sufferers suggested that they could carry a defect in the same gene, but researchers dismissed the possibility because their symptoms were so different from those in people with FMF, says immunologist Seth Masters of the Walter and Eliza Hall Institute of Medical Research in Parkville, Australia, a co-author on the new paper. “It really didn’t look like the same disease.”

    Yet when Masters and colleagues sequenced the DNA of the Belgian family, they found a mutation in the gene for pyrin. It’s in a different location than in most people with FMF, the team reports today in Science Translational Medicine. After searching disease databases and hearing from other doctors who had patients with the similar symptoms, the researchers identified three other families in Lebanon, France, and the United Kingdom that had the same mutation. They’ve named the resulting disease pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND).

    Although the same gene is mutated in people with FMF, the type and severity of the symptoms confirm that PAAND is a unique disease, Kastner says. “It’s not FMF. Period.” It’s rare for different mutations in the same gene to cause distinct diseases, but PAAND and FMF are not the only examples, says medical geneticist Wayne Grody of the University of California, Los Angeles (UCLA), who wasn’t connected to the study. He notes, for instance, that mutations in the CFTR gene can trigger the potentially lethal disease cystic fibrosis or a milder illness that results in male infertility.

    Masters and colleagues further determined how the mutation in PAAND patients causes pyrin to go awry. When pyrin senses toxins released by some kinds of bacteria, it spurs formation of a structure called the inflammasome that in turn triggers inflammation. To prevent pyrin from switching on prematurely, cells typically shield it with another protein until they are in trouble. But the scientists found that this shield falls off the version of pyrin that the Belgian family produced, resulting in an overactive molecule. “In effect you take away the brake,” says co-author Adrian Liston, an immunologist at the University of Leuven in Belgium.

    What makes the paper stand out, says Grody, is the team’s thorough investigation. “They really have a mechanism—we don’t have anything like that to explain FMF,” he says. The work also points to a potential treatment, a drug that blocks an inflammation-promoting molecule that was abundant in the patients. When the researchers treated one member of the Belgian family with the drug, “all the signs of disease disappeared within a couple of weeks,” Liston says. “It was really quite remarkable.” The scientists now plan to launch a clinical trial of the drug in more PAAND patients. Masters and Liston say that the results could also help researchers better understand the role of inflammation in non–auto-inflammatory illnesses, including Alzheimer’s disease and inflammatory bowel disease.

    The study might provide more immediate benefits for some people as well. FMF is relatively common for an autoinflammatory disease, but even in the Mediterranean region only about one in 200 to one in 1000 people suffer from it. Although PAAND isn’t likely to be prevalent, researchers think that more patients are waiting for a diagnosis. Large numbers of people with the disease could live in populous countries such as India and China, Masters says. Grody and his colleagues at the FMF clinic at UCLA will be on the lookout for new cases. “I’m certain there are other families out there,” he says.

    Research Article

    Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

    Science team:

    Seth L. Masters1,2,*, Vasiliki Lagou3,4,5,†, Isabelle Jéru6,7,8,†, Paul J. Baker1,2,†, Lien Van Eyck4,5, David A. Parry9, Dylan Lawless10, Dominic De Nardo1,2, Josselyn E. Garcia-Perez4,5, Laura F. Dagley1,2,11, Caroline L. Holley12, James Dooley4,5, Fiona Moghaddas1,2, Emanuela Pasciuto4,5, Pierre-Yves Jeandel13, Raf Sciot14,15, Dena Lyras16, Andrew I. Webb2,11, Sandra E. Nicholson1,2, Lien De Somer15, Erika van Nieuwenhove4,5,15, Julia Ruuth-Praz7,8, Bruno Copin8, Emmanuelle Cochet8, Myrna Medlej-Hashim17, Andre Megarbane18, Kate Schroder12, Sinisa Savic19,20, An Goris3, Serge Amselem6,7,8, Carine Wouters4,15,*,‡ and Adrian Liston4,5,*,‡


    1Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
    2Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
    3Department of Neurosciences, KU Leuven, Leuven 3000, Belgium.
    4Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.
    5Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.
    6INSERM, UMR S933, Paris F-75012, France.
    7Université Pierre et Marie Curie–Paris, UMR S933, Paris F-75012, France.
    8Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d’Embryologie médicales, Paris F-75012, France.
    9Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh LS7 4SA, UK.
    10Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Wellcome Trust Brenner Building, Saint James’s University Hospital, Leeds LS7 4SA, UK.
    11Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
    12Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
    13Département de Médecine Interne, Hôpital Archet 1, Université Nice Sophia-Antipolis, 06202 Nice, France.
    14Department of Pathology, KU Leuven, Leuven 3000, Belgium.
    15University Hospitals Leuven, Leuven 3000, Belgium.
    16Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia.
    17Department of Life and Earth Sciences, Faculty of Sciences II, Lebanese University, Beirut 1102 2801, Lebanon.
    18Al-Jawhara Center, Arabian Gulf University, Manama 26671, Bahrain.
    19Department of Allergy and Clinical Immunology, Saint James’s University Hospital, Leeds LS9 7TF, UK.
    20National Institute for Health Research–Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Rheumatic and Musculoskeletal Medicine, Wellcome Trust Brenner Building, Saint James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK.

    ↵*Corresponding author. E-mail: masters@wehi.edu.au (S.L.M.); carine.wouters@uzleuven.be (C.W.); adrian.liston@vib.be (A.L.)

    ↵† These authors contributed equally as second authors.

    ↵‡ These authors contributed equally as co-last authors.

    See the full article here .

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  • richardmitnick 8:35 am on March 25, 2016 Permalink | Reply
    Tags: Biomedicine, Genetics,   

    From MIT Tech Review: “Genome Discovery Holds Key to Designer Organisms” 

    MIT Technology Review
    MIT Technology Review

    A cluster of synthetic cells with the fewest genes needed to grow and divide. In cultures, these so-called JCVI-syn.30 cells form a variety of structures.

    March 24, 2016
    Karen Weintraub

    For more than 20 years, J. Craig Venter has been trying to make a cell with the fewest possible genes in the hope that the stripped-down cell would tell us something about the necessities of life.

    In a paper published today in Science, Venter and his team announced that they’ve made a big step toward that goal—and found some surprises along the way.

    The parts list of basic life is one-third longer than scientists had thought, said Venter, who is known for winning the race to map the human genome. And it depends much more on context than they had realized.

    To get their synthetic cell to replicate and grow fast enough to use in the lab took 473 genes, 149 of which have an unclear function.

    Venter, founder, chairman, and CEO of the J. Craig Venter Institute, which led the research, said he started his hunt for genes assuming he’d be able to pinpoint the single or few genes responsible for this or that trait. Instead, he said at a Wednesday news conference, he’s learned that functions, diseases, and basic existence are dependent on the interplay of many genes.

    “Life is much more like a symphony orchestra than a piccolo player.”

    Most of the applications for this synthetic cell are years or decades off, but it is an important scientific advance.

    “This is really useful for giving you an insight to what’s really the minimal parts list it takes to keep an organism going,” said Jef Boeke, director of the Institute for Systems Genetics at New York University’s Langone Medical Center. “There’s tremendous value in terms of understanding the basic wiring of a cell.”

    The synthetic cell, dubbed JCVI-syn3.0, also has potential applications for advancing medicine, nutrition, agriculture, biofuels, and biochemicals, said Dan Gibson, vice president of DNA Technology for Synthetic Genomics, a company started by Venter to commercialize genetic advances, which was also involved in the new work.

    “Our long-term vision is to have the ability to design and build synthetic organisms on demand that perform specific functions that are programmed into the cellular genome,” Gibson wrote in a follow-up e-mail. Synthetic cells with a minimal parts list “would be devoting maximal energy to their purpose—they would simply grow and divide and make the product that was programmed into the cell.”

    When asked for specific examples of applications, Venter mentioned synthetic antibiotics, and an ongoing collaboration between Synthetic Genomics and United Therapeutics to grow transplantable organs in pigs. Humans cannot use pig hearts, lungs, or livers because of the risk of rejection and diseases, but the companies are trying to engineer changes into the pig genome to make that possible.

    Harvard University geneticist George Church prefers to edit functions into existing genomes, rather than build up from the bottom. Church said JCVI-syn3.0 is a significant academic achievement, but he doesn’t see much practical use for it in the short-term.

    “I don’t want to be impolite,” Church said. “I think it’s a lovely thing they did.”

    As a scientific feat, Church said he was more impressed with the group’s earlier work done more than five years ago, which showed that the team could synthesize a much larger genome that is much closer to the complexity needed for real-world applications.

    Venter said the work shows how far we still have to go to understand the genomes of even the simplest creatures.

    “The fact that this has taken a highly dedicated, extremely competent team with a Nobel laureate, three National Academy of Science members, and some brilliant junior scientists this long to get this far tells us a lot about the fundamentals of life and says the next phases are not going to be trivial,” he said.

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  • richardmitnick 5:16 pm on March 23, 2016 Permalink | Reply
    Tags: , , Genetics,   

    From LBL: “Unlocking the Secrets of Gene Expression” 

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    Berkeley Lab

    March 23, 2016
    Julie Chao (510) 486-6491

    Your DNA governs more than just what color your eyes are and whether you can curl your tongue. Your genes contain instructions for making all your proteins, which your cells constantly need to keep you alive. But some key aspects of how that process works at the molecular level have been a bit of a mystery—until now.

    Using cryo-electron microscopy (cryo-EM), Lawrence Berkeley National Laboratory (Berkeley Lab) scientist Eva Nogales and her team have made a significant breakthrough in our understanding of how our molecular machinery finds the right DNA to copy, showing with unprecedented detail the role of a powerhouse transcription factor known as TFIID.

    Berkeley Lab scientists Eva Nogales and Robert Louder at the electron microscope. (Credit: Roy Kaltschmidt/Berkeley Lab)

    This finding is important as it paves the way for scientists to understand and treat a host of malignancies. “Understanding this regulatory process in the cell is the only way to manipulate it or fix it when it goes bad,” said Nogales. “Gene expression is at the heart of many essential biological processes, from embryonic development to cancer. One day we’ll be able to manipulate these fundamental mechanisms, either to correct for expression of genes that should or should not be present or to take care of malignant states where the process has gone out of control.”

    Their study has been published online in the journal Nature in an article titled, Structure of promoter-bound TFIID and insight into human PIC assembly. The lead author is Robert Louder, a biophysics graduate student in Nogales’ lab, and other authors are Yuan He, José Ramón López-Blanco, Jie Fang, and Pablo Chacón.

    Nogales, a biophysicist who also has appointments at Howard Hughes Medical Institute and UC Berkeley, has been studying gene expression for 18 years. While she and her team have made several significant findings in recent years, she calls this the biggest breakthrough so far. “This is something that will go in biochemistry textbooks,” she said. “We now have the structure of the whole protein organization that is formed at the beginning of every gene. This is something no one has come close to doing because it is really very difficult to study by traditional methodologies.”

    Cryo-EM model of the human transcription pre-initiation complex. (Credit: Robert Louder/Berkeley Lab )

    How genetic information flows in living organisms is referred to as the “central dogma of molecular biology.” Cells are constantly turning genes on and off in response to what’s happening in their environment, and to do that, the cell uses its DNA, the big library of genetic blueprints, finds the correct section, and makes a copy in the form of messenger RNA; the mRNA is then used to produce the needed protein.

    The problem with this “library” is that it has no page numbers or table of contents. However, markers are present in the form of specific DNA sequences (called core promoter motifs) to indicate where a gene starts and ends. So how does the polymerase, the enzyme that carries out the transcription, know where to start? “DNA is a huge, huge molecule. Out of this soup, you have to find where this gene starts, so the polymerase knows where to start copying,” Nogales said. “This transcription factor, TFIID, is the protein complex that does exactly that, by recognizing and binding to DNA core promoter regions.”

    What Nogales and her team have been able to do is to visualize, with unprecedented detail, TFIID bound to DNA as it recognizes the start, or promoter, region of a gene. They have also found how it serves as a sort of landing pad for all the molecular machinery that needs to assemble at this position—this is called the transcription pre-initiation complex (PIC). This PIC ultimately positions the polymerase so it can start transcribing.

    TFIID (blue) as it contacts the DNA and recruits the polymerase (grey) for gene transcription. The start of the gene is shown with a flash of light. (Credit: Eva Nogales/Berkeley Lab)

    “TFIID has to do not only the binding of the DNA, recruitment, and serving as landing pad, it has to somehow do all that differently for different genes at any given point in the life of the organism,” Nogales said.

    Added Louder: “We have generated the first ever structural model of the full human TFIID-based PIC. Our model yields novel insights into human PIC assembly, including the role of TFIID in recruiting other components of the PIC to the promoter DNA and how the long observed conformational flexibility of TFIID plays a role in the regulation of transcription initiation.”

    Proteins have traditionally been studied using X-ray crystallography, but that technique has not been possible for this kind of research. “TFIID has not been accessible to protein crystallography because there’s not enough material to crystallize it, it has very flexible elements, and it is of a huge size,” Nogales said. “All of those things we can overcome through cryo-EM.”

    Cryo-EM, in which samples are imaged at cryogenic temperatures without need for dyes or fixatives, has been used since the 1980s in structural biology. With extensive computational analysis of the images researchers are able to obtain three-dimensional structures. However, cryo-EM has undergone a revolution in the last few years with the advent of new detectors—developed, in fact, at Berkeley Lab—that improve resolution and reduce the amount of data needed by up to a hundred-fold.

    “Many biological systems we had thought were impossible to study at high resolution have become accessible,” she said. “Now the resolution allows us to get atomic details. This is an area in which Berkeley Lab has been one of the leaders.”

    While this study has revealed important new insights into gene expression, Nogales notes that much work remains to be done. Next she plans to investigate how TFIID is able to recognize different sequences for different gene types and also how it is regulated by cofactors and activators.

    “We are just at the beginning,” she said. “This complex, TFIID, is very, very critical. Now we have broken barriers in the sense that we can start generating atomic models and get into details of how DNA is being bound.”

    This research was supported by the National Institutes of Health’s National Institute of General Medical Sciences and by the Spanish Ministry of Economy and Competitiveness. Computational work was carried out at the National Energy Research Scientific Computing Center (NERSC), a DOE Office of Science User Facility hosted at Berkeley Lab. Nogales is a Senior Faculty Scientist in Berkeley Lab’s Molecular Biophysics and Integrated Bioimaging Division; additional information on her lab can be found here.

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  • richardmitnick 1:42 pm on March 22, 2016 Permalink | Reply
    Tags: , , Genetics, ,   

    From UNSW: “A golden age of ancient DNA science begins” 

    U NSW bloc

    University of New South Wales

    22 Mar 2016
    Darren Curnoe

    A reconstruction of a male our evolutionary cousin the Neanderthals (Modified from an image by Cicero Moraes). Wikimedia Commons, CC BY-SA

    OPINION: If I had taken a straw poll among anthropologists 10 years ago asking them how far genetic research would come in the next decade, I doubt anyone would have come close to predicting the big impact fossil DNA work would come to have.

    Back then, this nascent field was bogged down with fundamental issues like distinguishing authentic DNA from contamination. Simply recovering enough nuclear DNA to say anything sensible at all about human origins would have been a really big achievement.

    But following some remarkable technical developments in that time, including next generation sequencing, ancient DNA research is beginning to come of age.

    And it’s no exaggeration to say that it’s dramatically rewriting our understanding of the human evolutionary story and, unexpectedly, resolving some old, seemingly intractable, questions along the way.

    I say ‘beginning’ because despite the remarkable findings over the last half decade or so, many of which I have written about before, ancient DNA, particularly fossil genome research, has really only just begun.

    But, boy, what start!

    Two studies out last week in the journals Science and Nature are characteristic of the coming of age of ancient DNA studies; I’ll return to them shortly.

    As I see it – from the viewpoint of someone who studies the fossils – this field is beginning to provide answers to some big questions we’ve been wrestling with for a long, long, time.

    Here are three big issues which I think geneticists are making headway on, following decades of stalled progress by fossil specialists.

    1. There’s been a shift from merely documenting the occurrence of interbreeding between modern humans and archaic groups, like the Neanderthals and Denisovans, to a focus on the circumstances surrounding it and its consequences for living people.

    A few years back we fossil-jocks couldn’t agree about whether interbreeding had actually occurred or not. The case now seems to be closed thanks to the geneticists.

    Interbreeding occurred, but it wasn’t terribly common. Around 2 per cent of the genome of non-African people was inherited from Neanderthals, with slightly more DNA in Indigenous Oceanic Southeast Asians, New Guineans and Australians coming from the mysterious Denisovans (on top of their Neanderthal inheritance).

    Even among some living African populations, there is evidence for DNA inherited from an archaic species living on that continent perhaps as late as 30 thousand years ago.

    I suspect there will be more evidence found in the future, from other, perhaps as yet unknown, archaic species.

    One of the new studies – led by Benjamin Vernot from the University of Washington – examined 35 new genomes sequenced from people living in 11 locations in the Bismarck Archipelago of New Guinea to get a better handle on gene sharing with our archaic cousins.

    They confirmed evidence for ancient gene flow with the Neanderthals and have better characterised mating with the mysterious Denisovans, by comparing their new genomes with around 1,500 other human samples.

    The New Guinean samples showed between 1.9 and 3.4 per cent of their genomes to be derived from the Deniosvans.

    They also showed that a second ‘pulse’ of interbreeding is seen among living East Asians, Europeans and South Asians that wasn’t shared with New Guineans.

    There were seemingly three separate interbreeding events with the Neanderthals: one with the ancestors of New Guineans and Australians, one with early East Asians and one with the ancestors of South Asians and Europeans.

    Geneticists have now turned their attention to the specific genes that have been inherited by living humans from our archaic cousins and their consequences for understanding human adaptations and disease.

    I’ve looked at some of these previously, like those associated with the human immune system and high altitude adaptation.

    The really exciting area to be explored in the future is whether genes associated with features of the skeleton can be identified, helping us to make a direct connection with the physical changes documented in the fossil record and to understand how and why such changes came about.

    2. Ancient DNA is finally placing a framework around the vexed question, ‘how can we pick a new species from among the fossils’?

    For decades, anthropologists have been locking horns over how many species there might be in the human evolutionary tree; with estimates presently ranging from 5 to more than 25 species.

    So far, we’ve lacked an independent, objective, way to test our ideas. But, surprisingly, this is now emerging from comparisons of the human genome with those of our archaic cousins.

    For example, for over 100 years anthropologists have argued about whether the Neanderthals are a separate species to modern humans, or merely a sub-species of our kind.

    DNA has now given us an answer, and it should satisfy even the more hard nosed of anthropologists; although, experience tells me some of my colleagues will go the grave believing otherwise.

    Neanderthal, Denisovan and other archaic DNA is found unevenly throughout the human genome, occurring in hotspots, with vast deserts separating large stretches of archaic genes.

    One example is the human X-chromosome which is largely free of archaic DNA. This indicates that natural selection weeded out archaic genes, and also that male hybrid offspring of archaic and modern human matings were probably infertile.

    Anyone with a passing interest in the species questions will recognise immediately the importance of such a finding: humans and Neanderthals were different species, even if one applies the very strict criterion of ‘interbreeding’, so widely assumed to be indicative of species differences.

    Now, most anthropologists have considered the Neanderthals to be the closest extinct relative we humans have, regardless of their species status. Yet, DNA work shows they were highly biologically distinct from us, in accordance, as I see it, with their unusual physical features.

    To me, this indicates we should be prepared to recognise and accommodate many more species in the human tree, even after humans and Neanderthal had split.

    You might like to read my article about the complex question of species and their recognition in human evolution studies.

    3. Fossil DNA is now sorting out evolutionary relationships among human species.

    The second study from last week, led by Matthias Meyer of the Max Planck Institute for Evolutionary Anthropology, recovered nuclear DNA from two specimens from the Spanish fossil site of Sima de Los Huesos (the ‘pit of bones’).

    These fossils are at least 430 thousand years old, and the new work builds on research by the team published last year where they were able to recover the much smaller and less informative mitochondrial genome from a fossil from the site.

    The mitochondrial DNA was found to be identical to the Deniosvans, but the new nuclear sequences are related to Neanderthals.

    So, the Sima de Los Huesos specimens are either very early Neanderthals or the ancestors of the Neanderthals; retaining the mitochondrial genome of their Denisovan ancestors, or perhaps even acquiring it through interbreeding.

    The work confirms nicely what some anthropologists have thought about the Sima de Los Huesos fossils from their anatomy.

    It also shows that the common ancestor of Neanderthals and modern humans lived more than 430 thousand years ago; in fact, the molecular clock in this new research indicates a split somewhere in the range of 550-765 thousand years ago.

    This means that the immediate ancestors of living humans evolved for at least 600 thousand years, probably longer, separately from the Neanderthals.

    I take away from this that it takes about 600 thousand years for hybrid sterility to kick in in humans. And, remembering that hybrid sterility is at the end of the process of species formation, we should expect there to be many more, short-lived, species in the human tree than we’ve recognised until now.

    Human evolution should be seen as a bush, with lot’s of twigs, rather than a thickly trunked tree, with only a small number of branches (species). I imagine diversity was the rule as we see in other living primates today.

    We modern humans were just one of many kinds of human, but oddly, the only one to persist today. Perhaps genomics might help us answer this mother of all mysteries in the not too distant future as well.

    See the full article here .

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  • richardmitnick 9:32 am on February 19, 2016 Permalink | Reply
    Tags: , Genetics,   

    From UCLA: “Study identifies specific gene network that promotes nervous system repair” 

    UCLA bloc


    February 18, 2016
    Mark Wheeler

    Whether or not nerve cells are able to regrow after injury depends on their location in the body. Injured nerve cells in the peripheral nervous system, such as those in the arms and legs, can recover and regrow, at least to some extent. But nerve cells in the central nervous system — the brain and spinal cord — can’t recover at all.

    Nerve cells

    A UCLA-led collaboration has identified a specific network of genes and a pattern of gene expression mice that promote repair in the peripheral nervous system in a mouse model. This network, the researchers found, does not exist in the central nervous system. The researchers also found a drug that can promote nerve regeneration in the central nervous system.

    The study appears in the online edition of the journal Neuron.

    Nerve cells throughout the body are responsible for transmitting and receiving electrical messages to cells and tissues in other organ systems. “We know this transmission of messages can be impaired by injury, and the recovery of nerve cells after injury largely depends on their location,” said Vijayendran Chandran, a project scientist in the department of neurology at UCLA and the study’s first author.

    “Understanding these molecular differences in injured nerve cells in the limbs, where regeneration happens, versus injured nerve cells in the spinal cord, where regeneration fails, would open up the possibility to design treatment to enhance neuron regeneration in the central nervous system after injury.”

    The researchers measured the response of gene regulation at the level of messenger RNA, or mRNA, in each instance of injury. Gene regulation is the process of turning genes on and off, ensuring that genes are expressed at the right times. Messenger RNA carries information from a gene that, in a long molecular cascade, ultimately tells a protein what to do.

    The researchers developed a unique set of algorithms to look at the interactions of various groups of genes and the order in which they were expressed.

    “That allowed us to find common patterns that correlated with regeneration in the peripheral nervous system, and within those patterns we were able to identify several genes not previously known that enhanced repair,” said Dr. Dan Geschwind, the study’s senior author and a professor of neurology, psychiatry and human genetics at UCLA.

    “But we did not find these patterns in the central nervous system. That was the major advance — identifying, in an unbiased way, the entire network of pathways turned on in the peripheral nervous system when it regenerates, key aspects of which are missing in the central nervous system.”

    Next, as a proof of principle that global patterns of gene expression could be used to screen for drugs that mimic the same pattern, the researchers used a publicly available database at the Broad Institute to look for such a drug. That led them to one called Ambroxol, which significantly enhanced central nervous system repair.

    “We’re excited about this study because there are a number of firsts that came out of it,” Geschwind said. “While we still have a long way to go from a mouse study to humans, we present a novel paradigm that has never been applied to the nervous system.”

    Other institutions involved in the research include the Broad Institute, Boston Children’s Hospital and Harvard Medical School, UC San Diego, Tel Aviv University and the University Hospital Heidelberg. Funding was provided by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the National Institutes of Health (R01 NS038253) and the Bertarelli Foundation.

    See the full article here .

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    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 4:50 pm on January 22, 2016 Permalink | Reply
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    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 Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

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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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