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End of cancer-genome project prompts to rethink: Should effort switch from sequencing to functional analysis?

End of cancer-genome project prompts to rethink: Should effort switch from sequencing to functional analysis? | Amazing Science | Scoop.it

A mammoth US effort to genetically profile 10,000 tumors has officially come to an end. Started in 2006 as a US$100-million pilot, The Cancer Genome Atlas (TCGA) is now the biggest component of the International Cancer Genome Consortium, a collaboration of scientists from 16 nations that has discovered nearly 10 million cancer-related mutations.


The question is what to do next. Some researchers want to continue the focus on sequencing; others would rather expand their work to explore how the mutations that have been identified influence the development and progression of cancer.


“TCGA should be completed and declared a victory,” says Bruce Stillman, president of Cold Spring Harbor Laboratory in New York. “There will always be new mutations found that are associated with a particular cancer. The question is: what is the cost–benefit ratio?”


Stillman was an early advocate for the project, even as some researchers feared that it would drain funds away from individual grants. Initially a three-year project, it was extended for five more years. In 2009, it received an additional $100 million from the US National Institutes of Health plus $175 million from stimulus funding that was intended to spur the US economy during the global economic recession.


On 2 December, Staudt announced that once TCGA is completed, the NCI will continue to intensively sequence tumours in three cancers: ovarian, colorectal and lung adenocarcinoma. It then plans to evaluate the fruits of this extra effort before deciding whether to add back more cancers. But this time around, the studies will be able to incorporate detailed clinical information about the patient’s health, treatment history and response to therapies. Because researchers can now use paraffin-embedded samples, they can tap into data from past clinical trials, and study how mutations affect a patient’s prognosis and response to treatment. Staudt says that the NCI will be announcing a call for proposals to sequence samples taken during clinical trials using the methods and analysis pipelines established by the TCGA.


The rest of the International Cancer Gene Consortium, slated to release early plans for a second wave of projects in February, will probably take a similar tack, says co-founder Tom Hudson, president of the Ontario Institute for Cancer Research in Toronto, Canada. A focus on finding sequences that make a tumour responsive to therapy has already been embraced by government funders in several countries eager to rein in health-care costs, he says. “Cancer therapies are very expensive. It’s a priority for us to address which patients would respond to an expensive drug.”


The NCI is also backing the creation of a repository for data not only from its own projects, but also from international efforts. This is intended to bring data access and analysis tools to a wider swathe of researchers, says Staudt. At present, the cancer genomics data constitute about 20 petabytes (10**15 bytes), and are so large and unwieldy that only institutions with significant computing power can access them. Even then, it can take four months just to download them.

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How DNA Sequencing In Sewers Could Detect Disease Outbreaks

How DNA Sequencing In Sewers Could Detect Disease Outbreaks | Amazing Science | Scoop.it

Disease prevention and mapmaking have been inextricably intertwined since 1854, when an English physician named John Snow plotted a cholera outbreak on a grid to locate–and shut down–a bacteria-tainted water pump, inventing the modern science of epidemiology along the way.

In 2010 geneticist Eric Schadt, then the chief scientific officer at DNA sequencer maker Pacific Biosciences, had a brainstorm as to how to update Snow’s breakthrough for the modern age. The germs that infect us–everything from influenza to measles to bubonic plague–wind up in our waste. Why not look for them by using DNA technology to sequence raw sewage?


Snippets of DNA in wastewater could then be matched to known pathogens–and specific physical locations. Public health officials would no longer have to wait for someone to spike a fever to know that Ebola virus was in Manhattan–they would be alerted by the sequences coming from the sewers, and they would know within a few blocks where it was.


Schadt tried the project out using samples from the San Francisco sewers, but bringing sewage back to PacBio’s expensive, heavy sequencers was impractical at best. Christopher Mason, a Weill Cornell Medical College professor, has picked up a simpler version of the idea, applying swabs to surfaces all over New York City to create a “Pathomap” of germs that will be unveiled early next year.


But Schadt, who now heads a sweeping Carl Icahn-funded genomics effort at the Mount Sinai School of Medicine in Manhattan, still wants a more detailed map produced automatically from sewage. Possible? One new DNA sequencer, made by Oxford Nanopore, is a thumb drive that can take sequences on the spot. Who knows what another generation of innovation could bring? Says Mason: “It’s futuristic, but not unrealistic.”



Via Integrated DNA Technologies
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Singapore scientists develop genome-wide mutation hunting computational software for genomic medicine

Singapore scientists develop genome-wide mutation hunting computational software for genomic medicine | Amazing Science | Scoop.it

Phen-Gen is the first computer analysis software that cross-references a patient’s symptoms and a person’s genome sequence, to better aid doctors in diagnosing diseases. The software was created by a team of scientists at A*STAR’s Genome Institute of Singapore (GIS), led by Dr. Pauline Ng. Results from the research were published in the prestigious journal Nature Methods on 4th August 2014.
 
Phen-Gen can detect faulty genes responsible for diseases by up to 88 per cent, yielding results in 15 to 30 minutes. It has been proven to be faster and more efficient compared to current methods analysing genomes for this purpose.
 
One area that Dr Ng is currently working on is incorporating the Phen-Gen technique in the diagnosis of rare diseases. Rare diseases are often hard to diagnose based on symptoms alone. By using Phen-Gen, doctors are able to make a more accurate diagnosis based on a patient’s unique genetic code.
 
Dr Ng’s team is working with doctors in local and international hospitals to incorporate Phen-Gen to diagnose patients with rare disorders.  “We aim to translate scientific research to help people directly,” said senior author Pauline Ng. “To this end, GIS has created a programme to help diagnose patients with rare disorders. Phen-Gen works with both exome and whole genome sequencing data. It is the first algorithm to leverage disease symptoms and give genome-wide predictions.”
 
Most rare diseases, such as those that affect neurological, brain or cardiac development, manifest early in life. “There is little else more satisfying than the opportunity to help a sick patient, and through our research at GIS, we want others in the world to benefit as well,” said first author Dr. Asif Javed. “The program is also downloadable online for those who prefer to keep their DNA information private.”
 
The Executive Director of the GIS, Prof. Ng Huck Hui, commented “As we enter the genomics era with more powerful Next-Generation Sequencing technologies that can analyse the human genomes at a reduced cost, data analytics becomes a bottleneck. Dr. Pauline Ng’s group has taken on this exciting challenge to develop analytics capabilities. In partnership with the Singapore hospitals, the GIS has initiated a research project on sequencing patients with undiagnosed conditions or congenital disorders. The Phen-Gen method is timely as it fills an urgent gap in hospitals for accurate diagnosis of rare diseases.”

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Tooth loss in birds occurred about 116 million years ago

Tooth loss in birds occurred about 116 million years ago | Amazing Science | Scoop.it

The absence of teeth or "edentulism" has evolved on multiple occasions within vertebrates including birds, turtles, and a few groups of mammals such as anteaters, baleen whales and pangolins. Where early birds are concerned, the fossil record is fragmentary. A question that has intrigued biologists is: Based on this fossil record, were teeth lost in the common ancestor of all living birds or convergently in two or more independent lineages of birds? A research team led by biologists at the University of California, Riverside and Montclair State University, NJ, has found an answer. Using the degraded remnants of tooth genes in birds to determine when birds lost their teeth, the team reports in the Dec. 12 issue ofScience that teeth were lost in the common ancestor of all living birds more than 100 million years ago.


"One of the larger lessons of our finding is that 'dead genes,' like the remnants of dead organisms that are preserved in the fossil record, have a story to tell," said Mark Springer, a professor of biology and one of the lead authors of the study along with Robert Meredith at Montclair State University who was previously a graduate student and postdoctoral researcher in Springer's laboratory. "DNA from the crypt is a powerful tool for unlocking secrets of evolutionary history."


Springer explained that edentulism and the presence of a horny beak are hallmark features of modern birds. "Ever since the discovery of the fossil bird Archaeopteryx in 1861, it has been clear that living birds are descended from toothed ancestors," he said. "However, the history of tooth loss in the ancestry of modern birds has remained elusive for more than 150 years."


All toothless/enamelless vertebrates are descended from an ancestor with enamel-capped teeth. In the case of birds, it is theropod dinosaurs. Modern birds use a horny beak instead of teeth, and part of their digestive tract to grind up and process food.

Tooth formation in vertebrates is a complicated process that involves many different genes. Of these genes, six are essential for the proper formation of dentin (DSPP) and enamel (AMTN, AMBN, ENAM, AMELX, MMP20).


The researchers examined these six genes in the genomes of 48 bird species, which represent nearly all living bird orders, for the presence of inactivating mutations that are shared by all 48 birds. The presence of such shared mutations in dentin and enamel-related genes would suggest a single loss of mineralized teeth in the common ancestor of all living birds.


Springer, Meredith, and other members of their team found that the 48 bird species share inactivating mutations in both dentin-related (DSPP) and enamel-related genes (ENAMAMELX, AMTNMMP20), indicating that the genetic machinery necessary for tooth formation was lost in the common ancestor of all modern birds.

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Human genomes are extraordinarily individual, study finds

Human genomes are extraordinarily individual, study finds | Amazing Science | Scoop.it

In 2001 scientists announced the successful decoding of the first human genome. Since then, thousands more have been sequenced. The price of a genetic analysis will soon fall below the 1,000 dollar mark. Given this rapid pace of development, it’s easy to forget that the technology used only reads a mixed product of genetic information.


The analytical methods commonly employed do not take into account the fact that every person has two sets of genetic material. “So they are ignoring an essential property of the human genome. However, it’s important to know, for example, how mutations are distributed between the two chromosome sets,” says Margret Hoehe from the Max Planck Institute for Molecular Genetics, who carried out the study.


Hoehe and her team have developed molecular genetic and bioinformatic methods that make it possible to sequence the two sets of chromosomes in a human separately. The researchers decoded the maternal and paternal parts of the genome in 14 people and supplemented their analysis with the genetic material of 372 Europeans from the 1000 Genomes Project. “Fourteen people may not sound like a lot, but given the technical challenge, it is an unprecedented achievement,” says Hoehe.


The results show that most genes can occur in many different forms within a population: On average, about 250 different forms of each gene exist. The researchers found around four million different gene forms just in the 400 or so genomes they analysed. This figure is certain to increase as more human genomes are examined. More than 85 percent of all genes have no predominant form which occurs in more than half of all individuals. This enormous diversity means that over half of all genes in an individual, around 9,000 of 17,500, occur uniquely in that one person - and are therefore individual in the truest sense of the word.


Some of the many variants that alter the genome also have an effect at the protein level. The researchers have now identified a set of 4,000 genes that are altered by mutations so that their proteins occur especially frequently in two different forms in humans. These genes mainly control signal transmission between cells, the immune system and gene activity. This dual gene and protein arrangement has the advantage that it allows the activity of genes to be more flexibly adjusted and altered. By using the more favourable variant, the body is better able to adapt to changes in its own processes and to environmental conditions. If the duality of genes goes awry and the wrong protein form is used, this can trigger pathogenic mechanisms. This is probably why those 4,000 genes include many disease genes.


These findings will change the interpretation of genetic analyses and the prediction of diseases. Moreover, individualised medicine cannot ignore the “dual nature” of human genomes. “Our investigations at the protein level have shown that 96 percent of all genes have at least 5 to 20 different protein forms. This results in tremendous individual diversity in possible interactions between genes, and shows how daunting the challenge is to develop individually tailored therapies,” says Hoehe.

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For $25 a year, Google will keep a copy of any genome in the cloud

For $25 a year, Google will keep a copy of any genome in the cloud | Amazing Science | Scoop.it

Google is approaching hospitals and universities with a new pitch. Have genomes? Store them with us. The search giant’s first product for the DNA age is Google Genomics, a cloud computing service that it launched last March but went mostly unnoticed amid a barrage of high profile R&D announcements from Google, like one late last month about a far-fetched plan to battle cancer with nanoparticles (see “Can Google Use Nanoparticles to Search for Cancer?”).


Google Genomics could prove more significant than any of these moonshots. Connecting and comparing genomes by the thousands, and soon by the millions, is what’s going to propel medical discoveries for the next decade. The question of who will store the data is already a point of growing competition between Amazon, Google, IBM, and Microsoft.


Google began work on Google Genomics 18 months ago, meeting with scientists and building an interface, or API, that lets them move DNA data into its server farms and do experiments there using the same database technology that indexes the Web and tracks billions of Internet users.


“We saw biologists moving from studying one genome at a time to studying millions,” says David Glazer, the software engineer who led the effort and was previously head of platform engineering for Google+, the social network. “The opportunity is how to apply breakthroughs in data technology to help with this transition.”


Some scientists scoff that genome data remains too complex for Google to help with. But others see a big shift coming. When Atul Butte, a bioinformatics expert at Stanford heard Google present its plans this year, he remarked that he now understood “how travel agents felt when they saw Expedia.”


The explosion of data is happening as labs adopt new, even faster equipment for decoding DNA. For instance, the Broad Institute in Cambridge, Massachusetts, said that during the month of October it decoded the equivalent of one human genome every 32 minutes. That translated to about 200 terabytes of raw data.


This flow of data is smaller than what is routinely handled by large Internet companies (over two months, Broad will produce the equivalent of what gets uploaded to YouTube in one day) but it exceeds anything biologists have dealt with. That’s now prompting a wide effort to store and access data at central locations, often commercial ones. The National Cancer Institute said last month that it would pay $19 million to move copies of the 2.6 petabyte Cancer Genome Atlas into the cloud. Copies of the data, from several thousand cancer patients, will reside both at Google Genomics and in Amazon’s data centers.


The idea is to create “cancer genome clouds” where scientists can share information and quickly run virtual experiments as easily as a Web search, says Sheila Reynolds, a research scientist at the Institute for Systems Biology in Seattle. “Not everyone has the ability to download a petabyte of data, or has the computing power to work on it,” she says.

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corneja's curator insight, November 27, 2014 7:20 PM

"Our genome in the cloud"... it sounds like the title of a song. Google is offering to keep genome data in the cloud.

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Of the difference between mouse and man: A comparative encyclopedia of DNA elements in the mouse genome

Of the difference between mouse and man: A comparative encyclopedia of DNA elements in the mouse genome | Amazing Science | Scoop.it

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, the scientists could not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. These results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.


Advances in DNA sequencing technologies have led to the development of RNA-seq (RNA sequencing), DNase-seq (DNase I hypersensitive sites sequencing), ChIP-seq (chromatin immunoprecipitation followed by DNA sequencing), and other methods that allow rapid and genome-wide analysis of transcription, replication, chromatin accessibility, chromatin modifications and transcription factor binding in cells11. Using these large-scale approaches, the ENCODE consortium has produced a catalog of potential functional elements in the human genome12. Notably, 62% of the human genome is transcribed in one or more cell types13, and 20% of human DNA is associated with biochemical signatures typical of functional elements, including transcription factor binding, chromatin modification and DNase hypersensitivity. The results support the notion that nucleotides outside the mammalian-conserved genomic regions could contribute to species-specific traits61214.


Now, teams of scientists have applied the same high-throughput approaches to over 100 mouse cell types and tissues15, producing a coordinated group of data sets for annotating the mouse genome. Integrative analyses of these data sets uncovered widespread transcriptional activities, dynamic gene expression and chromatin modification patterns, abundant cis-regulatory elements, and remarkably stable chromosome domains in the mouse genome. The generation of these data sets also allowed an unprecedented level of comparison of genomic features of mouse and human. Described in the current article and companion works, these comparisons reveal both conserved sequence features and widespread divergence in transcription and regulation. Some of the key findings are:


  • Although much conservation exists, the expression profiles of many mouse genes involved in distinct biological pathways show considerable divergence from their human orthologues.
  • A large portion of the cis-regulatory landscape has diverged between mouse and human, although the magnitude of regulatory DNA divergence varies widely between different classes of elements active in different tissue contexts.
  • Mouse and human transcription factor networks are substantially more conserved than cis-regulatory DNA.
  • Species-specific candidate regulatory sequences are significantly enriched for particular classes of repetitive DNA elements.
  • Chromatin state landscape in a cell lineage is relatively stable in both human and mouse.
  • Chromatin domains, interrogated through genome-wide analysis of DNA replication timing, are developmentally stable and evolutionarily conserved.


To annotate potential functional sequences in the mouse genome, the scientists used ChIP-seq, RNA-seq and DNase-seq to profile transcription factor binding, chromatin modification, transcriptome and chromatin accessibility in a collection of 123 mouse cell types and primary tissues (Supplementary Tables). Additionally, to interrogate large-scale chromatin organization across different cell types, they also used a microarray-based technique to generate replication-timing profiles in 18 mouse tissues and cell types (Supplementary Table)16. Altogether, they produced over 1,000 data sets. The list of the data sets and all the supporting material for this manuscript are also available at website of the project: http://mouseencode.org.

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Whole-genome sequences of 17 of the world’s oldest living people published

Whole-genome sequences of 17 of the world’s oldest living people published | Amazing Science | Scoop.it

Using 17 genomes, researchers were unable to find rare protein-altering variants significantly associated with extreme longevity, according to a study published November 12, 2014 in the open-access journal PLOS ONE by Hinco Gierman from Stanford University and colleagues.


Supercentenarians are the world’s oldest people, living beyond 110 years of age. Seventy-four are alive worldwide; 22 live in the U.S. The authors of this study performed whole-genome sequencing on 17 supercentenarians to explore the genetic basis underlying extreme human longevity.


From this small sample size, the researchers were unable to find rare protein-altering variants significantly associated with extreme longevity compared to control genomes. However, they did find that one supercentenarian carries a variant associated with a heart condition, which had little or no effect on his/her health, as this person lived over 110 years.


Although the authors didn’t find significant association with extreme longevity, the authors have publicly published the genomes, making them available as a resource for future studies on the genetic basis of extreme longevity.


Reference:

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Deep Sequencing Identifies Noncanonical Editing of Ebola and Marburg Virus RNAs in Infected Cells

Deep Sequencing Identifies Noncanonical Editing of Ebola and Marburg Virus RNAs in Infected Cells | Amazing Science | Scoop.it

Deep sequencing of RNAs produced by Zaire ebolavirus (EBOV) or the Angola strain of Marburgvirus (MARV-Ang) identified novel viral and cellular mechanisms that diversify the coding and noncoding sequences of viral mRNAs and genomic RNAs. A team of scientists now identified previously undescribed sites within the EBOV and MARV-Ang mRNAs where apparent co-transcriptional editing has resulted in the addition of non-template-encoded residues within the EBOV glycoprotein (GP) mRNA, the MARV-Ang nucleoprotein (NP) mRNA, and the MARV-Ang polymerase (L) mRNA, such that novel viral translation products could be produced. Further, they found that the well-characterized EBOV GP mRNA editing site is modified at a high frequency during viral genome RNA replication. Additionally, editing hot spots representing sites of apparent adenosine deaminase activity were found in the MARV-Ang NP 3′-untranslated region. These studies identify novel filovirus-host interactions and reveal production of a greater diversity of filoviral gene products than was previously appreciated.


This study identifies novel mechanisms that alter the protein coding capacities of Ebola and Marburg virus mRNAs. Therefore, filovirus gene expression is more complex and diverse than previously recognized. These observations suggest new directions in understanding the regulation of filovirus gene expression.

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Fact or Fiction?: Mammoths Can Be Brought Back from Extinction

Fact or Fiction?: Mammoths Can Be Brought Back from Extinction | Amazing Science | Scoop.it

In a petri dish in the bowels of Harvard Medical School scientists have tweaked three genes from the cells of an Asian elephant that help control the production of hemoglobin, the protein in blood that carries oxygen. Their goal is to make these genes more like those of an animal that last walked the planet thousands of years ago: the woolly mammoth.

"Asian elephants are closer to mammoths than either is to African elephants, yet quite different in appearance and temperature range," notes Harvard geneticist and technology developer George Church. "We are not trying to make an exact copy of a mammoth, but rather a cold-resistant elephant."
 
But what if the new—and fast advancing—techniques of genome editing allowed scientists to engineer not only cold-resistance traits but also other characteristics of the woolly mammoth into its living Asiatic relatives? Scientists have found mammoth cells preserved in permafrost. If they were to recover cells with intact DNA, they could theoretically “edit” an Asian elephant’s genome to match the woolly mammoth’s. A single cell contains the complete genetic instruction set for its species, and by replicating that via editing a new individual can, theoretically, be created. But wouldsuch a hybrid—scion of an Asian elephant mother and genetic tinkerers—count as a true woolly mammoth?
 
In other words, is de-extinction a real possibility?
 
The answer is yes. On January 6, 2000, a falling tree killed the last bucardo, a wild Iberian ibex, which is a goatlike animal. Her name was Celia. On July 30, 2003, Celia's clone was born. To make the clone scientists removed the nucleus of a cell from Celia intact and inserted it into the unfertilized egg cell of another kind of ibex. They then transferred the resulting embryo to the womb of a living goat. Nearly a year later theydelivered the clone by cutting her from her mother.
 
Although she lived for a scant seven minutes due to lung defects, Celia’s clone proved that not only is de-extinction real, "it has already happened," in the words of environmentalist Stewart Brand, whose San Francisco-based Long Now Foundation is funding some of this de-extinction research, including Church's effort as well as bids to bring back the passenger pigeon and heath hen, among other candidate species. Nor is the bucardo alone in the annals of de-extinction. Several viruses have already been brought back, including the flu variant responsible for the 1918 pandemic that killed more than 20 million people worldwide.

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Siberian thighbone data adjust time of human and Neanderthal interbreeding to around 50,000 years ago

Siberian thighbone data adjust time of human and Neanderthal interbreeding to around 50,000 years ago | Amazing Science | Scoop.it

New research on a 45,000-year-old Siberian thighbone has narrowed the window of time when humans and Neanderthals interbred to between 50,000 and 60,000 years ago, and has shown that modern humans reached northern Eurasia substantially earlier than some scientists thought.


Qiaomei Fu, a postdoctoral fellow at Harvard Medical School (HMS) and first author of a paper describing the research, said the sample had a long history before making its way into her hands.


The bone was found eroding out of a Siberian riverbank, but no one knows precisely where. The bone changed hands several times before finding its way to the Max Planck Institute for Evolutionary Anthropology in Germany, where Fu was working with professors Janet Kelso and Svante Pääbo. Fu put the finishing touches on the research after she started in the laboratory of David Reich, HMS genetics professor.


Carbon dating and molecular analysis filled in many of the blanks about the sample. Testing determined that the sample was from an individual who lived 45,000 years ago on a diet that included plants or plant eaters and fish or other aquatic life.


Reich and Fu said the sample was remarkable because of the extraordinary preservation of its DNA, which allowed Fu, using the latest techniques for ancient DNA analysis, to extract a high-quality genome sequence. The sequence, Reich said, is significantly higher in quality than most genome sequences of present-day people generated for analysis of disease risk.


The sequence revealed that the bone came from a modern human, a man whose remains are the oldest ever found and carbon-dated outside of Africa and the Middle East. Comparison to diverse humans around the world today showed that the man was a member of one of the most ancient non-African populations.


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Geneticist George Church: A Future Without Limits

Geneticist George Church: A Future Without Limits | Amazing Science | Scoop.it

In the future, George Church believes, almost everything will be better because of genetics. If you have a medical problem, your doctor will be able to customize a treatment based on your specific DNA pattern. When you fill up your car, you won't be draining the world's dwindling supply of crude oil, because the fuel will come from microbes that have been genetically altered to produce biofuel. When you visit the zoo, you'll be able to take your children to the woolly mammoth or passenger pigeon exhibits, because these animals will no longer be extinct. You'll be able to do these things, that is, if the future turns out the way Church envisions it—and he's doing everything he can to see that it does.


In 2005 he launched the Personal Genome Project, with the goal of sequencing and sharing the DNA of 100,000 volunteers. With an open-source database of that size, he believes, researchers everywhere will be able to meaningfully pursue the critical task of correlating genetic patterns with physical traits, illnesses, and exposure to environmental factors to find new cures for diseases and to gain basic insights into what makes each of us the way we are. Church, tagged as subject hu43860C, was first in line for testing. Since then, more than 13,000 people in the U.S., Canada, and the U.K. have volunteered to join him, helping to establish what he playfully calls the Facebook of DNA.


Church has made a career of defying the impossible. Propelled by the dizzying speed of technological advancement since then, the Personal Genome Project is just one of Church's many attempts to overcome obstacles standing between him and the future.


"It's not for everyone," he says. "But I see a trend here. Openness has changed since many of us were young. People didn't use to talk about sexuality or cancer in polite society. This is the Facebook generation." If individuals were told which diseases or medical conditions they were genetically predisposed to, they could adjust their behavior accordingly, he reasoned. Although universal testing still isn't practical today, the cost of sequencing an individual genome has dropped dramatically in recent years, from about $7 million in 2007 to as little as $1,000 today.


"It's all too easy to dismiss the future," he says. "People confuse what's impossible today with what's impossible tomorrow.", especially through the emerging discipline of "synthetic" biology. The basic idea behind synthetic biology, he explained, was that natural organisms could be reprogrammed to do things they wouldn't normally do, things that might be useful to people. In pursuit of this, researchers had learned not only how to read the genetic code of organisms but also how to write new code and insert it into organisms. Besides making plastic, microbes altered in this way had produced carpet fibers, treated wastewater, generated electricity, manufactured jet fuel, created hemoglobin, and fabricated new drugs. But this was only the tip of the iceberg, Church wrote. The same technique could also be used on people.


"Every cell in our body, whether it's a bacterial cell or a human cell, has a genome," he says. "You can extract that genome—it's kind of like a linear tape—and you can read it by a variety of methods. Similarly, like a string of letters that you can read, you can also change it. You can write, you can edit it, and then you can put it back in the cell."


This April, the Broad Institute, where Church holds a faculty appointment, was awarded a patent for a new method of genome editing called CRISPR (clustered regularly interspersed short palindromic repeats), which Church says is one of the most effective tools ever developed for synthetic biology. By studying the way that certain bacteria defend themselves against viruses, researchers figured out how to precisely cut DNA at any location on the genome and insert new material there to alter its function. Last month, researchers at MIT announced they had used CRISPR to cure mice of a rare liver disease that also afflicts humans. At the same time, researchers at Virginia Tech said they were experimenting on plants with CRISPR to control salt tolerance, improve crop yield, and create resistance to pathogens.


The possibilities for CRISPR technology seem almost limitless, Church says. If researchers have stored a genetic sequence in a computer, they can order a robot to produce a piece of DNA from the data. That piece can then be put into a cell to change the genome. Church believes that CRISPR is so promising that last year he co-founded a genome-editing company, Editas, to develop drugs for currently incurable diseases.

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Scientists identify more than 400 genetic regions that influence height

Scientists identify more than 400 genetic regions that influence height | Amazing Science | Scoop.it

The researchers say their findings, reached by analyzing genome-wide data from more than 250,000 people, can explain around 20% of height heritability in humans, increasing from 12% prior to this study.


"The study also narrows down the genomic regions that contain a substantial proportion of remaining variation - to be discovered with even larger sample sizes," says co-senior investigator Peter Visscher, PhD, of the University of Queensland in Australia.


The researchers publish their findings in the journal Nature Genetics.


Height is a model characteristic for determining the mechanisms behind human genetics, according to the investigators. It particularly helps improve understanding of traits that are produced by multiple genes. They note that height is simple to measure, and approximately 80% of height variation is genetic. The remaining 20% is thought to be influenced by environmental and lifestyle factors.


Previous studies have suggested that height is influenced by lots of genes, most of which come from common genetic variants rather than rare ones. But the investigators involved in this latest research say that these studies have not been large enough to confirm such findings.

697 genetic variants in 424 genetic regions linked to height

With this in mind, the researchers set up the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. This involved analyzing the genomic data of 253,288 individuals from more than 300 worldwide institutions.


The team searched approximately 2 million genetic variants that were present in at least 5% of participants. From this, they identified 697 genetic variants located in 424 genetic regions that were linked to height.

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House fly genome reveals an expanded immune system combatting many animal pathogens

House fly genome reveals an expanded immune system combatting many animal pathogens | Amazing Science | Scoop.it

Scientists have sequenced the house fly genome for the first time, revealing robust immune system genes, as one might expect from an insect that thrives in pathogen-rich dung piles and garbage heaps.

The research, published Oct. 13, 2014, in the journal Genome Biology, will increase our understanding of house fly genetics and biology and of how flies quickly adapt to resist insecticides, which could lead to novel control methods.

Adult house flies (Musca domestica) carry and transmit more than 100 human and animal diseases, including salmonellosis, anthrax, typhoid fever, tuberculosis, cholera and diarrhea as well as parasites such as pinworms, roundworms, hookworms and tapeworms. House fly larvae are important animal waste decomposers and live in close contact with many animal pathogens.

“Anything that comes out of an animal, such as bacteria and viruses, house flies can take from that waste and deposit on your sandwich,” said Jeff Scott, the paper’s lead author and a Cornell professor of entomology. “House flies are the movers of any disgusting pathogenic microorganism you can think of,” Scott added.

The genome, roughly twice the size of the fruit fly’s genome, revealed an expanded number of immune response and defense genes. The researchers also discovered an expansion in the number of cytochrome P450s, which help the flies metabolize environmental toxins. “House flies have a lot more of these enzymes than would be expected based on other insects they are related to,” said Scott, noting that the house fly’s close relative, Glossina morsitans (tsetse fly), has half as many cytochrome P450s. These enzymes are more ancient than insecticides. “We don’t have a clear handle on why house flies need so many,” Scott said.

The M. domestica genome also revealed many genes for chemoreceptors, which detect certain chemical stimuli in the environment. These receptors are important in sensing food and moving in ways critical for survival, allowing house flies to detect a wide variety of different things, Scott said.

“If you think of the genome like a phone book, we now have the phone number of every gene,” said Scott. “We now can study every gene. For any scientific question, we have a highway to get us there.”

One of those questions will focus on controlling house flies and developing new toxins that disrupt the fly’s internal balance by poisoning them or using RNAi to turn off specific genes and killing them, Scott said.

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Plants with pocket-sized genomes: Record for smallest plant genome found

Plants with pocket-sized genomes: Record for smallest plant genome found | Amazing Science | Scoop.it
Members of Genlisea, a genus of carnivorous plants, possess the smallest genomes known in plants. To elucidate genomic evolution in the group as a whole, researchers have now surveyed a wider range of species, and found a new record-holder.


The genus Genlisea (corkscrew plants) belongs to the bladderwort family (Lentubulariaceae), a family of carnivorous plants. Some of the 29 species of Genlisea that have been described possess tiny genome sizes. Indeed, the smallest genome yet discovered among flowering plants belongs to a member of the group. The term 'genome' here refers to all genetic material arranged in a set of individual chromosomes present in each cell of a given species. An international team of researchers, led by Professor Günther Heubl of LMU's Department of Biology, has now explored, for the first time, the evolution of genome size and chromosome number in the genus. Heubl and his collaborators studied just over half the known species of Genlisea, and their findings are reported in the latest issue of the journal Annals of Botany.


"During the evolution of the genus, the genomes of some Genlisea species must have undergone a drastic reduction in size, which was accompanied by miniaturization of chromosomes, but an increase in chromosome number," says Dr. Andreas Fleischmann, a member of Heubl's research group. Indeed, the chromosomes of the corkscrew plants are so minute that they can only just be resolved by conventional light microscopy. With the aid of an ingenious preparation technique, Dr. Aretuza Sousa, a specialist in cytogenetics and cytology at the Institute of Systematic Botany at LMU, was able to visualize the ultrasmall chromosomes of Genlisea species by fluorescence microscopy. Thanks to this methodology, the researchers were able to identify individual chromosomes and determine their number, as well as measuring the total DNA content of the nuclear genomes of selected representatives of the genus.


The LMU researchers also discovered a new record-holder. Genlisea tuberosa, a species that was discovered only recently from Brazil, and was first described by Andreas Fleischmann in collaboration with Brazilian botanists, turns out to have a genome that encompasses only 61 million base pairs (= Mbp; the genome size is expressed as the total number of nucleotide bases found on each of the paired strands of the DNA double helix) Thus G. tuberosa possesses now the smallest plant genome known, beating the previous record by 3 Mbp. Moreover, genome sizes vary widely between different Genlisea species, spanning the range from ~60 to 1700 Mbp.

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Discovering the Undiscovered: The time is right to apply genomic technologies to discover new life on Earth

Discovering the Undiscovered: The time is right to apply genomic technologies to discover new life on Earth | Amazing Science | Scoop.it

In a perspective piece published November 6 in the journal Science,Eddy Rubin, Director of the U.S. Department of Energy Joint Genome Institute (DOE JGI), a DOE Office of Science User Facility, along with Microbial Program Head Tanja Woyke, discusses why the time is right to apply genomic technologies to discover new life on Earth. In this perspective they propose the division of microbial life on Earth into three categories: explored, unexplored, and undiscovered. The first can be grown in the laboratory. The second encompasses the uncultivated organisms from environmental samples known only by their molecular signatures. The third, the focus of the perspective, is the yet-undiscovered life that up until now has eluded detection.


“We are poised, armed with a new toolkit of powerful genomic technologies to generate and mine the increasingly large datasets to discover new life that may be strikingly different from those that we catalogued thus far,” said Rubin. “Nature has been tinkering with life for at least three billion years and we now have a new set of ways to look for novel life that have so far eluded discovery.”


“Massive-scale metagenomic sequencing of environmental DNA and RNA samples should, in principle, generate sequence data from any entity for which nucleic acids can be extracted,” Rubin noted. “Analysis of these data to identify outliers to previously defined life represents a powerful means to explore the unknown.”


In addition, Rubin pointed to the advent of single-cell sequencing with microfluidic and cell sorting approaches, focused specifically on cells that lack genes that match previously identified ones, as another approach in the search for completely novel organisms.


“We also need to choose particularly suitable environmental niches so that we are not just looking, ‘under the street lamp’ — at environments that we have already previously studied.”


Rubin suggested targets for the discovery of novel life including extreme, inhospitable and isolated environments that are expected to be preferred niches for early life, potentially sheltered from more modern microbial competitors. This would include low oxygen subsurface sites with environmental conditions predating the Great Oxidation Event that occurred about 2.3 billion years ago when the atmosphere went from very low to high oxygen concentrations. Support for the idea that isolated low-oxygen environments may be preferred niches for early life comes from observations that anaerobic niches deep within Earth’s crust tend to harbor ancient branches within the domains of life.


Exploring the “undiscovered” classification is expected to be a boon for enriching the public data portals, Rubin said. He also noted that lurking among these difficult ones may well be the discovery of a “fourth domain” of life, to which a reasonable mariner, ancient or contemporary, may proclaim, “full speed ahead.”


Rubin presented recent work on “microbial dark matter” at the DOE Joint Genome Institute’s 2014 Genomics of Energy and Environment Meeting that can be viewed at http://bit.ly/JGIUM9Rubin. The DOE JGI’s 10th Annual Meeting will be held March 24-26, 2015 and the list of preliminary speakers can be found here: http://usermeeting.jgi.doe.gov/.

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Dahl Winters's curator insight, December 18, 2014 8:00 AM

A big use of big data - exploring the genomes of life on Earth.  One of the biggest data sets in the world is the one we carry around with us and on us every day.

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Paging through history: parchment as a reservoir of ancient DNA for next generation sequencing

Paging through history: parchment as a reservoir of ancient DNA for next generation sequencing | Amazing Science | Scoop.it

Parchment represents an invaluable cultural reservoir. Retrieving an additional layer of information from these abundant, dated livestock-skins via the use of ancient DNA (aDNA) sequencing has been mooted by a number of researchers. However, prior PCR-based work has indicated that this may be challenged by cross-individual and cross-species contamination, perhaps from the bulk parchment preparation process.


A group of scientists now applied next generation sequencing to two parchments of seventeenth and eighteenth century northern English provenance. Following alignment to the published sheep, goat, cow and human genomes, it is clear that the only genome displaying substantial unique homology is sheep and this species identification is confirmed by collagen peptide mass spectrometry. Only 4% of sequence reads align preferentially to a different species indicating low contamination across species. Moreover, mitochondrial DNA sequences suggest an upper bound of contamination at 5%. Over 45% of reads aligned to the sheep genome, and even this limited sequencing exercise yield 9 and 7% of each sampled sheep genome post filtering, allowing the mapping of genetic affinity to modern British sheep breeds. The scientists conclude that parchment represents an excellent substrate for genomic analyses of historical livestock.

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Centipede Genome Yields Surprises: Loss of Light Receptor Genes and Circadian Clock

Centipede Genome Yields Surprises: Loss of Light Receptor Genes and Circadian Clock | Amazing Science | Scoop.it

A team of scientists has sequenced the genome of the centipede for the first time and found that it has around 15,000 genes -- about 7,000 fewer than humans do.


Arthropods -- the most species-rich group of animals on Earth -- are divided into four classes, including insects, crustaceans, chelicerates and myriapods. The latter group, which includes centipedes, is the only class for which no genome had yet been sequenced, scientists said in a study, published in the journal PLOS Biology.


“With genomes in hand from each of the four classes of living arthropod, we can now begin to build a picture of the genetic make-up of their common ancestor,” Frank Jiggins, of the University of Cambridge's genetics department, and one of the researchers involved in the study, said in a statement. “For example, by comparing flies and mosquitoes with centipedes, we have shown that the innate immune systems of insects are much older than previously appreciated.”


As part of the study, the scientists sequenced the genome of “Strigamia maritima,” a northern European centipede. They found that its genome is more conserved than that of many other arthropods, such as the fruit fly, suggesting that the centipede has evolved more slowly from their common ancestor. Despite their name, centipedes do not have hundred legs. Strigamia maritima, which lives in coastal habitats, can have between 45 and 51 pairs of legs, but the number of pairs is always odd.


The researchers also discovered that the centipedes have lost the genes encoding all of the known light receptors used by animals, as well as the genes controlling the circadian rhythm, or the body clock.


“Strigamia live underground and have no eyes, so it is not surprising that many of the genes for light receptors are missing, but they behave as if they are hiding from the light. They must have some alternative way of detecting when they are exposed,” Michael Akam of the University of Cambridge and one of the lead researchers of the study, said in the statement.

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Bernadette Cassel's curator insight, January 1, 6:47 PM


SUR ENTOMONEWS

→  Le premier génome de myriapode séquencé   


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CrAssphage: Previously Unknown Ancient Gut Virus Lives in Half of World's Population

CrAssphage: Previously Unknown Ancient Gut Virus Lives in Half of World's Population | Amazing Science | Scoop.it

CrAssphage is a bacteriophage (also known as phages or bacterial viruses), a member of a group of viruses that infect bacteria.

Prof Edwards and his colleagues named this virus after the Cross-Assembly (CrAss) software program used to discover it.

Interestingly, CrAssphage was discovered entirely by accident.

While sifting through data from previous studies on gut-inhabiting viruses, the virologists noticed an unusual cluster of viral DNA – about 97,000 base pairs long.


When they checked this discovery against a comprehensive listing of known viruses, they came up empty. They then screened for CrAssphage across the database of the NIH’s Human Microbiome Project, and Argonne National Laboratory’s MG-RAST database, and again found it in abundance in samples.


To prove that CrAssphage they discovered in their data actually exists in nature, the researchers used DNA amplification technique to locate the virus in the original samples used to build NIH’s database.


“So we have a biological proof that the virus they found with the computer actually exists in the samples. This was a new virus that about half the sampled people had in their bodies that nobody knew about,” said Dr John Mokili of San Diego State University, who is a co-author of the paper describing the discovery in the journal Nature Communications.


The fact that CrAssphage is so widespread indicates that it probably isn’t a particularly young virus, either. “As far as we can tell, it’s as old as humans are. We’ve basically found it in every population we’ve looked at,” Prof Edwards said. According to the scientists, CrAssphage infects one of the most common types of gut bacteria, Bacteroidetes.

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Genomically encoded analog memory with precise in vivo DNA writing using living bacteria populations

Genomically encoded analog memory with precise in vivo DNA writing using living bacteria populations | Amazing Science | Scoop.it

MIT engineers have transformed the genome of the bacterium E. coli into a long-term storage device for memory. They envision that this stable, erasable, and easy-to-retrieve memory will be well suited for applications such as sensors for environmental and medical monitoring.“You can store very long-term information,” says Timothy Lu, an associate professor of electrical engineering and computer science and biological engineering. “You could imagine having this system in a bacterium that lives in your gut, or environmental bacteria. You could put this out for days or months, and then come back later and see what happened at a quantitative level.


”The new strategy, described in the Nov. 13, 2014 issue of the journal Science ("Genomically encoded analog memory with precise in vivo DNA writing in living cell populations"), overcomes several limitations of existing methods for storing memory in bacterial genomes, says Lu, the paper’s senior author. Those methods require a large number of genetic regulatory elements, limiting the amount of information that can be stored.The earlier efforts are also limited to digital memory, meaning that they can record only all-or-nothing memories, such as whether a particular event occurred. Lu and graduate student Fahim Farzadfard, the paper’s lead author, set out to create a system for storing analog memory, which can reveal how much exposure there was, or how long it lasted. To achieve that, they designed a “genomic tape recorder” that lets researchers write new information into any bacterial DNA sequence.


The researchers showed that SCRIBE enables the recording of arbitrary transcriptional inputs into DNA storage registers in living cells by translating regulatory signals into ssDNAs. In E. coli, they expressed ssDNAs from engineered retrons that use a reverse transcriptase protein to produce hybrid RNA-ssDNA molecules. These intracellularly expressed ssDNAs are targeted into specific genomic loci where they are recombined and converted into permanent memory. The team could show that genomically stored information can be readily reprogrammed by changing the ssDNA template and controlled via both chemical and light inputs. This demonstrates that genomically encoded memory can be read with a variety of techniques, including reporter genes, functional assays, and high-throughput DNA sequencing.


SCRIBE enables the recording of analog information such as the magnitude and time span of exposure to an input. This convenient feature is facilitated by the intermediate recombination rate of our current system (~10–4 recombination events per generation), which we validated via a mathematical model and computer simulations. For example, the scientists stored the overall exposure time to chemical inducers in the DNA memory of bacterial populations for 12 days (~120 generations), independently of the induction pattern. The frequency of mutants in these populations was linearly related to the total exposure time. Furthermore, they were able to demonstrate that SCRIBE-induced mutations can be written and erased and can be used to record multiple inputs across the distributed genomic DNA of bacterial populations.

Finally, they could show that SCRIBE memory can be decomposed into independent “input,” “write,” and “read” operations and used to create genetic “logic-and-memory” circuits, as well as “sample-and-hold” circuits.

Conclusion: SCRIBE is a scalable platform that uses genomic DNA for analog, rewritable, and flexible memory distributed across living cell populations. The scientists anticipate that SCRIBE will enable long-term cellular recorders for environmental and biomedical applications. Future optimization of recombination efficiencies achievable by SCRIBE could lead to more efficient single-cell digital memories and enhanced genome engineering technologies. Furthermore, the ability to regulate the generation of arbitrary targeted mutations with other gene-editing technologies should enable genomically encoded memory in additional organisms.
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Graphene Nanopores with Optical Antennas for Direct Optical DNA Sequencing

Graphene Nanopores with Optical Antennas for Direct Optical DNA Sequencing | Amazing Science | Scoop.it

High-speed reading of the genetic code should get a boost with the creation of the world’s first graphene nanopores – pores measuring approximately 2 nanometers in diameter – that feature a “built-in” optical antenna. Researchers with Berkeley Lab and the University of California (UC) Berkeley have invented a simple, one-step process for producing these nanopores in a graphene membrane using the photothermal properties of gold nanorods.

“With our integrated graphene nanopore with plasmonic optical antenna, we can obtain direct optical DNA sequence detection,” says Luke Lee, the Arnold and Barbara Silverman Distinguished Professor at UC Berkeley. Lee and Alex Zettl, a physicist who holds joint appointments with Berkeley Lab’s Materials Sciences Division and UC Berkeley’s Physics Department, were the leaders of a study in which a hot spot on a graphene membrane formed a nanopore with a self-integrated optical antenna. The hot spot was created by photon-to-heat conversion of a gold nanorod.


“We believe our approach opens new avenues for simultaneous electrical and optical nanopore DNA sequencing and for regulating DNA translocation,” says Zettl, who is also a member of the Kavli Energy Nanoscience Institute (Kavli ENSI).

Nanopore sequencing of DNA, in which DNA strands are threaded through nanoscale pores and read one letter at a time, has been touted for its ability to make DNA sequencing a faster and more routine procedure. Under today’s technology, the DNA letters are “read” by an electrical current passing through nanopores fabricated on a silicon chip. Trying to read electrical signals from DNA passing through thousands of nanopores at once, however, can result in major bottlenecks. Adding an optical component to this readout would help eliminate such bottlenecks

“Direct and enhanced optical signals are obtained at the junction of a nanopore and its optical antenna,” says Lee. “Simultaneously correlating this optical signal with the electrical signal from conventional nanopore sequencing provides an added dimension that would be an enormous advantage for high-throughput DNA readout.”

A key to the success of this effort is the single-step photothermal mechanism that enables the creation of graphene nanopores with self-aligned plasmonic optical antennas. The dimensions of the nanopores and the optical characteristics of the plasmonic antenna are tunable, with the antenna functioning as both optical signal transducer and enhancer. The atomically thin nature of the graphene membrane makes it ideal for high resolution, high throughput, single-molecule DNA sequencing. DNA molecules can be labeled with fluorescent dyes so that each base-pair fluoresces at a signature intensity as it passes through the junction of the nanopore and its optical antenna.

“In addition, either the gold nanoplasmonic optical antenna or the graphene can be functionalized to be responsive to different base-pair combinations,” Lee says. “The gold plasmonic optical antenna can also be functionalized to enable the direct optical detection of RNA, proteins, protein-protein interactions, DNA-protein interactions, and other biological systems.”

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Sequenced genomes reveal mutations that disable single genes and can help to identify new drugs

Sequenced genomes reveal mutations that disable single genes and can help to identify new drugs | Amazing Science | Scoop.it
On average, every person carries mutations that inactivate at least one copy of 200 or so genes and both copies of around 20 genes. However, knockout mutations in any particular gene are rare, so very large populations are needed to study their effects. These ‘loss of function’ mutations have long been implicated in certain debilitating diseases, such as cystic fibrosis. Most, however, seem to be harmless — and some are even beneficial to the persons carrying them. “These are people we’re not going to find in a clinic, but they’re still really informative in biology,” says MacArthur.

His group and others had been focusing on genome data, but they are now also starting to mine patient-health records to determine the — sometimes subtle — effects of the mutations. In a study of more than 36,000 Finnish people, published in July (E. T. Lim et al. PLoS Genet. 10, e1004494; 2014), MacArthur and his team discovered that people lacking a gene called LPA might be protected from heart disease, and that another knockout mutation, carried in one copy of a gene by up to 2.4% of Finns, may cause fetuses to miscarry if it is present in both copies.

Bing Yu of the University of Texas Health Science Center in Houston told the meeting how he and his collaborators had compared knockout mutations found in more than 1,300 people with measurements of around 300 molecules in their blood. The team found that mutations in one gene, called SLCO1B1, were linked to high levels of fatty acids, a known risk factor for heart failure. And a team from the Wellcome Trust Sanger Institute in Hinxton, UK, reported that 43 genes whose inactivation is lethal to mice were found to be inactivated in humans who are alive and apparently well.


The poster child for human-knockout efforts is a new class of drugs that block a gene known as PCSK9 (see Nature 496, 152–155; 2013). The gene was discovered in French families with extremely high cholesterol levels in the early 2000s. But researchers soon found that people with rare mutations that inactivate one copy of PCSK9 have low cholesterol and rarely develop heart disease. The first PCSK9-blocking drugs should hit pharmacies next year, with manufacturers jostling for a share of a market that could reach US$25 billion in five years.


“I think there are hundreds more stories like PCSK9 out there, maybe even thousands,” in which a drug can mimic an advantageous loss-of-function mutation, says Eric Topol, director of the Scripps Translational Science Institute in La Jolla, California. Mark Gerstein, a bio­informatician at Yale University in New Haven, Connecticut, predicts that human knockouts will be especially useful for identifying drugs that treat diseases of ageing. “You could imagine there’s a gene that is beneficial to you as a 25-year-old, but the thing is not doing a good job for you when you’re 75.”

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High-speed evolution in the lab: Geneticists evaluate cost-effective pool genome analysis

High-speed evolution in the lab: Geneticists evaluate cost-effective pool genome analysis | Amazing Science | Scoop.it

Life implies change. And this holds true for genes as well. Organisms require a flexible genome in order to adapt to changes in the local environment. Christian Schlötterer and his team from the Institute for Population Genetics at the University of Veterinary Medicine, Vienna study the genomes of entire populations. The scientists want to know why individuals differ from each other and how these differences are encoded in the DNA. In two review papers published in the journals Nature Reviews Genetics and Heredity, they discuss why DNA sequencing of entire groups can be an efficient and cost-effective way to answer these questions.   

DNA analysis has become increasingly efficient and cost-effective since the human genome was first fully sequenced in the year 2001. Sequencing a complete genome, however, still costs around US$1,000. Sequencing the genetic code of hundreds of individuals would therefore be very expensive and time-consuming. In particular for non-human studies, researchers very quickly hit the limit of financial feasibility.  

The solution to this problem is pool sequencing (Pool-Seq). Schlötterer and his team sequence entire groups of fruit flies (Drosophila melanogaster) at once instead of carrying out many individual sequencing reactions. While the resulting genetic information cannot be attributed to a single individual, the complete data set still provides important genetic information about the entire population.


In order to understand how organisms react to changes in the local environment, the genomes of entire populations can be analysed using Pool-Seq, before and after changed conditions. To do so, the researchers use the method of evolve and resequence (E&R). Schlötterer received an ERC Advanced Grant for this approach in 2012. E&R is a method in which the DNA of a group of individuals is sequenced.  After exposing the descendents of this group for several generations to a certain stress, such as high temperature, extreme cold or UV radiation, and the evolved group is then sequenced again. A comparison of the two data sets uncovers genes that have changed in response to the selective stress. The approach makes it possible, for example, to filter out the genes that are involved in a darker pigmentation in response to UV radiation. 


“Using this principle, we can perform evolution experiments at high speed. We are using this method to address a broad range of questions, ranging from the identification of genes which influence aging, or genes protecting against diseases and finally to understand the genetic changes which reduce the impact of climate change,” Schlötterer explains.

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Bacteria Make Drug-Like Molecules in Humans: Over 14,000 biosynthetic Gene Clusters for Small Molecules Identified

Bacteria Make Drug-Like Molecules in Humans: Over 14,000 biosynthetic Gene Clusters for Small Molecules Identified | Amazing Science | Scoop.it

Small molecules encoded by biosynthetic gene clusters are widely used in the clinic and constitute much of the chemical language of interspecies interactions. In a recent study, researchers used a systematic approach to identify more than 3,000 small-molecule biosynthetic gene clusters in the genomes of human-associated bacteria. As reported in Cell, they discovered that biosynthetic gene clusters for thiopeptides—a class of antibiotics—are widely distributed in the genomes of the human microbiota.


“This study shows for the first time that our microbiota—the good microbes that live with humans—produce drug-like molecules to protect us from pathogens,” said lead study author Mohamed Donia of the University of California, San Francisco (UCSF). “For a long time, scientists used to go to remote and exotic places to find bacteria that produce novel chemical entities with drug-like properties. Who knew we could find similar ones in our own bodies?”


Donia and his collaborators used an algorithm they recently developed to systematically analyze about 2,400 reference genomes of the human microbiota from various body sites. They detected more than 14,000 biosynthetic gene clusters for a broad range of small-molecule classes. Reasoning that the products of these gene clusters are most likely to mediate conserved microbe-host and microbe-microbe interactions, they set out to identify the subset of gene clusters commonly found in healthy individuals by analyzing 752 metagenomic samples from the National Institutes of Health Human Microbiome Project.


Remarkably, nearly all of these gene clusters had never before been studied or even described, illustrating how little is known about their small-molecule products. “We need to study every single one of these molecules and understand what they are doing,” Donia said. “We have published the list of the small molecule-encoding genes that we identified, and we are reaching out to the scientific community to help us characterize them.”


Thiopeptides are perhaps the most interesting of these molecules because they have potent antibacterial activity against Gram-positive species. Currently, one semisynthetic member of this class is undergoing clinical trials for treating bacterial infections. But according to the authors, no thiopeptide biosynthetic gene cluster or small-molecule product from the human microbiome had ever been experimentally characterized. Surprisingly, their analysis revealed thiopeptide-like biosynthetic gene clusters in isolates from every human body site.


Donia and his collaborators went on to purify and solve the structure of a thiopeptide named lactocillin, which showed potent antibacterial activity against a range of Gram-positive vaginal pathogens. By analyzing human metatranscriptomic sequencing data, they showed that lactocillin and other thiopeptide biosynthetic gene clusters were expressed in vivo, suggesting a potential role in mediating microbe-microbe interactions.

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Shang Zhuo's curator insight, October 25, 2014 9:04 AM

We can find antibiotics from our own body! It is really fascinating news. Perhaps the microbiota in our gut is a good source of bioactive molecules but is ignored by scientists for a long time.

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Rats! NYC rats infected with at least 18 new viruses, but no bubonic plague bacteria found

Rats! NYC rats infected with at least 18 new viruses, but no bubonic plague bacteria found | Amazing Science | Scoop.it

Rats: some people enjoy their company as pets, to many others, they are virulent pests that helped the spread of the bubonic plague ("black death") in Medieval Europe. For New Yorkers, they are just one of many interesting local daily sights on the subway tracks and platforms. I can tell you from experience (source: I live in New York City) that they often seem healthier and in better spirits than many of the humans that call this fair city home. Yet it turns out some of them are carrying a surprising number of previously undocumented viruses, according to the results of a study of the Big Apple's rodents published today in the journal mBio and reported by The New York Times.


Specifically, scientists captured 133 rats from traps set in five locations around New York City, euthanized them, then took genetic samples of the bacteria and viral specimens found in their tissues and excretions (saliva, feces, etc). The scientists found lots of viruses, not surprisingly. But while many of the bacteria detected were expected — including e. coli and salmonella — the scientists also found at 18 completely new viruses. None of these new viruses have been found in humans, at least not yet, but two of them are structurally similar to Hepatitis C, which does occur in people and raises the risk of liver scarring and cancer. While there's no immediate cause for alarm, the scientists note that that the spread of these new viruses from rats to humans could theoretically already be occurring and is possible in the future, and are advocating for more comprehensive disease monitoring in humans. Something to think about the next time you're waiting for the downtown F train.

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