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.
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 | July 28, 2011
The Australian Information Industry Association (AIIA) has found a new CEO to fill the shoes of outgoing chief Ian Birks. Suzanne Campbell has been selected by the AIIA to helm the industry group today after the three-year tenure of previous CEO Ian Birks. Campbell has a long list of industry experience to her credit having held positions as the head of professional services for Telstra, state general manager for services business Kaz and managing director of MCI WorldCom. Campbell said her first priority is to meet with members to solidify herself into the role and source an agenda of issues to tackle. "I am particularly pleased to be taking on this role at such an interesting point in the development of the national industry. "AIIA's membership base now represents one of the most dynamic and influential elements in the national economy and I am very much looking forward to the opportunity to work with them directly," she said in a statement today.
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
News Article | September 1, 2016
To treat or not to treat? That is the question researchers at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) hope to answer with a new advance that could help doctors and their cancer patients decide if a particular therapy would be worth pursuing. Berkeley Lab researchers identified 14 genes regulating genome integrity that were consistently overexpressed in a wide variety of cancers. They then created a scoring system based upon the degree of gene overexpression. For several major types of cancer, including breast and lung cancers, the higher the score, the worse the prognosis. Perhaps more importantly, scores could accurately predict patient response to specific cancer treatments. The researchers said the findings, to be published Wednesday, Aug. 31, in the journal Nature Communications, could lead to a new biomarker for the early stages of tumor development. The information obtained could help reduce the use of cancer treatments that have a low probability of helping. "The history of cancer treatment is filled with overreaction," said the study's principal investigator, Gary Karpen, a senior scientist in Berkeley Lab's Division of Biological Systems and Engineering with a joint appointment at UC Berkeley's Department of Molecular and Cell Biology. "It is part of the ethics of cancer treatment to err on the side of overtreatment, but these treatments have serious side effects associated with them. For some people, it may be causing more trouble than if the growth was left untreated." One of the challenges is that there has been no reliable way to determine at an early stage if patients will respond to chemotherapy and radiation therapy, said study lead author Weiguo Zhang, a project scientist at Berkeley Lab. "Even for early stage cancer patients, such as lung cancers, adjuvant chemotherapy and radiotherapy are routinely used in treatment, but overtreatment is a major challenge," said Zhang. "For certain types of early stage lung cancer patients, there are estimates that adjuvant chemotherapy improves five-year survival only about 10 percent, on average, which is not great considering the collateral damage caused by this treatment." The researchers noted that there are many factors a doctor and patient must consider in treatment decisions, but this biomarker could become a valuable tool when deciding whether to use a particular therapy or not. Study co-author Anshu Jain, an oncologist at the Ashland Bellefonte Cancer Center in Kentucky and a clinical instructor at the Yale School of Medicine, added that the real value of this work may be in helping doctors and patients consider alternatives to the typical course of treatment. "These findings are very exciting," said Jain. "The biomarker score provides predictive and prognostic information separate from and independent of clinical and pathologic tumor characteristics that oncologists have available today and which often provide only limited clinical value." The study authors focused on genes regulating the function of centromeres and kinetochores - the essential sites on chromosomes that spindle fibers attach to during cell division - based upon results from earlier research by the Karpen group and other labs in the field. In normal cell division, microtubule spindles latch on to the kinetochores, pulling the chromosome's two chromatids apart. What the Karpen team previously found in fruit flies is that the overexpression of a specific centromere protein resulted in extra spindle attachment sites on the chromosomes. "This essentially makes new centromeres functional at more than one place on the chromosome, and this is a huge problem because the spindle tries to connect to all the sites," said Karpen. "If you have two or more of these sites on the chromosome, the spindles are pulling in too many directions, and you end up breaking the chromosome during cell division. So overexpression of these genes may be a major contributing factor to chromosomal instability, which is a hallmark of all cancers." This chromosomal instability has long been recognized as a characteristic of cancer, but its cause has remained unclear. To determine if centromeres play a role in chromosome instability in human cancers, the researchers analyzed many public datasets from the National Center for Biotechnology Information, the Broad Institute and other organizations that together contained thousands of human clinical tumor samples from at least a dozen types of cancers. The researchers screened 31 genes involved in regulating centromere and kinetochore function to find the 14 that were consistently overexpressed in cancer tissue. The extensive records included information on DNA mutations and chromosome rearrangements, the presence and levels of specific proteins, the stage of tumor growth at the time the patient was diagnosed, treatments given, and patient status in the years following diagnosis and treatment. This allowed the researchers to correlate the centromere and kinetochore gene expression score (CES) with patient outcomes either with or without treatments. "We were surprised to find such a strong correlation between CES and things like whether the patient survived five years later," said Karpen. "Another finding - one that is counterintuitive - is that high expression of these centromere genes is also related to more effective chemotherapy and radiation therapy." The researchers hypothesized that the degree of chromosomal instability may also make cancer cells more vulnerable to the effects of chemotherapy or radiation therapy. "In other words, there's a threshold of genome instability," said Zhang. "At low to medium-high levels, the cancer thrives. But at much higher levels, the cancer cells are more susceptible to the additional DNA damage caused by the treatment. This is a really key point." The researchers pointed out that they found no link between very high levels of genome instability and improved patient survival without adjuvant treatments. Translating these findings into clinical advice and practice will take more research, the study authors caution. They are working to find that threshold of genome instability so that in the future, doctors and patients can make informed decisions about how to move forward. "Future steps will include investigating the CES in prospective clinical studies for validation in carefully selected patient cohorts," said Jain. "By establishing the clinical significance of the CES, oncologists will have greater confidence in guiding cancer patients toward treatments with the greatest benefit."