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    Displaying items by tag: genome

    sugar beet and field

    A study published in Nature today describes the sugar beet reference genome sequence generated by researchers both from the Centre for Genomic Regulation (CRG), the Max Planck Institute for Molecular Genetics and the University of Bielefeld, in cooperation with other centres and plant breeders.
    Sugar beet accounts for nearly 30% of the world's annual sugar production, according to FAO, and provides a source for bioethanol and animal feed.
    The sugar beet genome sequence provides insights into how the genome has been shaped by artificial selection along time.
    What do foodstuff like muffins, bread or tomato sauce have in common? They all contain different amounts of white refined sugar. But, what perhaps may result amazing is that this sugar is probably sourced from a plant very similar to spinach or chard, but much sweeter: the sugar beet. In fact, this plant accounts for nearly 30% of the world's annual sugar production, according to the Food and Agriculture Organization for the United Nations (FAO). Not in vain for the last 200 years, has it been a crop plant in cultivation all around the world because of its powerful sweetener property.
    Now, a team of researchers from the Centre for Genomic Regulation (CRG) and the Max Planck Institute for Molecular Genetics (Berlin, Germany), lead by Heinz Himmelbauer, head of the Genomics Unit at the CRG in Barcelona, together with researchers from Bielefeld and further partners from academia and the private sector, have been able to sequence and analyse for the first time the sweet genes of beetroot. The results of the study, that will be published today in Nature, shed light on how the genome has been shaped by artificial selection.
    "Information held in the genome sequence will be useful for further characterization of genes involved in sugar production and identification of targets for breeding efforts. These data are key to improvements of the sugar beet crop with respect to yield and quality and towards its application as a sustainable energy crop," the authors suggest.
    Sugar beet is the first representative of a group of flowering plants called Caryophyllales, comprising 11,500 species, which has its genome sequenced. This group encompasses other plants of economic importance, like spinach or quinoa, as well as plants with an interesting biology, for instance carnivorous plants or desert plants.
    27,421 protein-coding genes were discovered within the genome of the beet, more than are encoded within the human genome. "Sugar beet has a lower number of genes encoding transcription factors than any flowering plant with already known genome," adds Bernd Weisshaar, a principle investigator from Bielefeld University who was involved in the study. The researchers speculate that beets may harbor so far unknown genes involved in transcriptional control, and gene interaction networks may have evolved differently in sugar beet compared to other species. The researchers also studied disease resistance genes (the equivalent to the immune system in animals) which can be identified based on protein-domains. These genes turned out as particularly plastic, with beet-specific gene family expansions and gene losses.
    Many sequencing projects nowadays targeted at the analysis of novel genomes also address the description of genetic variation within the species of interest. Commonly, "this is achieved by generating sequencing reads obtained from high-throughput sequencing technologies, followed by alignment of these reads against the reference genome to identify differences," explains Heinz Himmelbauer, a principle investigator of this study.
    The current work went one step further and generated genome assemblies from four additional sugar beet lines. This allowed the researchers to obtain a much better picture of intraspecific variation in sugar beet than would have been possible otherwise. In summary, 7 million variants were discovered throughout the genome. However, variation was not uniformly distributed: The authors found regions of high, but also of very low variation, "reflecting both the small population size from which the crop was established, as well as the human selection, which has shaped the plants' genomes. Additionally, gene numbers varied between different sugar beet cultivars, which contained up to 271 genes not shared with any of the other lines", as Juliane Dohm and André Minoche, two scientists involved in the study commented.
    The researchers also performed an evolutionary analysis of each sugar beet gene in order to put them into context with already known genes of other plants. This analysis allowed them to identify gene families that are expanded in sugar beet compared to other plants, but also families that are absent. Notably such gene families were most commonly associated with stress response or with disease resistance, added Toni Gabaldon, group leader in the CRG Bioinformatics and Genomics programme and ICREA research professor.
    Finally, the work also provides a first genome sequence of spinach, which is a close relative of sugar beet.
    Thanks to the sugar beet genome sequence made by the researchers and the associated resources generated, future studies on the molecular dissection of natural and artificial selection, gene regulation and gene-environment interaction, as well as biotechnological approaches to customize the crop to different uses in the production of sugar and other natural products, are expected to be held.
    "Sugar beet will be an important cornerstone of future genomic studies involving plants, due to its taxonomic position", the authors claim.

    Published in News

    CoyoteRidge-630With estimates of losing 15 to 40 percent of the world's species over the next four decades – due to climate change and habitat loss, researchers ponder in the Sept. 26 issue of Nature whether science should employ genetic engineering to the rescue.
    The technique would involve "rescuing a target population or species with adaptive alleles, or gene variants, using genetic engineering," write Josh Donlan, Cornell visiting fellow in ecology and evolutionary biology, and his colleagues. The method is "an increasingly viable … option, which we call 'facilitated adaptation,' [but it] has been little discussed," they add.
    To avert mass extinctions, the group thinks that three options, each with its own set of challenges, complications and risks, exist. They are:

    - Animals or plants could be crossed with individuals of the same species from better-adapted populations to introduce adapted alleles into threatened animal or plant populations.

    - Direct transfers from populations with adapted genomes could be introduced into the threatened populations of the same species.

    - Genes from a well-adapted species could be incorporated into the genomes of endangered species.

    The Nature commentary draws from a recent National Science Foundation-funded workshop, "Ecological and Genomic Exploration of Environmental Change," in March, where scientists met to understand issues surrounding climate change adaptation. In those spirited discussions, a hot question emerged: Is managed relocation of animal and plant species really the only approach to averting extinction? Instead of moving plant and animal populations, could genes be moved into populations? "Thus, the term 'facilitated adaptation' was born," said Donlan.
    Averting climate change altogether would be a preferable – albeit unlikely – outcome. The scientists fear that implementing genetic solutions could potentially deter other climate change action.
    "A serious concern is that even the possibility of using genetic-engineering tools to rescue biodiversity will encourage inaction with regard to climate change. Before genetic engineering can be seriously entertained as a tool for preserving biodiversity, conservationists need to agree on the types of scenario for which facilitated adaptation, managed relocation and other adaptation strategies might be appropriate, and where such strategies are likely to fail or introduce more serious problems," they write.
    Joining Donlan on the Nature commentary, "Gene Tweaking for Conservation," are Michael A. Thomas, Idaho State University, first and corresponding author; Gary W. Roemer, New Mexico State University, Las Cruces, N.M.; Brett G. Dickson, Conservation Science Partners, Truckee, Calif.; and Marjorie Matocq and Jason Malaney, University of Nevada, Reno. Donlan is also executive director of the Advanced Conservation Strategies, Midway, Utah.

    Published in News

    newroleforprPioneering new research from a team of Indiana University Bloomington biologists has shown for the first time that a protein which has been long known to be critical for the initiation of protein synthesis in all organisms can also play a role in the regulation of gene expression in some bacteria, and probably land plants as well.
    The protein, called translation initiation factor 3, or IF3, is one of three proteins that make up the core structure of the machinery needed to guide the joining of messenger RNAs and ribosomes as protein translation commences. These three proteins have been widely considered to simply operate in a constitutive manner and play little, if any, role in regulating the expression of genes.
    The new findings, from the laboratory of David M. Kehoe, professor of biology in the Indiana University Bloomington College of Arts and Sciences, reveals that IF3, in addition to its well-accepted function during translation initiation, also regulates the expression of genes that encode components of the photosynthetic machinery in response to changes in the color of light in the surrounding environment, a process known as "chromatic acclimation."
    These photosynthesis genes produce red-pigmented proteins called phycoerythrin in cyanobacteria when the cells are grown in green light and allow these organisms to efficiently absorb the predominant ambient light color for photosynthesis. The team uncovered the novel function of IF3 while searching for mutants that incorrectly regulated phycoerythrin. The discovery of this mutant was at first surprising, because in all other bacteria that have been examined, mutations in infC (the gene that encodes IF3) are lethal.
    The team solved this puzzle by uncovering a second infC gene in Fremyella diplosiphon, the model organism for the study of light color responsiveness in cyanobacteria. While both IF3s, which have been named IF3a and IF3b, can act in the traditional role of translation initiation, only IF3a was found to also regulate photosynthetic gene expression.
    By exploring the genomes of hundreds of prokaryotes and eukaryotes in collaboration with members of the laboratory of Indiana University Distinguished Professor and Class of 1955 Professor Jeffrey Palmer, the group identified a wide range of species whose genomes appear to have the potential to encode multiple IF3s, with one organism apparently encoding five distinct IF3 family members. And since almost none of these species are capable of chromatic acclimation, Kehoe believes that multiple IF3s must be used to regulate a wide range of environmental and perhaps developmental responses in both prokaryotes and eukaryotes.
    "Particularly interesting was our finding that IF3 families exist in a number of plant species, including commercially important crops," Kehoe said. "This means that new approaches to the modification of traits in agriculturally significant plant species may be possible by manipulating the expression patterns of different IF3 family members."
    The discovery has generated excitement for an additional reason. Historically, scientists have had a difficult time studying IF3 because it is so essential for translation initiation that it can not be altered without causing death. In fact, it remains one of the few proteins involved in translation for which no effective antibiotic has been developed. But the ability of the Kehoe team to delete either of the two infC genes in F. diplosiphon without causing lethality will allow the group to modify both IF3a and IF3b at will.
    "Now that we know that F. diplosiphon contains two functionally different IF3s, and that each is nonessential, we have a unique opportunity to enhance our understanding of how the structural features of IF3 are related to its function," Kehoe said. "Advancing our understanding of the role of IF3 in translation is likely to provide opportunities to develop new antibiotics that are targeted to this class of proteins."
    "A unique role for translation initiation factor 3 in the light color regulation of photosynthetic gene expression" is now available in early online editions of the Proceedings of the National Academy of Sciences. Co-authors with Kehoe and Palmer were Andrian Gutu, a former Ph.D. student in the Kehoe lab who is now a Howard Hughes Medical Institute Postdoctoral Fellow at Harvard University; April Nesbit, a former postdoctoral researcher in the Kehoe lab who is now a lecturer at Purdue Northwest; and Andrew Alverson, a former postdoctoral fellow in the Palmer lab who is now a faculty member at the University of Arkansas. Primary funding for the work was provided by the National Science Foundation, with support provided to Nesbit by the National Institutes of Health.

    Published in News

    genome-breast-cancer-gentaur-antibodiesTwo recent studies by CRG researchers delve into the role of chromatin modifying enzymes and transcription factors in tumour cells.

    In one, published on September 9 in Genes & Development, it was found that the PARP1 enzyme activated by kinase CDK2 is necessary to induce the genes responsible for the proliferation of breast cancer cells in response to progesterone. In addition, extensive work has been undertaken to identify those genes activated by the administration of progesterone in breast cancer, the sequences that can be recognised and how these genes are induced. This work will be published on November 21 in the journal Molecular Cell.

    Cancer is a complex set of diseases and only thanks to advances in genomic techniques have researchers begun to understand, at a cellular and molecular level, the mechanisms which are disrupted in cancer cells, a prerequisite for developing effective strategies to treat these diseases.

    One clear example of this is breast cancer. It has long been known that hormones such as estrogen and progesterone encourage the proliferation of cancer cells. Because of this, one of the most common treatments is the administration of hormone receptor blockers. The block, however, affects all the cells of the body not only the cancer cells, and causes a number of side effects in patients. Additionally, most cancers develop resistance after a time and continue to grow despite anti-hormone therapy. To treat these patients it is necessary to understand the mechanisms that trigger the proliferation, which will allow their direct inhibition.

    The scientists from the Cromatin and Gene Expression lab at the CRG, led by Miguel Beato, are dedicated to understanding how hormones activate cell division in breast cancer, focusing on regulating the expression of the genes that control the cell cycle.

    Hormone receptors are transcription factors that bind to DNA sequences in the vicinity of the genes they regulate. But the DNA of the genes is packed into a dense structure known as "chromatin," which is considered a barrier preventing the access of transcription factors to genes. Therefore the chromatin must be decompacted for the transcription factors to activate the target genes expressed in RNA and subsequently translate them into proteins that stimulate cell proliferation. This is where the progesterone, via its receptor, activates various enzymes initiating chromatin opening.

    In the study published on September 1 in the journal Genes & Development, the researchers looked at the role of an enzyme, PARP-1, which is primarily responsible for the repair of cuts in DNA. "It was not known how PARP-1 is activated and we found that it happens via the activation of another enzyme, CDK2, which phosphorylates and activates PARP-1, which in turn modifies the histone H1 and the chromatin displacement. And if PARP1 does not do this, many of the progesterone's target genes are not regulated," explains Roni Wright, first author of the study. Wright is a postdoctoral researcher in Beato's lab. She believes that much remains to be discovered in this area of research. "This experiment was conducted on cell lines, but now we have to do it on real, patient cells to see if their behaviour is the same," adds the researcher.

    How do we know how the proliferation of cancer cells is controlled?

    Gene regulation (how genes activate and deactivate) is the key to the overall understanding of how our genome works and when this function is altered. "It is important to discover the mechanism by which genes are activated around chromatin," explains Miguel Beato, head of the Chromatin and Gene Expression group. The chromatin packs the DNA at several levels, the first being the "nucleosomes," which help stabilise the DNA chain. "It was thought that the chromatin structure was not relevant to explaining how genes turn on and off, but we have discovered that it is crucial," adds Beato.

    The second study, published online on November 21, 2012 in the journal Molecular Cell, addresses this issue. Firstly, all the genes that progesterone activates or represses in breast cancer cells were identified. Then the researchers identified which DNA sequences recognise the progesterone receptor in the genome. They found that these represented only a small proportion of the possibilities, making them think that interaction with DNA was not sufficient. It was necessary for the sequences which bind to the receptor to be incorporated into nucleosomes, which also provide interaction sites. "It seems that chromatin has a lot to do with determining which genes are activated and which are not," says Cecilia Ballaré, first author of this second paper.

    The researchers believe that the only way to create increasingly specific and effective cancer treatments is by studying the role of all the elements that regulate gene expression and cell proliferation in response to hormones. "Knowing the exact way progesterone affects the proliferation of cancer cells may help develop more specific treatments that fight only cancer cells and thus produces fewer side effects," adds Ballaré.

    Published in News

    The Tibetan antelope lives at dizzying altitudes of 4000-5000mHow can the Tibetan antelope live at elevations of 4,000-5,000m on the Qinghai-Tibetan Plateau? Investigators rom Qinghai University, BGI, and other institutes now provide evidence of genetic factors that may be associated with the species' adaption to harsh highland environments. The data in this work will also provide implications for studying specific genetic mechanisms and the biology of other ruminant species.

    The Tibetan antelope (Pantholops hodgsonii) is a native of the high mountain steppes and semi-desert areas of the Tibetan plateau. Interestingly, it is the only member of the genus Pantholops. Tibetan antelope is a medium sized antelope with the unique adaptations to against the harsh high-altitude climate. For non-native mammals such as humans, they may experience life-threatening acute mountain sickness when visiting high-altitude regions.

    In this study, researchers suggest that Tibetan antelopes must have evolved exceptional mechanisms to adapt to this extremely inhospitable habitat. Using next-gen sequencing technology, they have decoded the genome of Tibetan antelope and studied the underlying genetic mechanism of high-altitude adaptations.

    Through the comparison between Tibetan antelope and other plain-dwelling mammals, researchers found the Tibetan antelope had the signals of adaptive evolution and gene-family expansion in genes associated with energy metabolism and oxygen transmission, indicating that gene categories involved in energy metabolism appear to have an important role for Tibetan antelope via efficiently providing energy in conditions of low partial pressure of oxygen (PO2).

    Further research revealed that both the Tibetan antelope and the highland American pika have signals of positive selection for genes involved in DNA repair and the production of ATPase. Considering the exposure to high levels of ultraviolet radiation, positive selective genes related to DNA repair may be vital to protect the Tibetan antelope from it.

    Qingle Cai, Project manager from BGI, said, "The completed genome sequence of the Tibetan antelope provides a more complete blueprint for researchers to study the genetic mechanisms of highland adaptation. This work may also open a new way to understand the adaptation of the low partial pressure of oxygen in human activities."

    Published in News
    Sunday, 03 February 2013 00:00

    Mutant Gene Gives Pigeons Fancy Hairdos

    DECODED GENOME REVEALS SECRETS OF PIGEON TRAITS AND ORIGINS

    Old Dutch capuchine manecrest2University of Utah researchers decoded the genetic blueprint of the rock pigeon, unlocking secrets about pigeons’ Middle East origins, feral pigeons’ kinship with escaped racing birds, and how mutations give pigeons traits like a fancy feather hairdo known as a head crest.

    “Birds are a huge part of life on Earth, and we know surprisingly little about their genetics,” especially compared with mammals and fish, says Michael D. Shapiro, one of the study’s two principal authors and an assistant professor of biology at the University of Utah. “There are more than 10,000 species of birds, yet we know very little about what makes them so diverse genetically and developmentally.”

    He adds that in the new study, “we’ve shown a way forward to find the genetic basis of traits – the molecular mechanisms controlling animal diversity in pigeons. Using this approach, we expect to be able to do this for other traits in pigeons, and it can be applied to other birds and many other animals as well.”

    The study appears Jan. 31 on Science Express, the website of the journal Science. Shapiro led the research with Jun Wang of China’s BGI-Shenzhen (formerly Beijing Genomics Institute) and other scientists from BGI, the University of Utah, Denmark’s University of Copenhagen and the University of Texas M.D. Anderson Cancer Center in Houston.

    Key findings of the study of pigeons, which first were domesticated some 5,000 years ago in the Mediterranean region:

    – The researchers sequenced the genome, or genetic blueprint, of the rock pigeon, Columba livia, among the most common and varied bird species on Earth. There are some 350 breeds with different sizes, shapes, colors, color patterns, beaks, bone structure, vocalizations and arrangements of feathers on the feet and head – including head crests that come in shapes known as hoods, manes, shells and peaks.

    The pigeon is among the few bird genomes sequenced so far, along with those of the chicken, turkey, zebra finch and a common parakeet known as a budgerigar or budgie, so “this will give us new insights into bird evolution,” Shapiro says.

    – Using innovative software developed by study co-author Mark Yandell, a University of Utah professor of human genetics, the scientists revealed that a single mutation in a gene named EphB2 causes head and neck feathers to grow upward instead of downward, creating head crests.

    “This same gene in humans has been implicated as a contributor to Alzheimer’s disease as well as prostate cancer and possibly other cancers,” Shapiro says, noting that more than 80 of the 350 pigeon breeds have head crests, which play a role in attracting mates in many bird species.

    – The researchers compared the pigeon genome to those of chickens, turkeys and zebra finches. “Despite 100 million years of evolution since these bird species diverged, their genomes are very similar,” Shapiro says.

    – The study turned up more conclusive evidence that major pigeon breed groups originated in the Middle East, and that North American feral pigeons – which are free-living but not wild – are close relatives of racing pigeons, named racing homers.

    A Genome for the Birds, a Gene for Head Crests

    The study assembled 1.1 billion base pairs of DNA in the rock pigeon genome, and the researchers believe there are about 1.3 billion total, compared with 3 billion base pairs in the human genome. The rock pigeon’s 17,300 genes compare with about 21,000 genes in people.

    The researchers first constructed a “reference genome” – a full genetic blueprint – from a male of the pigeon breed named the Danish tumbler. They did less complete sequencing of two feral pigeons and 38 other pigeons from 36 breeds.

    Shapiro says his team’s study is the first to pinpoint a gene mutation responsible for a pigeon trait, in this case, head crests.

    “A head crest is a series of feathers on the back of the head and neck that point up instead of down,” Shapiro says. “Some are small and pointed. Others look like a shell behind the head; some people think they look like mullets. They can be as extreme as an Elizabethan collar.”

    The study found strong evidence that the EphB2 (Ephrin receptor B2) gene acts like an on-off switch to create a head crest when mutant, and no head crest when normal. It also showed the mutation and related changes in nearby DNA are shared by all crested pigeons, so the trait evolved just once and was spread to numerous pigeon breeds by breeders. They ruled out the alternate possibility the mutation arose several times independently in different breeds.

    The researchers analyzed full or partial genetic sequences for 69 crested birds from 22 breeds, and 95 uncrested birds from 57 breeds. They found a perfect association between the mutant gene and the presence of head crests.

    “The way we tracked this trait was innovative,” Shapiro says. “We used gene-finding software from Mark Yandell’s group that was developed to find mutations that control human diseases. We adapted this software to find mutations that control interesting traits in pigeons. This should be extendable to other animals as well.”

    The scientists also showed that while the head crest trait becomes apparent in juvenile pigeons, the mutant gene affects pigeon embryos by reversing the direction of feather buds – from which feathers later grow – at a molecular level.

    Other genetic factors – not identified in the new study – determine what kind of head crest east pigeon develops: shell, peak, mane or hood, according to Shapiro.

    Tracking the Origins of Pigeons

    A 2012 by Shapiro study provided limited evidence of pigeons’ origins in the Middle East and some breeds’ origins in India, and indicated kinship between common feral or free-living city pigeons and escaped racing pigeons.

    In the new study, “we included some different breeds that we didn’t include in the last analysis,” Shapiro says. “Some of those breeds only left the Middle East in the last few decades. They’ve probably been there for hundreds if not thousands of years. If we find that other breeds are closely related to them, then we can infer those other breeds probably also came from the Middle East. That’s what we did.”

    “We found that the owl breeds – which are pigeon breeds with very short beaks and that are very popular with breeders – likely came from the Middle East,” he says. “They are very closely related to breeds we know came from Syria, Lebanon and Egypt.”

    Shapiro says the study also “found a lot of shared genetic heritage between breeds from Iran and breeds we suspect are from India, consistent with historical records of trade routes between those regions. People were not only trading goods along those routes, but probably also interbreeding their pigeons.”

    As for the idea that free-living pigeons descended from escaped racing pigeons, Shapiro says his 2012 study was based on “relatively few genetic markers scattered throughout the genome. We now have stronger evidence based on 1.5 million markers, confirming the previous result with much better data.”

    The scientists analyzed partial genomes of two feral pigeons: one from a U.S. Interstate-15 overpass in the Salt Lake Valley, and the other from Lake Anna in Virginia.

    “Despite being separated by 1,000 miles, they are genetically very similar to each other and to the racing homer breed,” Shapiro says.

    He notes that pigeons were one of evolutionist Charles Darwin’s “favorite examples of how selection works. He used this striking example of artificial selection [by breeding] to communicate how natural selection works. Now we can get to the DNA-level changes that are responsible for some of the diversity that intrigued Darwin 150 years ago.”

    The study’s University of Utah co-authors were Yandell; Eric Domyan, biology postdoctoral fellow; Zev Kronenberg and Michael Campbell, Ph.D. students in human genetics; Anna Vickery, biology undergraduate student; Sydney Stringham, Ph.D. student in biology; and Chad Huff, a former postdoctoral fellow in human genetics now at the University of Texas.

    The study was funded by the Burroughs Wellcome Fund, the National Science Foundation, the University of Utah Research Foundation, the National Institutes of Health and the Danish National Research Foundation.

    Published in News
    Monday, 20 May 2013 08:58

    New Stem Cells on the Block

    NT-hESCs 310Researchers have for the first time produced human embryonic stem cells (hESCs) using somatic nuclear transfer (SCNT), a method in which the nucleus of a donor cell—in this case a skin cell or fibroblast—is transferred to an egg cell whose own nucleus has been removed.

    The work, published in Cell, opens up the possibility of an alternative source of patient-specific stem cells to help scientists understand disease and develop personalized cell-based therapies. What’s more, hESCs produced via nuclear transfer (NT-hESCs) may not have the genetic and epigenetic abnormalities found in induced pluripotent stem cells (iPSCs), made by adding key genes to reprogram adult cells.

    “I think it is a beautiful piece of work,” said George Daley of Boston Children’s Hospital and the Harvard Stem Cell Institute, who was not involved in the research, in an email to The Scientist. “This group has become remarkably proficient at a very technically demanding procedure and has shown that SCNT-ESCs may in fact be a practical source of cells for regenerative medicine.”

    SCNT has previously been used to clone animals and to successfully reprogram somatic cells into ESCs is mice and primates, but little is known about how it works and which factors in the egg cell are responsible stimulating the reversion of the implanted mature nucleus to a pluripotent state.

    Moreover, all previous attempts to produce NT-ESCs have failed. Researchers have been unable to get human SCNT embryos to progress past the 8-cell stage, never mind to the 150-cell blastocyte stage from which hESCs can be plucked. The causes of the roadblock are not clear, but likely involve certain key embryonic genes from the donor cell nucleus that could not be activated.

    To overcome these obstacles, Shoukhrat Mitalipov of Oregon Health and Science University and colleagues first examined failed attempts with human cells and successful work in rhesus macaques to identify factors that could be responsible.

    The researchers evaluated various activation and culture protocols that led to successful SCNT reprogramming in monkeys, and set about testing various combinations on human oocytes. They found that the optimized protocols that worked in monkeys also worked in humans. In particular, the incorporation of caffeine into the cocktails of chemicals used during host nucleus removal and donor transplantation and the use of electrical pulses to activate embryonic development in the recipient egg improved cellular reprograming and blastocyte development, allowing human SCNT embryos to reach a stage that yielded hESCs.

    “[The researchers] worked diligently to overcome the early embryo blockade that we and others have confronted as a barrier to human SCNT,” said Daley. “Their distinct culture media, which was supplemented with caffeine, and their optimized activation protocol appears to have been the needed breakthrough.”

    “It was a huge battery of changes to the protocols over a number of different steps,” said Mitalipov. “I was worried that we might need a couple of thousand eggs to make all these optimizations, to find that winning combination. But it actually took just 128 [eggs], which is a surprisingly low number to make 6 [hESC] lines.”

    The researchers then analyzed four of these cell lines and found that their NT-hESCs could successfully differentiate into beating heart cells in vitro and into a variety of cell types in teratoma tumors on live mice. The cells also closely resembled those derived from fetal fibroblasts, had no chromosomal abnormalities, and displayed fewer problematic epigenetic leftovers from parental somatic cells than are typically seen in iPSCs. Mitalipov said more comparisons are required, however.

    “We are now left to analyze the detailed molecular nature of SCNT-ES cells to determine how closely they resemble embryo-derived ES cells and whether they have any advantages over iPS cells,” added Daley. “iPS cells are easier to produce and have wide applications in research and regenerative medicine, and it remains to be shown whether SCNT-ES cells have any advantages.”

    But Milatipov pointed out one fundamental difference: while their nuclear genome comes from the donor cell, NT-hESCs contain mitochondrial DNA (mtDNA) from the egg cell. So unlike in iPSCs, nuclear transfer not only reprograms the cell but also corrects any mtDNA mutations that the donor may carry, meaning that patient-specific NT-hESCs could be used to treat people with diseases caused by mitochondrial mutations. “That’s one of the clear advantages with SCNT,” Milatipov said.

     

    Published in News
    Friday, 19 April 2013 10:28

    The Human Papillomavirus

    The 3D model of HPVPapillomaviruses are a very diverse group of viruses that infect human skin and mucosal cells, which serve as a barrier between the environment and a human being. Most representatives of this group do not cause any symptoms, but highly pathogenic types may cause cancer. Ancient literature contains the first known mention of skin warts. The first classification of warts was introduced by Roman physician Aulus Cornelius Celsus in 25 AD, and the assumption that warts may be transmitted via infection originated even earlier. However, the viral nature of papillomas was not demonstrated until the beginning of the twentieth century (reviewed in 4). The first papillomavirus was isolated in 1933 by the American virologist Richard Shope, who also isolated an influenza virus.

    The evolutionary history of papillomaviruses seems to coincide with the origin of higher-order vertebrates, amniotes (including reptiles, birds, and mammals). Mammalian skin structure appears to make them the most suitable hosts for the papillomaviruses, and — today — papillomaviruses are widespread in mammals and rarely found in birds. The relationship between papillomaviruses and similar groups of DNA-viruses, such as polyomaviruses, is not well-demonstrated at the present time. There are more than a hundred types of papillomaviruseshigh-risk that can infect humans. These are collectively referred to as human papilloma viruses or HPV and are divided into (HR) and low-risk (LR) types by their carcinogenic properties. HPV are transmitted through direct skin-to-skin contact, and approximately 30 types are transmitted sexually. LR HPV are much more common than HR HPV among humans and often do not cause any symptoms. In fact, only 18 types of HPV pose a cancer risk, mostly for anogenital cancers.

    Current research suggests that LR HPVs produce more virions and infect more human hosts whereas HR types are less virulent but more difficult for the immune system to neutralize. The most dangerous HR HPV types are also the most widespread, HPV16 (reference strain) and HPV18, and the main cause of skin warts (especially in the anogenital zone) are HPV types 6 and 11. These and several other types of HPV attract serious attention.

    Human papilloma virus particles lack a lipid envelope and are relatively small, with a diameter of only about 30 nm. In comparison, the human immunodeficiency virus (HIV) and influenza virus virions are enveloped by a lipid bilayer derived from the host cell and are approximately four times larger. The papillomavirus genome consists of double-stranded DNA decorated and packed by histones of the host cell. It encodes two types of proteins, early (E) proteins and late (L) proteins: early HPV proteins maintain regulatory functions (and are responsible for oncotransformation of the host cell in the case of HR types), and late proteins form the capsid of the virion. The life cycle of HPV is bound to the life cycle of its host cells, keratinocytes, and HPV can only be cultivated in special organotypic raft cultures containing a population of cells at different developmental stages — similar to the skin of a living organism. Keratinocytes are the main cells of epidermis, the outermost layer of the skin. Actively dividing young keratinocytes are found near the basal membrane that separates the epidermis from other layers of the skin and move towards the skin surface during maturation. Viral particles infect non-differentiated cells, and new virions are produced inside the keratinocytes during the terminal stage of differentiation.

    The HPV early proteins are responsible for maintaining a proper amount of viral DNA inside the host cell nucleus. However, they also coordinate the expression of viral genes. Proteins E1 and E2 form a complex with viral DNA, which recruits the cell replication systems. Proteins E6 and E7 are responsible for the carcinogenic effect in HR HPV types. E6 is able to bind to the tumor suppressor p53 and promote its ubiquitination and degradation. Protein E7 binds several cell proteins and tumor suppressors, including theretinoblastoma protein. The activity of the E6 and E7 proteins leads to uncontrolled cell division.

    Late proteins of HPV form the viral capsid and mediate packaging of DNA into the virion. The pentamer-forming L1 protein is the major component of the HPV capsid, and the L2 protein is a minor constituent. The HPV capsid looks roughly spherical, but, in fact, it has a icosahedral symmetry with the triangulation number that equals 7. Rather than a structure based on pentamers mixed with hexamers (like that of the soccer ball), the HPV capsid is composed of 72 L1 pentamers of two different types — 60 hexavalent pentamers and 12 pentavalent pentamers (reviewed in 2, chapter 3). Remarkably, the fold of HPV L1 proteins is similar to that of human nucleoplasmins, the proteins that regulate the assembly of nucleosomes. Whether they share a common ancestor or whether their similarity is the result of convergent evolution is not yet clear. Perhaps the interaction between L1 and nucleosomes on viral DNA is crucial for the encapsidation of the HPV genetic material.

    One monomer of L2 is associated with each L1 pentamer of the HPV virion, and current research suggests that L2 is crucial for DNA recruitment to the viral particle. Some hypothesize that L2 — as well as L1 — may interact not with viral DNA but rather with its histones. To date, however, much of the process through which HPV DNA is packed inside the virion remains unknown. One facet of the process that is known may make HPV an important tool in human gene therapy: any segment of DNA less than 8 kb long may be packed inside the capsid [link], which enables the development and use of HPV-based transformation vectors. Interestingly, human cyclophilin participates in HPV capsid unpacking, a mechanism that has also been demonstrated for HIV.

    A growing interest in HPV research can be partially — if not wholly — attributed to discovery of the relationship between HPV and cancer and the subsequent Nobel Prize in Physiology or Medicine (2008) awarded for this work. German scientist Harald zur Hausen has shown that nearly all cases of cervical cancer are the result of HPV infection. Vaccines against HPV are currently being actively developed and introduced, and the main targets for such vaccines include the most dangerous and common HPV types: HPV6, HPV11, HPV16, HPV18.

    Dr. Christopher Buck from the U.S. National Cancer Institute: Current vaccines against human papillomaviruses (HPVs) are a triumph of applied structural virology. However, the current vaccines, which use recombinant virus-like particles composed of the L1 major capsid protein, do not protect against all disease-causing HPV types. Fortunately, a new generation of HPV vaccines targeting conserved „Achilles’ heel“ epitopes present in the L2 minor capsid protein promise to offer broad protection against all HPVs, including all types that cause cancer, as well as types that cause benign skin warts (for which the papillomavirus family is named). Current knowledge about the structure, dynamics, and function of L2 during the infectious entry process is very limited. This structural information is desperately needed to inform the development of pan-protective HPV vaccines.

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