Category Archives: Genome

IISc division will lead drive to map 1,000 genomes

New Delhi, July 12:

Indian scientists are embarking on an ambitious programme to map thousands of genomes from the countrys many ethnic communities.

The initiative, the first of its kind from India, will help identify genes and genetic variations that underlie many diseases, particularly hereditary ailments, for which there is no cure currently.

The decision to launch the project was taken at a meeting of top genome scientists at the Centre for Brain Research (CBR), which is an autonomous body at the Indian Institute of Science (IISc), Bengaluru.

The CBR, set up with liberal funding from the Pratiksha Trust of Infosys co-founder Kris Gopalakrishnan and his wife Sudha Gopalakrishnan, has promised to fund the mapping of at least 1,000 genomes from across the country, said a scientist, who requested anonymity. Sequencing of each genome is expected to cost about $1,000.

The scientists rued that India never felt it important to map the genomes of its citizens. A country like India, which has so much ethnic diversity, should have mapped at least 10,000 genomes by now. I am surprised that it wasnt a priority for the authorities even now, the scientist said.

Genetic variations in individuals are important in health and disease treatment and are useful tools to study evolution, migration and population history of various groups of individuals.

According to some estimates, India has more than 4,000 well-defined anthropological groups. Many of these groups shunned inter-marriage for centuries due to cultural and societal reasons.

This, in turn, has led to creation of different population groups with their own genetic make-up.

Apart from identifying subtle genetic variations that set Indians apart from the Caucasian or African population, building such a genetic catalogue would help unravel genes responsible for genetic disorders.

Every year, over 1lakh babies in India are born with congenital diseases, but there is very limited understanding of the genes involved.

Currently, there is no Indian genome available in the public domain, said Bratati Kahali, a researcher with CBR. The genome project, she says, will help address this lacuna.

We are really excited to be part of this venture, said Dinabandhu Sahoo, Director of the Institute of Bioresources and Sustainable Development (IBSD) at Imphal. IBSD, he said, would gather samples from the North-East, a region with over 220 ethnic groups.

Apart from IBSD, the Centre for Cellular and Molecular Biology in Hyderabad, LV Prasad Eye Hospital (Hyderabad), the Rajiv Gandhi Centre for Biotechnology (Thiruvananthapuram) and IIT Jodhpur will participate in the ambitious project.

(This article was published on July 12, 2017)

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Genome project promises to root out your origins - Hindu Business Line

New biological information gleaned from the red vizcacha rat, a native species of Argentina, demonstrates how genomes can rapidly change in size.

Researchers from McMaster University set out to study this particular species because its genome, or its complete set of DNA, is the largest of all mammals, and appears to have increased in size very rapidly.

The rats genome is roughly two-and-a-half times as large as the human genome, including 102 chromosomes versus 46 for humans, and is about twice as large as one of its closest relatives, the mountain vizcacha rat. The most recent common ancestor of these species existed only about five million years ago.

This genomic transformation is striking because it happened over a very short period of time in evolutionary terms, says Ben Evans, a biologist at McMaster and lead author of the new research published in the journal Genome Biology and Evolution.

The mechanism behind that growth has caused much debate among scientists, some of whom suggest the rapid expansion is due to whole genome duplication when its entire set of DNA doubles.

Whole genome duplication is relatively common in some groups such as plantsit occurred in ancestors of corn, tobacco, potatoes, and many other flowering plants, say researchers.

Others argue the rats rapid genome expansion is due to repetitive DNAbits of DNA that are repeated many times in a genomecoupled with chromosomal fissioning, a process where one chromosome divides into two or more over evolutionary time.

To settle the debate, researchers compared and contrasted genomic datasets from the red vizcacha rat and the mountain vizcacha rat.

Their analysis suggests the genome grew quickly due to the expansion of a diverse set of highly repetitive elements, and they found no strong evidence of genome duplication.

This is interesting because these same mechanisms the expansion of repetitive DNA operate in humans and contribute to genomic baggage or extra DNA. This can influence disease through the interruption of gene function, says Evans.

Still, many questions remain. Researchers hope to further characterize the nature of those repetitive elements. For example, what are they and why did they expand? And are they still expanding?

Researchers also plan to explore whether or not this genetic evolution played a part in the rats high tolerance for a highly saline diet. This species can feed on extremely salty plants that grow in its desert habitat, whereas the mountain vizcacha rat cannot tolerate the same diet.

Read more from the original source:
New Analysis of Rare Argentinian Rat Unlocks Origin of the Largest Mammalian Genome - Laboratory Equipment

The molecular constraints affecting Zika virus (ZIKV) evolution are not well understood. To investigate ZIKV genetic flexibility, we used transposon mutagenesis to add 15-nucleotide insertions throughout the ZIKV MR766 genome and subsequently deep sequenced the viable mutants. Few ZIKV insertion mutants replicated, which likely reflects a high degree of functional constraints on the genome. The NS1 gene exhibited distinct mutational tolerances at different stages of the screen. This result may define regions of the NS1 protein that are required for the different stages of the viral life cycle. The ZIKV structural genes showed the highest degree of insertional tolerance. Although the envelope (E) protein exhibited particular flexibility, the highly conserved envelope domain II (EDII) fusion loop of the E protein was intolerant of transposon insertions. The fusion loop is also a target of pan-flavivirus antibodies that are generated against other flaviviruses and neutralize a broad range of dengue virus and ZIKV isolates. The genetic restrictions identified within the epitopes in the EDII fusion loop likely explain the sequence and antigenic conservation of these regions in ZIKV and among multiple flaviviruses. Thus, our results provide insights into the genetic restrictions on ZIKV that may affect the evolution of this virus.

IMPORTANCE Zika virus recently emerged as a significant human pathogen. Determining the genetic constraints on Zika virus is important for understanding the factors affecting viral evolution. We used a genome-wide transposon mutagenesis screen to identify where mutations were tolerated in replicating viruses. We found that the genetic regions involved in RNA replication were mostly intolerant of mutations. The genes coding for structural proteins were more permissive to mutations. Despite the flexibility observed in these regions, we found that epitopes bound by broadly reactive antibodies were genetically constrained. This finding may explain the genetic conservation of these epitopes among flaviviruses.

Citation Fulton BO, Sachs D, Schwarz MC, Palese P, Evans MJ. 2017. Transposon mutagenesis of the Zika virus genome highlights regions essential for RNA replication and restricted for immune evasion. J Virol 91:e00698-17. https://doi.org/10.1128/JVI.00698-17.

Supplemental material for this article may be found at https://doi.org/10.1128/JVI.00698-17.

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Transposon Mutagenesis of the Zika Virus Genome Highlights Regions Essential for RNA Replication and Restricted ... - Journal of Virology

Representation of the Cpf1 protein in complex with its target RNA and target DNA. The determination of its structure at high resolution has allowed to reveal the modus operandi of this genetic engineering tool. / University of Copenhagen

A scientific team from in the Novo Nordisk Foundation Center for Protein Research (NNF-CPR), at the University of Copenhagen, has succeeded in visualizing and describing how a new system for genome editing, known as Cpf1, works. This protein belongs to the Cas family and enables the cleavage of double stranded DNA, thus allowing the initiation of the genome modification process. The results of the study have been published in the journal Nature.

Guillermo Montoya, a researcher in the fields of biochemistry and molecular biology who led the study, explains to SINC that the new molecular scissors will enable us to more safely modify and edit the instructions written in the genome, due to the utmost precision of the target DNA sequence recognition.

The CRISPR Cas9 system for cutting and paste genome sequences is already being used to modify animal and plant genomes. Also to treat illnesses, such as cancer and retinal diseases, in humans and its applications are growing very fast.

X-Ray Crystallography Technique

Researchers across the world are trying to perfect this genome editing technique with the aim of making it yet more precise and efficient. To achieve this, they have also focused on other proteins that specifically cut DNA, such as Cpf1, whose manipulation can direct them to specific locations in the genome. Montoyas team has achieved this using an X-ray Crystallography to decipher the molecular mechanisms controlling this process.

We radiated the crystals of the Cpf1 protein using X-rays to be able to observe its structure at atomic resolution, enabling us to see all its components, points out the co-author of this study. X-ray diffraction is one of the main biophysical techniques used to elucidate biomolecular structures, he continues.

In his opinion, the main advantage of Cpf1 lies in its high specificity and the cleaving mode of the DNA, since it is possible to create staggered ends with the new molecular scissors, instead of blunt-ended breaks as is the case with Cas9, which facilitates the insertion of a DNA sequence.

The high precision of this protein recognising the DNA sequence on which it is going to act functions like a GPS, directing the Cpf1 system within the intricate map of the genome to identify its destination. In comparison with other proteins used for this purpose, it is also very versatile and easy to be reprogrammed, Montoya adds.

Genetic diseases and tumours

These properties make this system particularly suitable for its use in the treatment of genetic diseases and tumours, he affirms.

The team has previously worked with the French biotechnology company Celletics on the use of meganucleases other proteins that can be redesigned to cut the genome in a specific location to treat certain types of leukemia.

The new technology can also be used to modify microorganisms, with the aim of synthesising the metabolites required in the production of drugs and biofuels, adds Montoya.

This researcher, from Getxo (Biscay, Spain), says that there are many companies interested in this new technology. They are mostly from the biotechnology sector in the field of microorganism manipulation, but cannot be named due to confidentiality agreements.

This article has been republished frommaterialsprovided by SINC. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference

Stella, S., Alcn, P., & Montoya, G. (2017). Structure of the Cpf1 endonuclease R-loop complex after target DNA cleavage. Nature.

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Improving Genome Editing: CRISPR Cpf1 mechanism visualized - Technology Networks

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Credit: Will Ludwig/C&EN/Shutterstock

Synthetic biologists have been creating the genomes of organisms such as viruses and bacteria for the past 15 years. They aim to use these designer genetic codes to make cells capable of producing novel therapeutics and fuels. Now, some of these scientists have set their sights on synthesizing the human genomea vastly more complex genetic blueprint. Read on to learn about this initiative, called Genome Project-write, and the challenges researchers will faceboth technical and ethicalto achieve success.

Nineteenth-century novels are typically fodder for literature conferences, not scientific gatherings. Still, at a high-profile meeting of about 200 synthetic biologists in May, one presenter highlighted Mary Shelleys gothic masterpiece Frankenstein, which turns 200 next year.

Frankensteins monster, after all, is what many people think of when the possibility of human genetic engineering is raised, said University of Pennsylvania ethicist and historian Jonathan Moreno. The initiative being discussed at the New York City meetingGenome Project-write (GP-write)has been dogged by worries over creating unnatural beings. True, part of GP-write aims to synthesize from scratch all 23 chromosomes of the human genome and insert them into cells in the lab. But proponents of the project say theyre focused on decreasing the cost of synthesizing and assembling large amounts of DNA rather than on creating designer babies.

The overall project is still under development, and the projects members have not yet agreed on a specific road map for moving forward. Its also unclear where funding will come from.

What the members of GP-write do agree on is that creating a human genome from scratch is a tremendous scientific and engineering challenge that will hinge on developing new methods for synthesizing and delivering DNA. They will also need to get better at designing large groups of genes that work together in a predictable way, not to mention making sure that even larger assembliesgenomescan function.

GP-write consortium members argue that these challenges are the very thing that should move scientists to pick up the DNA pen and turn from sequence readers to writers. They believe writing the entire human genome is the only way to truly understand how it works. Many researchers quoted Richard Feynman during the meeting in May. The statement What I cannot create, I do not understand was found on the famed physicists California Institute of Technology blackboard after his death. I want to know the rules that make a genome tick, said Jef Boeke, one of GP-writes four coleaders, at the meeting.

To that end, Boeke and other GP-write supporters say the initiative will spur the development of new technologies for designing genomes with software and for synthesizing DNA. In turn, being better at designing and assembling genomes will yield synthetic cells capable of producing valuable fuels and drugs more efficiently. And turning to human genome synthesis will enable new cell therapies and other medical advances.

In 2010, researchers at the Venter Institute, including Gibson, demonstrated that a bacterial cell controlled by a synthetic genome was able to reproduce. Colonies formed by it and its sibling resembled a pair of blue eyes.

Credit: Science

Genome writers have already synthesized a few complete genomes, all of them much less complex than the human genome. For instance, in 2002, researchers chemically synthesized a DNA-based equivalent of the poliovirus RNA genome, which is only about 7,500 bases long. They then showed that this DNA copy could be transcribed by RNA polymerase to recapitulate the viral genome, which replicated itselfa demonstration of synthesizing what the authors called a chemical [C332,652H492,388N98,245O131,196P7,501S2,340] with a life cycle (Science 2002, DOI: 10.1126/science.1072266).

After tinkering with a handful of other viral genomes, in 2010, researchers advanced to bacteria, painstakingly assembling a Mycoplasma genome just over about a million bases in length and then transplanting it into a host cell.

Last year, researchers upped the ante further, publishing the design for an aggressively edited Escherichia coli genome measuring 3.97 million bases long (Science, DOI: 10.1126/science.aaf3639). GP-write coleader George Church and coworkers at Harvard used DNA-editing softwarea kind of Google Docs for writing genomesto make radical systematic changes. The so-called rE.coli-57 sequence, which the team is currently synthesizing, lacks seven codons (the three-base DNA words that code for particular amino acids) compared with the normal E. coli genome. The researchers replaced all 62,214 instances of those codons with DNA base synonyms to eliminate redundancy in the code.

Note: A 17th synthetic neochromosome is not shown in the plot above. The number of DNA bases plotted is for the synthetic yeast chromosome as opposed to the native yeast chromosome. Synthetic chromosomes have been modified slightly from native ones to remove, for instance, transfer RNA coding segments that might destabilize the chromosomes. BGI is a genome sequencing center in Guangdong, China. GenScript is a New Jersey-based biotech firm. AWRI = Australian Wine Research Institute. JGI = Joint Genomics Institute of the U.S. Department of Energy. U = University. Source: Science 2017, DOI: 10.1126/science.aaf4557

Bacterial genomes are no-frills compared with those of creatures in our domain, the eukaryotes. Bacterial genomes typically take the form of a single circular piece of DNA that floats freely around the cell. Eukaryotic cells, from yeast to plants to insects to people, confine their larger genomes within a cells nucleus and organize them in multiple bundles called chromosomes. An ongoing collaboration is now bringing genome synthesis to the eukaryote realm: Researchers are building a fully synthetic yeast genome, containing 17 chromosomes that range from about 1,800 to about 1.5 million bases long. Overall, the genome will contain more than 11 million bases.

The synthetic genomes and chromosomes already constructed by scientists are by no means simple, but to synthesize the human genome, scientists will have to address a whole other level of complexity. Our genome is made up of more than 3 billion bases across 23 paired chromosomes. The smallest human chromosome is number 21, at 46.7 million baseslarger than the smallest yeast chromosome. The largest, number 1, has nearly 249 million. Making a human genome will mean making much more DNA and solving a larger puzzle in terms of assembly and transfer into cells.

Today, genome-writing technology is in what Boeke, also the director for the Institute of Systems Genetics at New York University School of Medicine, calls the Gutenberg phase. (Johannes Gutenberg introduced the printing press in Europe in the 1400s.) Its still early days.

DNA synthesis companies routinely create fragments that are 100 bases long and then use enzymes to stitch them together to make sequences up to a few thousand bases long, about the size of a gene. Customers can put in orders for small bits of DNA, longer strands called oligos, and whole geneswhatever they needand companies will fabricate and mail the genetic material.

Although the technology that makes this mail-order system possible is impressive, its not prolific enough to make a human genome in a reasonable amount of time. Estimates vary on how long it would take to stitch together a more than 3 billion-base human genome and how much it would cost with todays methods. But the ballpark answer is about a decade and hundreds of millions of dollars.

Synthesis companies could help bring those figures down by moving past their current 100-base limit and creating longer DNA fragments. Some researchers and companies are moving in that direction. For example, synthesis firm Molecular Assemblies is developing an enzymatic process to write long stretches of DNA with fewer errors.

Synthesis speeds and prices have been improving rapidly, and researchers expect they will continue to do so. From my point of view, building DNA is no longer the bottleneck, says Daniel G. Gibson, vice president of DNA technology at Synthetic Genomics and an associate professor at the J. Craig Venter Institute (JCVI). Some way or another, if we need to build larger pieces of DNA, well do that.

Gibson isnt involved with GP-write. But his research showcases what is possible with todays toolseven if they are equivalent to Gutenbergs movable type. He has been responsible for a few of synthetic biologys milestones, including the development of one of the most commonly used genome-assembly techniques.

The Gibson method uses chemical means to join DNA fragments, yielding pieces thousands of bases long. For two fragments to connect, one must end with a 20- to 40-base sequence thats identical to the start of the next fragment. These overlapping DNA fragments can be mixed with a solution of three enzymesan exonuclease, a DNA polymerase, and a DNA ligasethat trim the 5 end of each fragment, overlap the pieces, and seal them together.

To make the first synthetic bacterial genome in 2008, that of Mycoplasma genitalium, Gibson and his colleagues at JCVI, where he was a postdoc at the time, started with his eponymous in vitro method. They synthesized more than 100 fragments of synthetic DNA, each about 5,000 bases long, and then harnessed the prodigious DNA-processing properties of yeast, introducing these large DNA pieces to yeast three or four at a time. The yeast used its own cellular machinery to bring the pieces together into larger sequences, eventually producing the entire Mycoplasma genome.

Next, the team had to figure out how to transplant this synthetic genome into a bacterial cell to create what the researchers called the first synthetic cell. The process is involved and requires getting the bacterial genome out of the yeast, then storing the huge, fragile piece of circular DNA in a protective agarose gel before melting it and mixing it with another species of Mycoplasma. As the bacterial cells fuse, some of them take in the synthetic genomes floating in solution. Then they divide to create three daughter cells, two containing the native genomes, and one containing the synthetic genome: the synthetic cell.

When Gibsons group at JCVI started building the synthetic cell in 2004, we didnt know what the limitations were, he says. So the scientists were cautious about overwhelming the yeast with too many DNA fragments, or pieces that were too long. Today, Gibson says he can bring together about 25 overlapping DNA fragments that are about 25,000 bases long, rather than three or four 5,000-base segments at a time.

Gibson expects that existing DNA synthesis and assembly methods havent yet been pushed to their limits. Yeast might be able to assemble millions of bases, not just hundreds of thousands, he says. Still, Gibson believes it would be a stretch to make a human genome with this technique.

One of the most ambitious projects in genome writing so far centers on that master DNA assembler, yeast. As part of the project, called Sc2.0 (a riff on the funguss scientific name, Saccharomyces cerevisiae), an international group of scientists is redesigning and building yeast one synthetic chromosome at a time. The yeast genome is far simpler than ours. But like us, yeasts are eukaryotes and have multiple chromosomes within their nuclei.

Synthetic biologists arent interested in rebuilding existing genomes by rote; they want to make changes so they can probe how genomes work and make them easier to build and reengineer for practical use. The main lesson learned from Sc2.0 so far, project scientists say, is how much the yeast chromosomes can be altered in the writing, with no apparent ill effects. Indeed, the Sc2.0 sequence is not a direct copy of the original. The synthetic genome has been reduced by about 8%. Overall, the research group will make 1.1 million bases worth of insertions, deletions, and changes to the yeast genome (Science 2017, DOI: 10.1126/science.aaf4557).

So far, says Boeke, whos also coleader of Sc2.0, teams have finished or almost finished the first draft of the organisms 16 chromosomes. Theyre also working on a neochromosome, one not found in normal yeast. In this chromosome, the designers have relocated all DNA coding for transfer RNA, which plays a critical role in protein assembly. The Sc2.0 group isolated these sequences because scientists predicted they would cause structural instability in the synthetic chromosomes, says Joel Bader, a computational biologist at Johns Hopkins University who leads the projects software and design efforts.

The team is making yeast cells with a new chromosome one at a time. The ultimate goal is to create a yeast cell that contains no native chromosomes and all 17 synthetic ones. To get there, the scientists are taking a relatively old-fashioned approach: breeding. So far, theyve made a yeast cell with three synthetic chromosomes and are continuing to breed it with strains containing the remaining ones. Once a new chromosome is in place, it requires some patching up because of recombination with the native chromosomes. Its a process, but it doesnt look like there are any significant barriers, Bader says. He estimates it will take another two to three years to produce cells with the entire Sc2.0 genome.

So far, even with these significant changes to the chromosomes, the yeast lives at no apparent disadvantage compared with yeast that has its original chromosomes. Its surprising how much you can torture the genome with no effect, Boeke says.

Boeke and Bader have founded a start-up company called Neochromosome that will eventually use Sc2.0 strains to produce large protein drugs, chemical precursors, and other biomolecules that are currently impossible to make in yeast or E. coli because the genetic pathways used to create them are too complex. With synthetic chromosomes well be able to make these large supportive pathways in yeast, Bader predicts.

Whether existing genome-engineering methods like those used in Sc2.0 will translate to humans is an open question.

Bader believes that yeast, so willing to take up and assemble large amounts of DNA, might serve as future human-chromosome producers, assembling genetic material that could then be transferred to other organisms, perhaps human cells. Transplanting large human chromosomes would be tricky, Synthetic Genomics Gibson says. First, the recipient cell must be prepped by somehow removing its native chromosome. Gibson expects physically moving the synthetic chromosome would also be difficult: Stretches of DNA larger than about 50,000 bases are fragile. You have to be very gentle so the chromosome doesnt breakonce its broken, its not going to be useful, he says. Some researchers are working on more direct methods for cell-to-cell DNA transfer, such as getting cells to fuse with one another.

Once the scientists solve the delivery challenge, the next question is whether the transplanted chromosome will function. Our genomes are patterned with methyl groups that silence regions of the genome and are wrapped around histone proteins that pack the long strands into a three-dimensional order in cells nuclei. If the synthetic chromosome doesnt have the appropriate methylation patterns, the right structure, it might not be recognized by the cell, Gibson says.

Biologists might sidestep these epigenetic and other issues by doing large-scale DNA assembly in human cells from the get-go. Ron Weiss, a synthetic biologist at Massachusetts Institute of Technology, is pushing the upper limits on this sort of approach. He has designed methods for inserting large amounts of DNA directly into human cells. Weiss endows human cells with large circuits, which are packages of engineered DNA containing groups of genes and regulatory machinery that will change a cells behavior.

In 2014, Weiss developed a landing pad method to insert about 64,000-base stretches of DNA into human and other mammalian cells. First, researchers use gene editing to create the landing pad, which is a set of markers at a designated spot on a particular chromosome where an enzyme called a recombinase will insert the synthetic genetic material. Then they string together the genes for a given pathway, along with their regulatory elements, add a matching recombinase site, and fashion this strand into a circular piece of DNA called a plasmid. The target cells are then incubated with the plasmid, take it up, and incorporate it at the landing site (Nucleic Acids Res. 2014, DOI: 10.1093/nar/gku1082).

This works, but its tedious. It takes about two weeks to generate these cell lines if youre doing well, and the payload only goes into a few of the cells, Weiss explains. Since his initial publication, he says, his team has been able to generate cells with three landing pads; that means they could incorporate a genetic circuit thats about 200,000 bases long.

Weiss doesnt see simple scale-up of the landing pad method as the way forward, though, even setting aside the tedium. He doesnt think the supersized circuits would even function in a human cell because he doesnt yet know how to design them.

The limiting factor in the size of the circuit is not the construction of DNA, but the design, Weiss says. Instead of working completely by trial and error, bioengineers use computer models to predict how synthetic circuits or genetic edits will work in living cells of any species. But the larger the synthetic element, the harder it is to know whether it will work in a real cell. And the more radical the deletion, the harder it is to foresee whether it will have unintended consequences and kill the cell. Researchers also have a hard time predicting the degree to which cells will express the genes in a complex synthetic circuita lot, a little, or not at all. Gene regulation in humans is not fully understood, and rewriting on the scale done in the yeast chromosome would have far less predictable outcomes.

Besides being willing to take up and incorporate DNA, yeast is relatively simple. Upstream from a yeast gene, biologists can easily find the promoter sequence that turns it on. In contrast, human genes are often regulated by elements found in distant regions of the genome. That means working out how to control large pathways is more difficult, and theres a greater risk that changing the genetic sequencesuch as deleting what looks like repetitive nonsensewill have unintended, currently unpredictable, consequences.

Gibson notes that even in the minimal cell, the organism with the simplest known genome on the planet, biologists dont know what one-third of the genes do. Moving from the simplest organism to humans is a leap into the unknown. One design flaw can change how the cell behaves or even whether the cells are viable, Gibson says. We dont have the design knowledge.

Many scientists believe this uncertainty about design is all the more reason to try writing human and other large genomes. People are entranced with the perfect, Harvards Church says. But engineering and medicine are about the pretty good. I learn much more by trying to make something than by observing it.

Others arent sure that the move from writing the yeast genome to writing the human genome is necessary, or ethical. When the project to write the human genome was made public in May 2016, the founders called it Human Genome Project-write. They held the first organizational meeting behind closed doors, with no journalists present. A backlash ensued.

In the magazine Cosmos, Stanford University bioengineer Drew Endy and Northwestern University ethicist Laurie Zoloth in May 2016 warned of unintended consequences of large-scale changes to the genome and of alienating the public, potentially putting at risk funding for the synthetic biology field at large. They wrote that the synthesis of less controversial and more immediately useful genomes along with greatly improved sub-genomic synthesis capacities should be pursued instead.

GP-write members seem to have taken such criticisms to heart, or come to a similar conclusion on their own. By this Mays conference, human was dropped from the projects name. Leaders emphasized that the human genome would be a subproject proceeding on a conservative timescale and that ethicists would be involved at every step along the way. We want to separate the overarching goal of technology development from the hot-button issue of human genome writing, Boeke explains.

Bringing the public on board with this kind of project can be difficult, says Alta Charo, a professor of law and bioethics at the University of Wisconsin, Madison, who is not involved with GP-write. Charo cochaired a National Academy of Sciences study on the ethics and governance of human gene editing, which was published in February.

She says the likelihood of positive outcomes, such as new therapies or advances in basic science, must be weighed against potential unintended consequences or unforeseen uses of genome writing. People see their basic values at stake in human genetic engineering. If scientists achieve their goalsmaking larger scale genetic engineering routine and more useful, and bringing it to the human genomemajor changes are possible to what Charo calls the fabric of our culture and society. People will have to decide whether they feel optimistic about that or not. (Charo does.)

Given humans cautiousness, Charo imagines in early times we might have decided against creating fire, saying, Lets live without that; we dont need to create this thing that might destroy us. People often see genetic engineering in extreme terms, as a fire that might illuminate human biology and light the way to new technologies, or one that will destroy us.

Charo says the GP-write plan to keep ethicists involved going forward is the right approach and that its difficult to make an ethical or legal call on the project until its leaders put forward a road map.

The group will announce a specific road map sometime this year, but it doesnt want to be restrictive ahead of time. You know when youre done reading something, Boeke said at the meeting in May. But writing has an artistic side to it, he added. You never know when youre done.

Katherine Bourzac is a freelance science writer based in San Francisco.

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Writing the human genome - The Biological SCENE

So she kept fast by the maidens of Boaz to glean unto the end of barley harvest and of wheat harvest; and she dwelt with her mother-in-law. Ruth 2:23 (The Israel Bible)

Wild emmer wheat spike (Photo: Raz Avni)

A global team of researchers has published the first-ever Wild Emmer wheat genome sequence inSciencemagazine (Wild emmer genome architecture and diversity elucidate wheat evolution and domestication).

Wild Emmer wheat is the original form of nearly all the domesticated wheat in the world, including durum (pasta) and bread wheat. Wild emmer is too low-yielding to be of use to farmers today, but it contains many attractive characteristics that are being used by plant breeders to improve wheat.

The study was led by Dr. Assaf Distelfeld of Tel Aviv Universitys School of Plant Sciences and Food Security and Institute for Cereal Crops Improvement, in collaboration with several dozen scientists from institutions around the world and an Israel-based company, NRGene, which developed the bioinformatics technology that accelerated the research.

This research is a synergistic partnership among public and private entities, said Dr. Daniel Chamovitz, Dean of TAUs George S. Wise Faculty of Life Sciences, who was also involved in the research. Ultimately, this research will have a significant impact on global food security.

Our ability to generate the Wild Emmer wheat genome sequence so rapidly is a huge step forward in genomic research, said Dr. Curtis Pozniak from the University of Saskatchewan, a project team member and Chair of the Canadian Ministry of Agriculture Strategic Research Program. Wheat accounts for almost 20% of the calories humans consume worldwide, so a strong focus on improving the yield and quality of wheat is essential for our future food supply.

From a biological and historical viewpoint, we have created a time tunnel we can use to examine wheat from before the origins of agriculture, said Dr. Distelfeld. Our comparison to modern wheat has enabled us to identify the precise genes that allowed domestication the transition from wheat grown in the wild to modern day varieties. While the seeds of wild wheat readily fall off the plant and scatter, a change in two genes meant that in domesticated wheat, the seeds remained attached to the stalk; it is this trait that enabled humans to harvest wheat.

This new resource allowed us to identify a number of other genes controlling main traits that were selected by early humans during wheat domestication and that served as foundation for developing modern wheat cultivars, said Dr. Eduard Akhunov of Kansas State University. These genes provide invaluable resource for empowering future breeding efforts. Wild Emmer is known as a source of novel variation that can help to improve the nutritional quality of grain as well as tolerance to diseases and water-limiting conditions.

New genomic tools are already being implemented to identify novel genes for wheat production improvement under changing environment, explains Dr. Zvi Peleg of the Hebrew University of Jerusalem, Israel. While many modern wheat cultivars are susceptible to water stress, Wild Emmer has undergone a long evolutionary history under the drought-prone Mediterranean climate. Thus, utilization of the wild genes in wheat breeding program promote producing more yield for less water.

The wheat genome is much more complex than most of the other crops and has a genome three times the size of a human genome. said Dr. Gil Ronen, NRGenes CEO. Still, the computational technology we developed has allowed us to quickly assemble the very large and complex genome found in Wild Emmers 14 chromosomes, to a standard never achieved before in genomic studies.

For the first time, the sequences of the 14 chromosomes of wild emmer wheat are collapsed into a refined order, thanks to additional technology that utilizes DNA and protein links. It was originally tested in humans and recently demonstrated in barley, both of which have smaller genomes than Wild Emmer wheat. says Dr. Nils Stein, the Head of Genomics of Genetic Resources at Leibniz Institute of Plant Genetics and Crop Plant Research in Germany. These innovative technologies have changed the game in assembling the large cereal genomes,

This sequencing approach used for Wild Emmer wheat is unprecedented and has paved the way to sequence durum wheat (the domesticated form of Wild Emmer). Now we can better understand how humanity transformed this wild plant into a modern, high-yielding durum wheat, said Dr. Luigi Cattivelli, coauthor of the work and coordinator of the International Durum Wheat Genome Sequencing Consortium.

We now have the tools to study crops directly and to make and apply our discoveries more efficiently than ever before, concluded Dr. Distelfeld.

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Study Led By Israeli Scientist Discovers Wild Wheat Genome Sequencing - Breaking Israel News

An international research team led by Tel Aviv University scientist Dr. Assaf Distelfeld has reconstructed the genome of the wild wheat Triticum turgidum, the original form of nearly all the domesticated wheat in the world.

Triticum turgidum. Image credit: Stan Shebs / CC BY-SA 3.0.

Wheat is one of the founder crops that likely drove the Neolithic transition to agrarian societies in the Fertile Crescent more than 10,000 years ago.

Its domestication caused a shift in traits, which mostly relate to seed dormancy, spike morphology, and grain development.

For example, while the spikes of wild wheat shatter at maturity, all domesticated wheat spikes remain intact, which enables easier harvest.

From a biological and historical viewpoint, we have created a time tunnel we can use to examine wheat from before the origins of agriculture, Dr. Distelfeld said.

To reconstruct the 14 chromosomes of Triticum turgidum, Dr. Distelfeld and co-authors used 3D genetic sequencing data and software.

The wheat genome is much more complex than most of the other crops and has a genome three times the size of a human genome, said co-author Dr. Gil Ronen, CEO of NRGene Ltd, Israel.

Still, the computational technology we developed has allowed us to quickly assemble the very large and complex genome found in wild wheats 14 chromosomes, to a standard never achieved before in genomic studies.

Our ability to generate the wild wheat genome sequence so rapidly is a huge step forward in genomic research, added co-author Dr. Curtis Pozniak, from the University of Saskatchewan.

Wheat accounts for almost 20% of the calories humans consume worldwide, so a strong focus on improving the yield and quality of wheat is essential for our future food supply.

In order to understand genetic changes underlying the evolutionary transition to a non-shattering state, the researchers compared genes responsible for shattering in domesticated wheat to the corresponding genes in wild wheat.

They identified two clusters of genes in domesticated wheat that have lost their function.

When they engineered strains of wheat with one of these gene clusters restored, the wheat exhibited unique spikes where the upper part was brittle and the lower part was not brittle.

These results suggest that the two gene clusters play a part in the transforming the brittle qualities of wild wheat.

Our comparison to modern wheat has enabled us to identify the precise genes that allowed domestication the transition from wheat grown in the wild to modern day varieties, Dr. Distelfeld said.

While the seeds of wild wheat readily fall off the plant and scatter, a change in two genes meant that in domesticated wheat, the seeds remained attached to the stalk; it is this trait that enabled humans to harvest wheat.

This research is a synergistic partnership among public and private entities, said co-author Dr. Daniel Chamovitz, of Tel Aviv University.

Ultimately, this research will have a significant impact on global food security.

The research is published in the journal Science.

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Raz Avni et al. 2017. Wild emmer genome architecture and diversity elucidate wheat evolution and domestication. Science 357 (6346): 93-97; doi: 10.1126/science.aan0032

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Researchers Reconstruct Genome of Wild Wheat - Sci-News.com

The latest annual report of the Chief Medical Officer for England has recommended that personalised medicine approaches be adopted widely within the UK's NHS (National Health Service).

'Genomic medicine has huge implications for the understanding and treatment of rare diseases, cancer and infections,' says Professor Dame Sally Davies' report 'Generation Genome'. Patients should also benefit from speedier diagnosis and receiving the best available treatment.

It is hoped that the cost of sequencing, which continues to fall, will be offset by avoiding the wasted treatments and appointments caused by the current trial-and-error approach. The cost could be further reduced by concentrating the current 'cottage industry' of sequencing and interpreting genomes into a few specialist centres.

Around two-thirds of cancers currently have what are known as 'actionable genes', which allow a range of outcomes to be predicted with much greater accuracy than was previously possible. The number of these genes, and the number of cancers known to have them, are likely to rise as research progresses.

Actionable genes can indicate whether a patient is likely to suffer severe side effects from some treatments, whether a given treatment is likely to be effective, or even how likely a patient's cancer is to recur. These factors, if known, can help clinicians recommend the best treatment options for a given patient.

Sir Harpal Kumar, chief executive of Cancer Research UK, welcomed the report saying that it 'showcases just how much is now possible in genomics research and care within the NHS'. He told UK newspaper the Telegraph: 'Further understanding and application of genomics will be essential to successfully tackling cancer and saving many more lives from this devastating disease.'

Genome sequencing could also help diagnose individuals with rare diseases, many of which present in children and have a genetic basis. These can often take years to diagnose, and patients may end up seeing multiple specialists before receiving a diagnosis (see BioNews 903).

There are some concerns about data security, however. The NHS track record for IT includes a cyber attack in May this year, and a National Program for IT which consumed over 11 billion between 2002 and 2011 before it was eventually scrapped.

'This technology has the potential to change medicine forever but we need all NHS staff, patients and the public to recognise and embrace its huge potential,' said Professor Davies.

Visit link:
Generation Genome - sequencing is future for NHS, says report - BioNews

Photo Credit: Raz Avni

A global team of researchers has published the first-ever Wild Emmer wheat genome sequence inSciencemagazine (Wild emmer genome architecture and diversity elucidate wheat evolution and domestication).

Wild Emmer wheat is the original form of nearly all the domesticated wheat in the world, including durum (pasta) and bread wheat. Wild emmer is too low-yielding to be of use to farmers today, but it contains many attractive characteristics that are being used by plant breeders to improve wheat.

The study was led by Dr. Assaf Distelfeld of Tel Aviv Universitys School of Plant Sciences and Food Security and Institute for Cereal Crops Improvement, in collaboration with several dozen scientists from institutions around the world and an Israel-based company, NRGene, which developed the bioinformatics technology that accelerated the research.

This research is a synergistic partnership among public and private entities, said Dr. Daniel Chamovitz, Dean of TAUs George S. Wise Faculty of Life Sciences, who was also involved in the research. Ultimately, this research will have a significant impact on global food security.

Our ability to generate the Wild Emmer wheat genome sequence so rapidly is a huge step forward in genomic research, said Dr. Curtis Pozniak from the University of Saskatchewan, a project team member and Chair of the Canadian Ministry of Agriculture Strategic Research Program. Wheat accounts for almost 20% of the calories humans consume worldwide, so a strong focus on improving the yield and quality of wheat is essential for our future food supply.

From a biological and historical viewpoint, we have created a time tunnel we can use to examine wheat from before the origins of agriculture, said Dr. Distelfeld. Our comparison to modern wheat has enabled us to identify the precise genes that allowed domestication the transition from wheat grown in the wild to modern day varieties. While the seeds of wild wheat readily fall off the plant and scatter, a change in two genes meant that in domesticated wheat, the seeds remained attached to the stalk; it is this trait that enabled humans to harvest wheat.

This new resource allowed us to identify a number of other genes controlling main traits that were selected by early humans during wheat domestication and that served as foundation for developing modern wheat cultivars, said Dr. Eduard Akhunov of Kansas State University. These genes provide invaluable resource for empowering future breeding efforts. Wild Emmer is known as a source of novel variation that can help to improve the nutritional quality of grain as well as tolerance to diseases and water-limiting conditions.

New genomic tools are already being implemented to identify novel genes for wheat production improvement under changing environment, explains Dr. Zvi Peleg of the Hebrew University of Jerusalem, Israel. While many modern wheat cultivars are susceptible to water stress, Wild Emmer has undergone a long evolutionary history under the drought-prone Mediterranean climate. Thus, utilization of the wild genes in wheat breeding program promote producing more yield for less water.

The wheat genome is much more complex than most of the other crops and has a genome three times the size of a human genome. said Dr. Gil Ronen, NRGenes CEO. Still, the computational technology we developed has allowed us to quickly assemble the very large and complex genome found in Wild Emmers 14 chromosomes, to a standard never achieved before in genomic studies.

For the first time, the sequences of the 14 chromosomes of wild emmer wheat are collapsed into a refined order, thanks to additional technology that utilizes DNA and protein links. It was originally tested in humans and recently demonstrated in barley, both of which have smaller genomes than Wild Emmer wheat. says Dr. Nils Stein, the Head of Genomics of Genetic Resources at Leibniz Institute of Plant Genetics and Crop Plant Research in Germany. These innovative technologies have changed the game in assembling the large cereal genomes,

This sequencing approach used for Wild Emmer wheat is unprecedented and has paved the way to sequence durum wheat (the domesticated form of Wild Emmer). Now we can better understand how humanity transformed this wild plant into a modern, high-yielding durum wheat, said Dr. Luigi Cattivelli, coauthor of the work and coordinator of the International Durum Wheat Genome Sequencing Consortium.

We now have the tools to study crops directly and to make and apply our discoveries more efficiently than ever before, concluded Dr. Distelfeld.

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Wild Wheat Genome Sequencing May Boost Future Food Production, Safety - The Jewish Press - JewishPress.com

July 5, 2017 Genome-wide distribution of fast-neutron-induced mutations in the Kitaake rice mutant population (green). The genome-wide distribution of mutations indicates a non-biased saturation of the genome. Colored lines (center) represent translocations of DNA fragments from one chromosome to another. Credit: Guotian Li and Rashmi Jain/Berkeley Lab

Rice is a staple food for over half of the world's population and a model for studies of candidate bioenergy grasses such as sorghum, switchgrass, and Miscanthus. To optimize crops for biofuel production, scientists are seeking to identify genes that control key traits such as yield, resistance to disease, and water use efficiency.

Populations of mutant plants, each one having one or more genes altered, are an important tool for elucidating gene function. With whole-genome sequencing at the single nucleotide level, researchers can infer the functions of the genes by observing the gain or loss of particular traits. But the utility of existing rice mutant collections has been limited by several factors, including the cultivars' relatively long six-month life cycle and the lack of sequence information for most of the mutant lines.

In a paper published in The Plant Cell, a team led by Pamela Ronald, a professor in the Genome Center and the Department of Plant Pathology at UC Davis and director of Grass Genetics at the Department of Energy's (DOE's) Joint BioEnergy Institute (JBEI), with collaborators from UC Davis and the DOE Joint Genome Institute (JGI), reported the first whole-genome-sequenced, fast-neutron-induced mutant population of Kitaake, a model rice variety with a short life cycle.

Kitaake (Oryza sativa L. ssp. japonica) completes its life cycle in just nine weeks and is not sensitive to photoperiod changes. This novel collection will accelerate functional genetic research in rice and other monocots, a type of flowering plant species that includes grasses.

"Some of the most popular rice varieties people use right now only have two generations per year. Kitaake has up to four, which really speeds up functional genomics work," said Guotian Li, a project scientist at Lawrence Berkeley National Laboratory (Berkeley Lab) and deputy director of Grass Genetics at JBEI.

In a previously published pilot study, Li, Mawsheng Chern, and Rashmi Jain, co-first authors on The Plant Cell paper, demonstrated that fast-neutron irradiation produced abundant and diverse mutations in Kitaake, including single base substitutions, deletions, insertions, inversions, translocations, and duplications. Other techniques that have been used to generate rice mutant populations, such as the insertion of gene and chromosome segments and the use of gene editing tools like CRISPR-Cas9, generally produce a single type of mutation, Li noted.

"Fast-neutron irradiation causes different types of mutations and gives different alleles of genes so we really can get something that's not achievable from other collections," he said.

Whole-genome sequencing of this mutant population - 1,504 lines in total with 45-fold coverage - allowed the researchers to pinpoint each mutation at a single-nucleotide resolution. They identified 91,513 mutations affecting 32,307 genes, 58 percent of all genes in the roughly 389-megabase rice genome. A high proportion of these were loss-of-function mutations.

Using this mutant collection, the Grass Genetics group identified an inversion affecting a single gene as the causative mutation for the short-grain phenotype in one mutant line with a population containing just 50 plants. In contrast, researchers needed more than 16,000 plants to identify the same gene using the conventional approach.

"This comparison clearly demonstrates the power of the sequenced mutant population for rapid genetic analysis," said Ronald.

This high-density, high-resolution catalog of mutations provides researchers opportunities to discover novel genes and functional elements controlling diverse biological pathways. To facilitate open access to this resource, the Grass Genetics group has established a web portal called KitBase, which allows users to find information related to the mutant collection, including sequence, mutation and phenotypic data for each rice line.

Explore further: Scientists discover gene that influences grain yield

More information: Guotian Li et al, The Sequences of 1,504 Mutants in the Model Rice Variety Kitaake Facilitate Rapid Functional Genomic Studies, The Plant Cell (2017). DOI: 10.1105/tpc.17.00154

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A whole-genome sequenced rice mutant resource for the study of biofuel feedstocks - Phys.Org