Zebrafish – Tiny fish offers big hopes in genome research

Tiny fish offers big hopes in genome research (via AFP)

One of the world’s most popular aquarium fishes on Wednesday joined the rat, the mouse, fruitfly and nematode worm in the roll call of creatures whose DNA has been sequenced to help fight disease among humans. A consortium of researchers unveiled the genome of the zebrafish in the British journal Nature…

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Icy cosmic start for amino acids and DNA ingredients

The Green Bank Telescope and some of the molecules it has discovered. (Credit: Bill Saxton, NRAO/AUI/NSF)

Feb. 28, 2013 — Using new technology at the telescope and in laboratories, researchers have discovered an important pair of prebiotic molecules in interstellar space. The discoveries indicate that some basic chemicals that are key steps on the way to life may have formed on dusty ice grains floating between the stars.

The scientists used the National Science Foundation’s Green Bank Telescope (GBT) in West Virginia to study a giant cloud of gas some 25,000 light-years from Earth, near the center of our Milky Way Galaxy. The chemicals they found in that cloud include a molecule thought to be a precursor to a key component of DNA and another that may have a role in the formation of the amino acid alanine.

One of the newly-discovered molecules, called cyanomethanimine, is one step in the process that chemists believe produces adenine, one of the four nucleobases that form the “rungs” in the ladder-like structure of DNA. The other molecule, called ethanamine, is thought to play a role in forming alanine, one of the twenty amino acids in the genetic code.

“Finding these molecules in an interstellar gas cloud means that important building blocks for DNA and amino acids can ‘seed’ newly-formed planets with the chemical precursors for life,” said Anthony Remijan, of the National Radio Astronomy Observatory (NRAO).

In each case, the newly-discovered interstellar molecules are intermediate stages in multi-step chemical processes leading to the final biological molecule. Details of the processes remain unclear, but the discoveries give new insight on where these processes occur.

Previously, scientists thought such processes took place in the very tenuous gas between the stars. The new discoveries, however, suggest that the chemical formation sequences for these molecules occurred not in gas, but on the surfaces of ice grains in interstellar space.

“We need to do further experiments to better understand how these reactions work, but it could be that some of the first key steps toward biological chemicals occurred on tiny ice grains,” Remijan said.

The discoveries were made possible by new technology that speeds the process of identifying the “fingerprints” of cosmic chemicals. Each molecule has a specific set of rotational states that it can assume. When it changes from one state to another, a specific amount of energy is either emitted or absorbed, often as radio waves at specific frequencies that can be observed with the GBT.

New laboratory techniques have allowed astrochemists to measure the characteristic patterns of such radio frequencies for specific molecules. Armed with that information, they then can match that pattern with the data received by the telescope. Laboratories at the University of Virginia and the Harvard-Smithsonian Center for Astrophysics measured radio emission from cyanomethanimine and ethanamine, and the frequency patterns from those molecules then were matched to publicly-available data produced by a survey done with the GBT from 2008 to 2011.

A team of undergraduate students participating in a special summer research program for minority students at the University of Virginia (U.Va.) conducted some of the experiments leading to the discovery of cyanomethanimine. The students worked under U.Va. professors Brooks Pate and Ed Murphy, and Remijan. The program, funded by the National Science Foundation, brought students from four universities for summer research experiences. They worked in Pate’s astrochemistry laboratory, as well as with the GBT data.

“This is a pretty special discovery and proves that early-career students can do remarkable research,” Pate said.

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Newt Finding Might Set Back Efforts to Regrow Human Limbs: Scientific American

Unique proteins in these amphibians cast doubt on the existence of any latent potential for limb regeneration

By Zoe Cormier and Nature magazine

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The Eastern, or red-spotted, newt may have evolved the ability to regenerate organs and limbs in relatively recent times Image: Flickr/StoneHorse Studios

The ability of some animals to regenerate tissue is generally considered to be an ancient quality of all multicellular animals. A genetic analysis of newts, however, now suggests that it evolved much more recently.

Tiny and delicate it may be, but the red spotted newt (Notophthalmus viridescens) has tissue-engineering skills that far surpass the most advanced biotechnology labs. The newt can regenerate lost tissue, including heart muscle, components of its central nervous system and even the lens of its eye.

Doctors hope that this skill relies on a basic genetic program that is common — albeit often in latent form — to all animals, including mammals, so that they can harness it in regenerative medicine. Mice, for instance, are able to generate new heart cells after myocardial injury.

The newt study, by Thomas Braun at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, and his colleagues, suggest that it might not be so simple.

Attempts to analyze the genetics of newts in the same way as for humans, mice and flies have so far been hampered by the enormous size of the newt genome, which is ten times larger than our own. Braun and his colleagues therefore looked at the RNA produced when genes are expressed — known as the transcriptome — and used three analytical techniques to compile their data.

The team compiled the first catalogue of all the RNA transcripts expressed in N. viridescens, looking at both primary and regenerated tissue in the heart, limbs and eyes of both embryos and larvae.

The researchers found more than 120,000 RNA transcripts, of which they estimate 15,000 code for proteins. Of those, 826 were unique to the newt. What is more, several of those sequences were expressed at different levels in regenerated tissue than in primary tissue. Their results are published in Genome Biology.

Modern or ancestral?
The findings add to existing evidence that the ability evolved recently, says Jeremy Brockes of University College London, whose research provided the first evidence that regenerating tissue in salamanders express proteins that are not found in other vertebrates.

“I no longer believe that there is an ancestral program that is waiting to be reawakened,” Brockes says. “However, I absolutely do believe it’s possible to coax mammal tissues into regenerating to a greater degree with the lessons we learn from newts.”

But saying that the trait is either ancestral or recent is probably too “black and white”, says Elly Tanaka of the Center for Regenerative Therapies in Dresden, Germany. The truth, she says, could be somewhere in the middle. “It may in fact be that regeneration is ancestral, but that newts have species-specific adaptations that allow it to have such spectacular regenerative capacities compared with other vertebrates.”

Moreover, Tanaka adds, scientists would do well to look for more grey zones in the potential for harnessing the regenerative capacities of newts (and of other animals, such as fish). Rather than focusing on spectacular, but perhaps unlikely, scenarios in which amputees could regrow entire limbs, researchers should instead focus on more plausible options, such as improving the healing of scars and burns or increasing the speed of organ regeneration.

This article is reproduced with permission from the magazine Nature. The article was first published on February 21, 2013.

Common Ancestor of Mammals Plucked From Obscurity – NYTimes.com

An artist’s rendering of a placental ancestor. Researchers say the small, insect-eating animal is the most likely common ancestor of the species on the most abundant and diverse branch of the mammalian family tree.

By JOHN NOBLE WILFORD

Published: February 7, 2013 137 Comments

Humankind’s common ancestor with other mammals may have been a roughly rat-size animal that weighed no more than a half a pound, had a long furry tail and lived on insects.

In a comprehensive six-year study of the mammalian family tree, scientists have identified and reconstructed what they say is the most likely common ancestor of the many species on the most abundant and diverse branch of that tree — the branch of creatures that nourish their young in utero through a placenta. The work appears to support the view that in the global extinctions some 66 million years ago, all non-avian dinosaurs had to die for mammals to flourish.

Scientists had been searching for just such a common genealogical link and have found it in a lowly occupant of the fossil record, Protungulatum donnae, that until now has been so obscure that it lacks a colloquial nickname. But as researchers reported Thursday in the journal Science, the animal had several anatomical characteristics for live births that anticipated all placental mammals and led to some 5,400 living species, from shrews to elephants, bats to whales, cats to dogs and, not least, humans.

A team of researchers described the discovery as an important insight into the pattern and timing of early mammal life and a demonstration of the capabilities of a new system for handling copious amounts of fossil and genetic data in the service of evolutionary biology. The formidable new technology is expected to be widely applied in years ahead to similar investigations of plants, insects, fish and fowl.

Given some belated stature by an artist’s brush, the animal hardly looks the part of a progenitor of so many mammals (which do not include marsupials, like kangaroos and opossums, or monotremes, egg-laying mammals like the duck-billed platypus).

Maureen A. O’Leary of Stony Brook University on Long Island, a leader of the project and the principal author of the journal report, wrote that a combination of genetic and anatomical data established that the ancestor emerged within 200,000 to 400,000 years after the great dying at the end of the Cretaceous period. At the time, the meek were rapidly inheriting the earth from hulking predators like T. rex.

Within another two million to three million years, Dr. O’Leary said, the first members of modern placental orders appeared in such profusion that researchers have started to refer to the explosive model of mammalian evolution. The common ancestor itself appeared more than 36 million years later than had been estimated based on genetic data alone.

Although some small primitive mammals had lived in the shadow of the great Cretaceous reptiles, the scientists could not find evidence supporting an earlier hypothesis that up to 39 mammalian lineages survived to enter the post-extinction world. Only the stem lineage to Placentalia, they said, appeared to hang on through the catastrophe, generally associated with climate change after an asteroid crashed into Earth.

The research team drew on combined fossil evidence and genetic data encoded in DNA in evaluating the ancestor’s standing as an early placental mammal. Among characteristics associated with full-term live births, the Protungulatum species was found to have a two-horned uterus and a placenta in which the maternal blood came in close contact with the membranes surrounding the fetus, as in humans.

The ancestor’s younger age, the scientists said, ruled out the breakup of the supercontinent of Gondwana around 120 million years ago as a direct factor in the diversification of mammals, as has sometimes been speculated. Evidence of the common ancestor was found in North America, but the animal may have existed on other continents as well.

The publicly accessible database responsible for the findings is called MorphoBank , with advanced software for handling the largest compilation yet of data and images on mammals living and extinct. “This has stretched our own expertise,” Dr. O’Leary, an anatomist, said in an interview.

“The findings were not a total surprise,” she said. “But it’s an important discovery because it relies on lots of information from fossils and also molecular data. Other scientists, at least a thousand, some from other countries, are already signing up to use MorphoBank.”

John R. Wible, curator of mammals at the Carnegie Museum of Natural History in Pittsburgh, who is another of the 22 members of the project, said the “power of 4,500 characters” enabled the scientists to look “at all aspects of mammalian anatomy, from the skull and skeleton, to the teeth, to internal organs, to muscles and even fur patterns” to determine what the common ancestor possibly looked like.

The project was financed primarily by the National Science Foundation as part of its Assembling the Tree of Life program. Other scientists from Stony Brook, the American Natural History Museum and the Carnegie Museum participated, as well as researchers from the University of Florida, the University of Tennessee at Chattanooga, the University of Louisville, Western University of Health Sciences, in Pomona, Calif., Yale University and others in Canada, China, Brazil and Argentina.

Outside scientists said that this formidable new systematic data-crunching capability might reshape mammal research but that it would probably not immediately resolve the years of dispute between fossil and genetic partisans over when placental mammals arose. Paleontologists looking for answers in skeletons and anatomy have favored a date just before or a little after the Cretaceous extinction. Those who work with genetic data to tell time by “molecular clocks” have arrived at much earlier origins.

The conflict was billed as “Fossils vs. Clocks” in the headline for a commentary article by Anne D. Yoder, an evolutionary biologist at Duke University, which accompanied Dr. O’Leary’s journal report.

Dr. Yoder acknowledged that the new study offered “a fresh perspective on the pattern and timing of mammalian evolution drawn from a remarkable arsenal of morphological data from fossil and living mammals.” She also praised the research’s “level of sophistication and meticulous analysis.”

Even so, Dr. Yoder complained that the researchers “devoted most of their analytical energy to scoring characteristics and estimating the shape of the tree rather than the length of its branches.” She said that “the disregard for the consequences of branch lengths,” as determined by the molecular clocks of genetics, “leaves us wanting more.”

John Gatesy, an evolutionary biologist at the University of California, Riverside, who was familiar with the study but was not an author of the report, said the reconstruction of the common ancestor was “very reasonable and very cool.” The researchers, he said, “have used their extraordinarily large analysis to predict what this earliest placental looked like, and it would be interesting to extend this approach to more branch points in the tree” including for early ancestors like aardvarks, elephants and manatees.

But Dr. Gatesy said the post-Cretaceous date for the placentals “will surely be controversial, as this is much younger than estimates based on molecular clocks, and implies the compression of very long molecular branches at the base of the tree.”

Aztec conquest altered genetics among early Mexico inhabitants, new DNA study shows

Using ancient DNA (aDNA) sampling, Jaime Mata-Míguez, an anthropology graduate student and lead author of the study, tracked the biological comings and goings of the Otomí people following the incorporation of Xaltocan into the Aztec empire. (Credit: Photos provided by Lisa Overholtzer, Wichita State University.)

Jan. 30, 2013 — For centuries, the fate of the original Otomí inhabitants of Xaltocan, the capital of a pre-Aztec Mexican city-state, has remained unknown. Researchers have long wondered whether they assimilated with the Aztecs or abandoned the town altogether.

According to new anthropological research from The University of Texas at Austin, Wichita State University and Washington State University, the answers may lie in DNA. Following this line of evidence, the researchers theorize that some original Otomies, possibly elite rulers, may have fled the town. Their exodus may have led to the reorganization of the original residents within Xaltocan, or to the influx of new residents, who may have intermarried with the Otomí population.

Using ancient DNA (aDNA) sampling, Jaime Mata-Míguez, an anthropology graduate student and lead author of the study, tracked the biological comings and goings of the Otomí people following the incorporation of Xaltocan into the Aztec empire. The study, published in American Journal of Physical Anthropology, is the first to provide genetic evidence for the anthropological cold case.

Learning more about changes in the size, composition, and structure of past populations helps anthropologists understand the impact of historical events, including imperial conquest, colonization, and migration, Mata-Míguez says. The case of Xaltocan is extremely valuable because it provides insight into the effects of Aztec imperialism on Mesoamerican populations.

Historical documents suggest that residents fled Xaltocan in 1395 AD, and that the Aztec ruler sent taxpayers to resettle the site in 1435 AD. Yet archaeological evidence indicates some degree of population stability across the imperial transition, deepening the mystery. Recently unearthed human remains from before and after the Aztec conquest at Xaltocan provide the rare opportunity to examine this genetic transition.

As part of the study, Mata-Míguez and his colleagues sampled mitochondrial aDNA from 25 bodies recovered from patios outside excavated houses in Xaltocan. They found that the pre-conquest maternal aDNA did not match those of the post-conquest era. These results are consistent with the idea that the Aztec conquest of Xaltocan had a significant genetic impact on the town.

Mata-Míguez suggests that long-distance trade, population movement and the reorganization of many conquered populations caused by Aztec imperialism could have caused similar genetic shifts in other regions of Mexico as well.

In focusing on mitochondrial DNA, this study only traced the history of maternal genetic lines at Xaltocan. Future aDNA analyses will be needed to clarify the extent and underlying causes of the genetic shift, but this study suggests that Aztec imperialism may have significantly altered at least some Xaltocan households.

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‘Quadruple helix’ DNA discovered in human cells

Researchers have shown that four-stranded ‘quadruple helix’ DNA structures — known as G-quadruplexes — exist within the human genome. (Credit: Jean-Paul Rodriguez and Giulia Biffi)

Jan. 20, 2013 — In 1953, Cambridge researchers Watson and Crick published a paper describing the interweaving ‘double helix’ DNA structure — the chemical code for all life.

Now, in the year of that scientific landmark’s 60th Anniversary, Cambridge researchers have published a paper proving that four-stranded ‘quadruple helix’ DNA structures — known as G-quadruplexes — also exist within the human genome. They form in regions of DNA that are rich in the building block guanine, usually abbreviated to ‘G’.

The findings mark the culmination of over 10 years investigation by scientists to show these complex structures in vivo — in living human cells — working from the hypothetical, through computational modelling to synthetic lab experiments and finally the identification in human cancer cells using fluorescent biomarkers.

The research, published January 20 in Nature Chemistry and funded by Cancer Research UK, goes on to show clear links between concentrations of four-stranded quadruplexes and the process of DNA replication, which is pivotal to cell division and production.

By targeting quadruplexes with synthetic molecules that trap and contain these DNA structures — preventing cells from replicating their DNA and consequently blocking cell division — scientists believe it may be possible to halt the runaway cell proliferation at the root of cancer.

“We are seeing links between trapping the quadruplexes with molecules and the ability to stop cells dividing, which is hugely exciting,” said Professor Shankar Balasubramanian from the University of Cambridge’s Department of Chemistry and Cambridge Research Institute, whose group produced the research.

“The research indicates that quadruplexes are more likely to occur in genes of cells that are rapidly dividing, such as cancer cells. For us, it strongly supports a new paradigm to be investigated — using these four-stranded structures as targets for personalised treatments in the future.”

Physical studies over the last couple of decades had shown that quadruplex DNA can form in vitro — in the ‘test tube’, but the structure was considered to be a curiosity rather than a feature found in nature. The researchers now know for the first time that they actually form in the DNA of human cells.

“This research further highlights the potential for exploiting these unusual DNA structures to beat cancer — the next part of this pipeline is to figure out how to target them in tumour cells,” said Dr Julie Sharp, senior science information manager at Cancer Research UK.

“It’s been sixty years since its structure was solved but work like this shows us that the story of DNA continues to twist and turn.”

The study published January 20 was led by Giulia Biffi, a researcher in Balasubramaninan’s lab at the Cambridge Research Institute.

By building on previous research, Biffi was able to generate antibody proteins that detect and bind to areas in a human genome rich in quadruplex-structured DNA, proving their existence in living human cells.

Using fluorescence to mark the antibodies, the researchers could then identify ‘hot spots’ for the occurrence of four-stranded DNA — both where in the genome and, critically, at what stage of cell division.

While quadruplex DNA is found fairly consistently throughout the genome of human cells and their division cycles, a marked increase was shown when the fluorescent staining grew more intense during the ‘s-phase’ — the point in a cell cycle where DNA replicates before the cell divides.

Cancers are usually driven by genes called oncogenes that have mutated to increase DNA replication — causing cell proliferation to spiral out of control, and leading to tumour growth.

The increased DNA replication rate in oncogenes leads to an intensity in the quadruplex structures. This means that potentially damaging cellular activity can be targeted with synthetic molecules or other forms of treatments.

“We have found that by trapping the quadruplex DNA with synthetic molecules we can sequester and stabilise them, providing important insights into how we might grind cell division to a halt,” said Balasubramanian.

“There is a lot we don’t know yet. One thought is that these quadruplex structures might be a bit of a nuisance during DNA replication — like knots or tangles that form.

“Did they evolve for a function? It’s a philosophical question as to whether they are there by design or not — but they exist and nature has to deal with them. Maybe by targeting them we are contributing to the disruption they cause.”

The study showed that if an inhibitor is used to block DNA replication, quadruplex levels go down — proving the idea that DNA is dynamic, with structures constantly being formed and unformed.

The researchers also previously found that an overactive gene with higher levels of Quadruplex DNA is more vulnerable to external interference.

“The data supports the idea that certain cancer genes can be usefully interfered with by small molecules designed to bind specific DNA sequences,” said Balasubramanian.

“Many current cancer treatments attack DNA, but it’s not clear what the rules are. We don’t even know where in the genome some of them react — it can be a scattergun approach.

“The possibility that particular cancer cells harbouring genes with these motifs can now be targeted, and appear to be more vulnerable to interference than normal cells, is a thrilling prospect.

“The ‘quadruple helix’ DNA structure may well be the key to new ways of selectively inhibiting the proliferation of cancer cells. The confirmation of its existence in human cells is a real landmark.”

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