Daily Archives: March 4, 2017

Science Daily

Woolly mammoths experienced a genomic meltdown just before extinction Science Daily Dwindling populations created a "mutational meltdown" in the genomes of the last wooly mammoths, which had survived on an isolated island until a few thousand years ago. Rebekah Rogers and Montgomery Slatkin of the University of California, Berkeley, ... Mammoth Genome Analysis Points to Pre-Extinction Genome DeclinesGenomeWeb The last, lonely woolly mammoths faced a 'genomic meltdown'Science Magazine DNA clues to why woolly mammoth died outBBC News Nature.com -Sci-News.com -UPI.com -PLOS all 51 news articles »

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Woolly mammoths experienced a genomic meltdown just before extinction - Science Daily

March 2, 2017 Deletion of genomic DNA by paired CRISPR. Cas9 proteins (scissors) are guided to their target sites by single guide RNAs (sgRNAs, orange ribbons). The target region in between is removed. CRISPETa software enables researcher to design such deletion experiments quickly and conveniently. Credit: Pulido-Quetglas et al, CC BY

Until recently, genomics was a "read-only" science, but scientists have developed a tool for quick and easy deletion of DNA in living cells. This software, published in PLOS Computational Biology, will boost efforts to understand the vast regions of non-coding DNA, or "Dark Matter", in our DNA and may lead to discovery of new disease-causing genes and potential new drugs.

CRISPR-Cas9 is a revolutionary technique for editing genomes and until recently, most studies employing it were aimed at silencing protein-coding genes, the best-studied part of our genome. However our genome consists of 99% of DNA that does not encode any protein. Often described as the "Dark Matter" of the genome, this "non-coding DNA" is recognised to be crucially important for understanding all aspects of human biology, including disease and evolution.

The Johnson lab recently created a tool based on CRISPR-Cas9, called "DECKO", which can be used to delete any desired piece of non-coding DNA. The unique advantage of DECKO is that it uses two individual sgRNAs, acting like two "molecular scissors" that snip out a piece of DNA. The approach was widely adopted, but as no software was available for designing the pairs of sgRNAs that are required, designing deletion experiments was time-consuming.

In response to this, the researchers in this study led by Carlos Pulido, created a software pipeline called CRISPETa, a flexible solution for designing CRISPR deletion experiments. The user tells CRISPETa what region they wish to delete, and the software returns a set of optimised pairs of sgRNAs that can directly be used by experimental researchers. One of the key features is that it can create designs at high scales, with future screening experiments in mind.

The researchers showed that CRISPETa designs efficiently delete their desired targets in human cells. Most importantly, in those regions that give rise to RNA molecules, the researchers showed that the RNA molecules also carry the deletion.

"Ultimately, we expect that CRISPR deletion and other genome engineering tools to lead to a revolution in our ability to understand the genomic basis of disease, particularly in the 99% of DNA that does not encode proteins. Apart from being used as a basic research tool, CRISPR may even be used in the future as a powerful therapeutic to reverse disease-causing mutations," adds Rory Johnson.

CRISPETa is designed for use by non-experts so that it can be useful for scientific researchers, from even the most modest experimental laboratory. These users may, for example, delete a suspected functional region of non-coding DNA, and test the outcome on cellular or molecular activity. This software will also be potentially valuable for groups aiming to utilise CRISPR deletion for therapeutic purposes, by for example, deleting a region of non-coding DNA that is suspected to cause a disease state.

"We hope that this new software tool will allow the greatest possible number of researchers to harness the power of CRISPR deletion in their research," says Carlos Pulido, the student who wrote the CRISPETa software.

Explore further: Modifying fat content in soybean oil with the molecular scissors Cpf1

More information: Pulido-Quetglas C, Aparicio-Prat E, Arnan C, Polidori T, Hermoso T, Palumbo E, et al. (2017) Scalable Design of Paired CRISPR Guide RNAs for Genomic Deletion. PLoS Comput Biol 13(3): e1005341. DOI: 10.1371/journal.pcbi.1005341

A team from the Center for Genome Engineering, within the Institute for Basic Research (IBS), succeeded in editing two genes that contribute to the fat contents of soybean oil using the new CRISPR-Cpf1 technology: an alternative ...

Researchers from Memorial Sloan Kettering Cancer Center (MSK) have harnessed the power of CRISPR/Cas9 to create more-potent chimeric antigen receptor (CAR) T cells that enhance tumor rejection in mice. The unexpected findings, ...

Scientists at the Center for Genome Engineering, within the Institute for Basic Science (IBS), in collaboration with KIM Eunji (ToolGen Inc.) and KIM Jeong Hun (Seoul National University) have engineered the smallest CRISPR-Cas9 ...

Cystic fibrosis, sickle cell anemia, Huntington's disease and phenylketonuria are all examples of disorders caused by the mutation of a single nucleotide, a building block of DNA. The human DNA consists of approximately 3 ...

Scientists have developed a process that improves the efficiency of CRISPR, an up-and-coming technology used to edit DNA.

Genome editing using CRISPR/Cas9 "gene scissors" is a powerful tool for biological discovery and for identifying novel drug targets. In pooled CRISPR screens, a large number of cells are edited simultaneously using CRISPR ...

Within the human digestive tract, there are trillions of bacteria, and these communities contain hundreds or even thousands of species. The makeup of those populations can vary greatly from one person to another, depending ...

What makes a cluster of cells become a liver, or a muscle? How do our genes give rise to proteins, proteins to cells, and cells to tissues and organs?

The scientists who uncovered why zebras have black and white stripes (to repel biting flies), took the coloration question to giant pandas in a study published this week in the journal Behavioral Ecology.

Research by the University of Southampton has found that methods used to predict the effect of species extinction on ecosystems could be producing inaccurate results. This is because current thinking assumes that when a species ...

Zika may be spread by as many as 35 species of mosquitoes, including seven found in the United States, according to a predictive model created by University of Georgia ecologists and published Tuesday in the journal, eLife.

Out of the more than 300,000 plant species in existence, only three speciesrice, wheat, and maizeaccount for most of the plant matter that humans consume, partly because in the history of agriculture, mutations arose ...

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Genome editing: Pressing the 'delete' button on DNA - Phys.Org

Scientists at the University of Illinois,led by associate professor of chemistry Douglas Mitchell, Ph.D., report the development of a tool that searches through microbial genomes, identifying clusters of genes that indicate an organism's ability to synthesize therapeutically promising molecules.

In aNature Chemical Biologyarticle ("A New Genome-Mining Tool Redefines the Lasso Peptide Biosynthetic Landscape"), lead authors Jonathan Tietz, Ph.D., and Christopher Schwalen and their colleagues in Mitchell's laboratory describe how their custom software learns to recognize predictive genomic features.

"With genome sequencing going at the pace it has...there's a dearth of functional information about what these genes are doing," Dr. Mitchell said. "It becomes increasingly important to make sense of and interpret metabolic pathways, especially biosynthetic gene clusters encoded by microbes."

His group is particularly interested in a class of molecules commonly referred to as RiPPs (ribosomally synthesized and post-translationally modified peptides). RIPPsmay seem unfamiliar, but they are already present in the average consumer's daily life. A bacterially produced RiPP called nisin, for example, has been used as a pathogen-fighting additive in dairy products, meats, and beverages such as beer since the 1960s.

"RiPPs have some particular advantages compared to other, more traditional, classes of natural products. They're usually larger and more structurally complex," which allows them to interact with cellular machinery in ways a smaller molecule cannot, Dr. Tietz explained. More points of contact with their cellular targets means RiPPs can hang on better and perform more complicated tasks. "At the same time, despite their complexity, RiPP biosynthesis...makes for greater potential for genetic re-engineering of natural products to tailor physical and pharmacological properties," he noted.

For all their advantages, RiPPs present a challenge; it is hard to discover new ones. Traditionally, researchers found potentially useful natural products by screening microbes based on their biological activity. After decades of such efforts, which revealed a range of products including some RiPPs, searches turn up the same common compounds over and over again.

Dr. Mitchell and colleagues are members of a multilaboratory research group at the Carl R. Woese Institute for Genomic Biology (IGB) that has found a way to uncover novel natural productsgenome mining.The Mining Microbial Genomes research theme at the IGB aims to speed drug discovery by searching through the genomes of microbes, essentially skimming through cells' recipe books to see what they might be able to produce, before actually persuading them to do so in a laboratory setting. In this way, researchers can greatly increase the odds that they will isolate a compound that has never been seen before. However, this method relies on the ability to predict what a group of genes might be capable of producing.

"In a practical sense the question became, is there a better way to harness available genomes for augmenting these discovery pipelines," said Schwalen. "That's where we started."

Dr. Mitchell's group faced a tough challenge: creating software that could recognize the groups of genes whose products work together to synthesize a RiPP. They decided to make it even tougher by focusing on a class of RiPPs called lasso peptides, named for their looping structure. The clusters of genes that produce lasso peptides are small and generic-looking, making them difficult to identify even in a manual search.

"If you want to show that you have a useful tool, you pick the hardest example," Dr. Mitchell said. "But also, as a chemist, lasso peptides are extremely interesting. Peptides that are used as drugs cannot be given orally" because they would be digested, he explained. "Lasso peptides are different. You can actually boil these, you can throw proteases at them, you can autoclave them and they don't lose their activity; they are basically a little peptide knot that is extremely resistant to such assaults."

The informatics tool that Mitchell's laboratory designed, named RODEO (Rapid Open reading frame Description and Evaluation Online), dealt with the lasso challenge in part through a machine learning approach. They trained the software on known examples of lasso-producing gene clusters, allowing the program to hone in on key features. The resulting software identified promising gene clusters in a broad array of microbial genomes, and could be customized to search for the gene clusters of other classes of RiPPs as well.

RODEO identified 1300 novel lasso peptides, including several with particularly unusual structures that make them promising as potential therapeutics; the researchers confirmed that the empirically determined structures matched those predicted by the software.

"We can now use genomic prioritization to find molecules that without any doubt are structurally novel," said Dr. Mitchell. "The challenge is, is that a useful molecule or not? But the more molecules you can connect to genes, the better informed we're going to get. So that's the next 10 years of discovery."

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Genome Mining of Natural Products Could Lead to Novel Therapeutics - Genetic Engineering & Biotechnology News

In May 2016, scientists, lawyers and government representatives converged at Harvard to discuss the Human Genome Project-Write (HGP-Write), a plan to build whole genomes out of chemically synthesised DNA. It will build on the $3 billion (2.3bn) Human Genome Project, which mapped each letter in the human genome.

Moving beyond reading DNA to writing DNA is a natural next step, concedes Francis Collins, director of the US National Institutes of Health. He warns, however, that any project with real-world implications would require extensive discussion from different perspectives, most especially including the general public.

[N]one of the projects deliverables will be as exciting or as evocative as a baby, [Andrew Hessel, a researcher with the Bio/Nano research group at software company Autodesk] says. Some of the things that were said [after the meeting] were so ludicrous that it allowed us to get through that bubble of misinformation and misinterpretation quickly.

I want it to be as open and transparent as possible, says Hessel, and to keep up as much interest in this powerful universal technology, which will enable us to bring our intention into the machinery we call life. And boy, do we need to get good at it.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Humans 2.0: these geneticists want to create an artificial genome by synthesising our DNA

Excerpt from:
Human Genome Project 2: Should scientists synthesize our entire genetic blueprint? - Genetic Literacy Project