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Fernandez A.F.,University of Oviedo | Fraga M.F.,University of Oviedo | Fraga M.F.,National Center for Biotechnology
Epigenetics | Year: 2011

The physiological effects of the dietary polyphenol resveratrol are being extensively studied. Resveratrol has been proposed to promote healthy aging and to increase lifespan, primarily through the activation of the class III histone deacetylases (sirtuins). Although its positive effects are evident in yeast and mice, they still have to be confirmed in humans. The molecular mechanisms involved in the processes are not fully understood because resveratrol may have other targets than sirtuins and the direct activation of sirtuins by resveratrol is under debate. © 2011 Landes Bioscience. Source

News Article
Site: http://www.nature.com/nature/current_issue/

More than one million people have now had their genome sequenced, or its protein-coding regions (the exome). The hope is that this information can be shared and linked to phenotype — specifically, disease — and improve medical care. An obstacle is that only a small fraction of these data are publicly available. In an important step, we report this week the first publication from the Exome Aggregation Consortium (ExAC), which has generated the largest catalogue so far of variation in human protein-coding regions. It aggregates sequence data from some 60,000 people. Most importantly, it puts the information in a publicly accessible database that is already a crucial resource (http://exac.broadinstitute.org). There are challenges in sharing such data sets — the project scientists deserve credit for making this one open access. Its scale offers insight into rare genetic variation across populations. It identifies more than 7.4 million (mostly new) variants at high confidence, and documents rare mutations that independently emerged, providing the first estimate of the frequency of their recurrence. And it finds 3,230 genes that show nearly no cases of loss of function. More than two-thirds have not been linked to disease, which points to how much we have yet to understand. The study also raises concern about how genetic variants have been linked to rare disease. The average ExAC participant has some 54 variants previously classified as causal for a rare disorder; many show up at an implausibly high frequency, suggesting that they were incorrectly classified. The authors review evidence for 192 variants reported earlier to cause rare Mendelian disorders and found at a high frequency by ExAC, and uncover support for pathogenicity for only 9. The implications are broad: these variant data already guide diagnoses and treatment (see, for example, E. V. Minikel et al. Sci. Transl. Med. 8, 322ra9; 2016 and R. Walsh et al. Genet. Med. http://dx.doi.org/10.1038/gim.2016.90; 2016). These findings show that researchers and clinicians must carefully evaluate published results on rare genetic disorders. And it demonstrates the need to filter variants seen in sequence data, using the ExAC data set and other reference tools — a practice widely adopted in genomics. The ExAC project plans to grow over the next year to include 120,000 exome and 20,000 whole-genome sequences. It relies on the willingness of large research consortia to cooperate, and highlights the huge value of sharing, aggregation and harmonization of genomic data. This is also true for patient variants — there is a need for databases that provide greater confidence in variant interpretation, such as the US National Center for Biotechnology Information’s ClinVar database. Improving clinical genetics will need continued investment in such databases, more contributions from clinical labs, researchers and clinicians, expanding human genetic-reference panels and work to link these to phenotype data. This often involves re-contacting volunteers and donors; it will be trialled with an ExAC data subset where consents allow. More broadly, enabling the sharing of linked genetic and clinical data in ways that do not violate privacy requires fresh thinking in regulation and ethics. The US National Institutes of Health and the Global Alliance for Genomics and Health have begun to tackle this; others should follow. The ExAC study highlights the potential rewards.

News Article
Site: http://phys.org/biology-news/

A University of Cincinnati study highlights RNA-sequencing analysis on a pregnant insect, the beetle mimic cockroach, which primarily dwells in tropical rain forests. Credit: Emily Jennings The sequencing of the first genome involving a cockroach species may one day serve as a model system comparable to how research on mice can apply to humans. In this case, the model could hold new revelations about how stress during pregnancy could affect both the mother and her offspring. Emily Jennings, a University of Cincinnati doctoral student in the Department of Biological Sciences, will present a study using RNA-sequencing analysis on a pregnant insect at the annual national meeting of the Society for Integrative and Comparative Biology. The meeting takes place Jan. 3-7, in Portland, Oregon. The subject of the research does not involve the cockroach that sends us running for the bug spray when we find it in our home. The beetle mimic cockroach, Diploptera punctata, is much smaller and is not considered a pest around human habitats. Native to the Polynesian Islands, it primarily dwells in tropical forests. This is the first study of its kind to be performed on this particular insect. The study involved extracting Ribonucleic acid or RNA - found in the cells of all living organisms - to develop a transcriptome - the gene readouts in a cell - to examine what occurs during the different developmental stages of the cockroach pregnancy and to explore if those changes hold wider applications for other mammals. The four stages of the reproductive cycle included mated but not pregnant; pre-lactation pregnancy; early lactation pregnancy and late lactation pregnancy, along with a male-female comparison that revealed unique expressed genes corresponding to each stage. "When I started this project two-and-a-half years ago, we might have had a maximum of 80 sequenced genes for this animal," says Jennings. "Now, we've found as many as 11,000 possible genes. We're in the process of assigning functions, roles and names by comparing sequences to sequenced genomes, such as that of the fruit fly, stored in the database of the National Center for Biotechnology Information. "We're on the edge of creating an exciting new resource for examining how a mother nourishes her babies before birth, a process typically associated with mammals," says Jennings. Jennings explains that this particular cockroach generates a type of milky secretion that provides protein, carbohydrates and other necessary nutrients for the embryos - a process that is rather uncommon in insects but comparable with the placentas of pregnant mammals. The pregnancy lasts between 60-70 days while the pregnant cockroach expands and holds 15 developing embryos. The babies are born white, until their exoskeleton hardens and turns to the brown color of their species. Jennings' presentation on Jan. 7 will center on the gene expression that occurs during this process and if there are genes responsible for starting or stopping the procedure. The roaches have at least two reproductive cycles during their lifetime. It's believed their lifespan is between three-to-seven months. "Ultimately, our next step will be looking at how interaction between the mother and the embryos can be affected, so if the mother is stressed during pregnancy - such as being exposed to a toxin or being deprived of resources such as food and water - we want to see how that can affect development of the embryos," says Jennings. "This would be called the mother-offspring conflict, and one example would be how a pregnant human and her offspring are affected by gestational diabetes," explains Jennings. "This previously has not been studied in insects that give birth to babies that were nourished during pregnancy." Jennings adds that the housing and feeding of the insects also is considerably less expensive than traditional animal research models such as mice, a savings of hundreds of dollars compared with the care for just one mouse. "We have over 1,000 cockroaches in a fairly small space, an enormous population compared to what you can keep with mice," says Jennings. "The feeding regimen of the cockroaches is the cost of a large bag of dog food that can last for years." Explore further: Researcher wants to know if cockroaches turn genes off and on to protect their young

News Article | March 24, 2016
Site: http://motherboard.vice.com/

If synthetic biology has a rockstar, it’s Craig Venter, and he’s back with a new hit. Venter and his team say they’ve created one of the simplest organisms theoretically possible using a combination of genetic engineering techniques, in-lab DNA-synthesis, and trial-and-error. The work, published Thursday in Science, describes a self-replicating bacterium invented by Venter and his team that contains just 437 genes, a “genome smaller than that of any autonomously replicating cell found in nature,” according to the paper. The work sheds light on the function of the individual genes necessary to have life, and it also shows us just how little we actually know about specific gene functions. “We have long been interested in simplifying the genomic software of a bacterial cell by eliminating genes that are nonessential for cell growth under ideal conditions in the laboratory,” Venter wrote in the paper. “This facilitates the goal of achieving an understanding of the molecular and biological function of every gene that is essential for life.” A study published by the National Center for Biotechnology Information in 1995 suggested that a genome that coded the most basic lifeform would be roughly 256 genes. Venter said in a conference call with reporters that “everybody was off—by a third.” The team says that 149 of the genes have unknown functions, but were nonetheless necessary for the organism to grow and replicate. For comparison, E. Coli and other well-understood genes have roughly 5,000 genes. “We now know, in the end result, that 32 percent of the genes required for life in this most simple of all organisms are of unknown function,” Venter said. “If we don't understand the functions of a third of those genes—you know we're also involved in depth in analyzing the human genome with 20,000-some-odd genes, most of which we have no known function for. So I think these findings are very humbling in that regard.” So what does this all mean? Venter says his team and others will now work on identifying the purpose of some of the genes with unknown functions, and Daniel Gibson, a researcher who works at the J. Craig Venter Institute said that this work will ultimately lead to the creation of synthetic life with specific purposes, such as producing cheap biofuel and creating new medicines. “Our long-term vision has been to design and build synthetic organisms on demand, where you can add in specific functions and predict what the outcome is going to be,” Gibson said. You may remember Venter as one of the leaders of the Human Genome Project, or the first scientist to ever transfer a synthetic genome into a living cell and have it continue to function (the first synthetic life ever, many argue). He’s also friends with Elon Musk, with whom he casually talks about printing synthetic life on Mars to terraform the planet, and he’s cofounder of Human Longevity, which is dedicated to extending the human lifespan using genetics. These new findings make his more outlandish claims seem ever so slightly more attainable, but it’s important to recognize just how painstaking and slow this work was. Venter says he’s been working on the project off and on for 20 years, and that, essentially, the organism he’s dubbed JCBI Syn 3.0 was the result of some very sophisticated trial-and-error. At first, the team tried to model life using computer software alone, but found that when they actually went to synthesize the organism, it never worked. “Every one of our designs failed,” he said. And so the team took its original synthetic life, called SYN 1.0, and started knocking out and adding back in genes as necessary. The team found that it would regularly knock out a gene it thought to be “inessential,” only to find that, when they knocked out an analogous gene, the bacterium couldn’t survive. Venter likened it to a Boeing 747 plane—you can take out one engine and have it still fly, but if you take out both, the plane crashes. “That’s what happened over and over again, where we would have what appeared to be a non-essential component until we removed its counterpart,” he said. Only genes that were required for the bacterium to survive—not those that are required for it to thrive, such as specific growth genes—were included. Venter noted that, though this is a “minimal” bacterial genome, it is not necessarily the minimum, because other types of life may exist, and a couple of growth-related genes were kept in because it “had to grow at a sufficient pace to be a good experimental model.” “A typical experiment took three months, and so this study would have taken probably another five years if we didn’t insist on rapid growth,” he said. We’re still in the early days of synthetic biology, and it’s anyone’s guess when truly synthetic life will be used in an applied sense versus a lets-learn-more-about-the-basics-of-life sense, but increasingly impressive feats are being accomplished on a semi-yearly basis at this point. Venter created the first artificial life in 2010; in 2014, Floyd Romesberg of the Scripps Research Institute created synthetic life using DNA base pairs that are not found in nature; and genetic editing tools like CRISPR-Cas9 are being used in laboratories big and small to fundamentally alter DNA. These findings suggest that the definition of “life” is actively changing as we manipulate its code. It’s no surprise, then, that in the paper Venter regularly refers to the “genome” as “a piece of software.” “We view life as DNA software-driven,” Venter said. “And we're showing that by trying to understand that software, we're going to get better understandings of life.”

News Article
Site: http://phys.org/biology-news/

Starting from the four innermost letters and working to the outermost ring, this table shows shows which three-letter base sequence or codon encodes which amino acid. In the journal Angewandte Chemie International Ed., researchers from the US Department of Energy Joint Genome Institute (DOE JGI), a DOE Office of Science User Facility, and Yale University have discovered that microorganisms recognize more than one codon for the rare, genetically encoded amino acid selenocysteine. Credit: Wikimedia Commons A, C, G and T - stand in for the four chemical bases that store information in DNA. A sequence of these same four letters, repeating in a particular order, genetically defines an organism. Within the genome sequence are shorter, three-letter codons that represent one of the 20 regularly used amino acids, with three of the possible 64 three-letter codons reserved for stop signals. These amino acids are the building blocks of proteins that carry out a myriad of functions. For example, the amino acid alanine can be represented by the three-letter codon GCU and the amino acid cysteine by the three-letter codon UGU. In some organisms, the three-letter codon UGA, which normally signals the end of a protein-coding gene, is hijacked to code for a rare genetically encoded amino acid called selenocysteine. Published ahead online March 16, 2016 in the journal Angewandte Chemie International Ed., researchers from the U.S. Department of Energy Joint Genome Institute (DOE JGI), a DOE Office of Science User Facility, and Yale University have discovered that microorganisms recognize more than one codon for selenocysteine. The finding adds credence to recent studies indicating that an organism's genetic vocabulary is not as constrained as had been long held. The work is a follow-up to two 2014 publications; a Science paper by the JGI group finding that some organisms interpret the three "stop" codons which terminate translation to mean anything but. A synthetic biology experiment of the Yale group published in an Angewandte Chemie International Ed. paper revealed the astonishing fact that almost all codons in Escherichia coli could be replaced by selenocysteine. This posed the question whether the same phenomenon can also occur in nature. "Access to the tremendous resources at the JGI allowed us to quickly test challenging hypotheses generated from my research projects that have been supported over the long-term by DOE Basic Energy Sicences and the National Institutes of Health," said Dieter Soll, Sterling Professor of Molecular Biophysics and Biochemistry Professor of Chemistry at Yale, the lead author of the paper. Thus a fruitful collaboration resulted; the combined team scanned trillions of base pairs of public microbial genomes and unassembled metagenome data in the National Center for Biotechnology Information and the DOE JGI's Integrated Microbial Genomes (IMG) data management system to find stop codon reassignments in bacteria and bacteriophages. Delving into genomic data from uncultured microbes afforded researchers the opportunity to learn more about how microbes behave in their natural environments, which in turn provides information on their management of the various biogeochemical cycles that help maintain the Earth. From approximately 6.4 trillion bases of metagenomic sequence and 25,000 microbial genomes, the team identified several species that recognize the stop codons UAG and UAA, in addition to 10 sense codons, as acceptable variants for the selenocysteine codon UGA. The findings, the team reported, "opens our minds to the possible existence of other coding schemes... Overall our approach provides new evidence of a limited but unequivocal plasticity of the genetic code whose secrets still lie hidden in the majority of unsequenced organisms." This finding also illustrates the context-dependency of the genetic code, that accurately "reading" the code (and interpreting DNA sequences) and ultimately "writing" DNA (synthesizing sequences to carry out defined functions in bioenergy or environmental sciences) will require study of the language of DNA past the introductory course level. Explore further: Simplifying genetic codes to look back in time More information: Takahito Mukai et al. Facile Recoding of Selenocysteine in Nature, Angewandte Chemie International Edition (2016). DOI: 10.1002/anie.201511657

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