Human Genome Has Four Times More Imprinted Genes Than Previously Identified

Source:

http://www.sciencedaily.com/releases/2007/11/071130075016.htm

ScienceDaily (Nov. 30, 2007) — Scientists at Duke University have created the first map of imprinted genes throughout the human genome, and they say a modern-day Rosetta stone -- a form of artificial intelligence called machine learning -- was the key to their success. The study revealed four times as many imprinted genes as had been previously identified.

In classic genetics, children inherit two copies of a gene, one from each parent, and both actively shape how the child develops. But in imprinting, one of those copies is turned off by molecular instructions coming from either the mother or the father. This process of "imprinting" information on a gene is believed to happen during the formation of an egg or sperm, and it means that a child will inherit only one working copy of that gene. That's why imprinted genes are so vulnerable to environmental pressures: If the only functioning copy is damaged or lost, there's no backup to jump in and help out.
Many of the newly-identified imprinted genes lie within genomic regions linked to the development of major diseases like cancer, diabetes, autism, and obesity. Researchers say that if some of these genes are later shown to be active in these disorders, they may offer clues to better disease prevention or management.
"Imprinted genes have always been something of a mystery, partly because they don't follow the conventional rules of inheritance," says Dr. Randy Jirtle, a genetics researcher in the departments of radiation oncology and pathology at Duke and a senior author of the study. "We're hoping this new roadmap will help us and others find more information about how these genes affect our health and well-being."
The technical wizardry needed to find the genes fell to Dr. Alexander Hartemink, the other senior author of the study and an assistant professor in Duke's department of computer science, and Philippe Luedi, the first author of the study. They fed sequence data from two types of genes -- ones known to be imprinted and ones believed not to be imprinted -- into a computer and asked it to discover the differences. This machine learning approach led to an algorithm, which was able -- like the original Rosetta stone -- to decode seemingly impenetrable data, in this case, specific DNA sequences that pointed to the presence of imprinted genes.
"We can't say for certain that we identified all of them, but we think we found a large number," says Hartemink.
Jirtle, who has studied imprinting for years, notes that imprinting is an epigenetic event, meaning it's something that can change a gene's function without altering the sequence of its DNA. "Imprinted genes are unusually vulnerable to pressures in our environment -- even what we eat, drink, and breathe. On top of that, epigenetic changes can be inherited. I don't think people realize that."
Several years ago, Jirtle showed that Agouti mice -- normally fat and yellow -- when fed certain dietary supplements, would produce brown, normal weight babies. The babies' Agouti genes, the ones responsible for color, were the same as the mother's, yet they looked different. "That's epigenetics in action," says Jirtle.
It's estimated that imprinted genes comprise about 1 percent of the human genome, and until now, only several dozen had been identified. Using their new "Rosetta stone", however, Jirtle and Hartemink found 156 new likely imprinted genes, and validated two particularly interesting ones on chromosome 8, where none had been found before. One of them, KCNK9, is mostly active in the brain, is known to cause cancer, and may also be linked to bipolar disorder and epilepsy. The second, DLGAP2, is a possible bladder cancer tumor suppressor gene.
Hartemink says experiments to confirm that all 156 new genes are truly imprinted -- and not just statistically likely candidates -- will be difficult, mostly because gene expression varies from tissue to tissue and most genes turn on and off over time. "We've certainly narrowed the field, but we have a whole lot of work ahead of us."
This research is published in the December 3 issue of Genome Research.
Grants from the National Institutes of Health, National Science Foundation, U.S. Department of Energy and the Alfred Sloan Foundation supported the research.
Duke colleagues who also contributed to the work include Fred Dietrich, from the department of molecular genetics and microbiology; Jennifer Weidman, from the department of radiation oncology and Jason Bosko, an undergraduate in the department of computer science.
Adapted from materials provided by Duke University Medical Center.

Fausto Intilla

www.oloscience.com

Vascular Biologists Make A Significant Discovery In Neurobiology

Source:

http://www.sciencedaily.com/releases/2007/11/071129142714.htm

ScienceDaily (Nov. 30, 2007) — Researchers investigating blood vessels at Barts and The London School of Medicine have hit upon a new discovery in neurobiology that could have implications for patients experiencing peripheral nerve disorders.
Lead by Professor Sussan Nourshargh the research reports on the previously unknown expression and function of a particular cell adhesion molecule, junctional adhesion molecule-C (JAM-C), in peripheral nerves. JAM-C, largely associated to date with inflammatory disorders, was found to play a critical role in maintaining the integrity and function of peripheral nerves by forming an integral part of the insulating sheath that surrounds these nerves -- the myelin.
The work, which was conducted in close collaboration with scientists at Imperial College London, University College London, Cancer Research UK and the University of Geneva, is published in the journal Science.
Together with their collaborators, Professor Nourshargh and team member Christoph Scheiermann, discovered that mice in which the JAM-C gene had been deleted showed neuronal functional defects -- specifically, impaired nerve conduction and behavioural abnormalities indicating muscle weakness.
The findings of the study also indicated that in nerves from patients with particular peripheral nerve disorders the expression of JAM-C was defective. Collectively this study describes a previously unrecognised role for JAM-C and identifies this molecule as a key player in regulating the structural integrity and function of peripheral nerves. The study also potentially provides insight into the causes of some peripheral nerve disorders and presents a strong platform for further research into this area.
There are more than 100 kinds of peripheral nerve disorders affecting approximately 1 in 20 people, symptoms of which -- often starting gradually and steadily worsening -- include numbness, pain, tingling, muscle weakness and sensitivity to touch.
Commenting on the significance of the research findings Professor Nourshargh said: "The discovery of JAM-C in peripheral nerves has made a major contribution to the field of neurobiology at a fundamental molecular level, but has also raised the possibility that defective expression and/or function of this molecule may be associated with the pathology of certain peripheral nerve disorders."
This research was conducted in close collaboration with neurologist Professor Praveeen Anand of Imperial College London.
The paper; 'Expression and Function of Junctional Adhesion Molecule-C in Myelinated Peripheral Nerves,' is published in Science on 30 November 2007.
Adapted from materials provided by Queen Mary, University of London.

Fausto Intilla
www.oloscience.com

Gene Study Supports Single Main Migration Across Bering Strait

Source:

http://www.sciencedaily.com/releases/2007/11/071126170543.htm

ScienceDaily (Nov. 28, 2007) — Did a relatively small number of people from Siberia who trekked across a Bering Strait land bridge some 12,000 years ago give rise to the native peoples of North and South America?

Or did the ancestors of today's native peoples come from other parts of Asia or Polynesia, arriving multiple times at several places on the two continents, by sea as well as by land, in successive migrations that began as early as 30,000 years ago?
The questions -- featured on magazine covers and TV specials -- have agitated anthropologists, archaeologists and others for decades.
University of Michigan scientists, working with an international team of geneticists and anthropologists, have produced new genetic evidence that's likely to hearten proponents of the land bridge theory. The study, published online in PLoS Genetics, is one of the most comprehensive analyses so far among efforts to use genetic data to shed light on the topic.
The researchers examined genetic variation at 678 key locations or markers in the DNA of present-day members of 29 Native American populations across North, Central and South America. They also analyzed data from two Siberian groups. The analysis shows:
o genetic diversity, as well as genetic similarity to the Siberian groups, decreases the farther a native population is from the Bering Strait -- adding to existing archaeological and genetic evidence that the ancestors of native North and South Americans came by the northwest route.
o a unique genetic variant is widespread in Native Americans across both American continents -- suggesting that the first humans in the Americas came in a single migration or multiple waves from a single source, not in waves of migrations from different sources. The variant, which is not part of a gene and has no biological function, has not been found in genetic studies of people elsewhere in the world except eastern Siberia.
The researchers say the variant likely occurred shortly prior to migration to the Americas, or immediately afterwards.
"We have reasonably clear genetic evidence that the most likely candidate for the source of Native American populations is somewhere in east Asia," says Noah A. Rosenberg, Ph.D., assistant professor of human genetics and assistant research professor of bioinformatics at the Center for Computational Medicine and Biology at the U-M Medical School and assistant research professor at the U-M Life Sciences Institute.
"If there were a large number of migrations, and most of the source groups didn't have the variant, then we would not see the widespread presence of the mutation in the Americas," he says.
Rosenberg has previously studied the same set of 678 genetic markers used in the new study in 50 populations around the world, to learn which populations are genetically similar and what migration patterns might explain the similarities. For North and South America, the current research breaks new ground by looking at a large number of native populations using a large number of markers.
The pattern the research uncovered -- that as the founding populations moved south from the Bering Strait, genetic diversity declined -- is what one would expect when migration is relatively recent, says Mattias Jakobsson, Ph.D., co-first author of the paper and a post-doctoral fellow in human genetics at the U-M Medical School and the U-M Center for Computational Medicine and Biology. There has not been time yet for mutations that typically occur over longer periods to diversify the gene pool.
In addition, the study's findings hint at supporting evidence for scholars who believe early inhabitants followed the coasts to spread south into South America, rather than moving in waves across the interior.
"Assuming a migration route along the coast provides a slightly better fit with the pattern we see in genetic diversity," Rosenberg says.
The study also found that:
Populations in the Andes and Central America showed genetic similarities.
Populations from western South America showed more genetic variation than populations from eastern South America.
Among closely related populations, the ones more similar linguistically were also more similar genetically.
Citation: PLoS Genet 3(11): e185. doi:10.1371/journal.pgen.0030185
In addition to Rosenberg and Jakobsson, study authors include Cecil M. Lewis, Jr., former post-doctoral fellow in the U-M Department of Human Genetics, and 24 researchers at U.S., Canadian, British, Central and South American universities.
Adapted from materials provided by University of Michigan Health System.

Fausto Intilla

www.oloscience.com

New Microscope Peers Into Secret Lives Of Cells

Source:

http://www.sciencedaily.com/releases/2007/11/071121094738.htm

ScienceDaily (Nov. 26, 2007) — “See those white sparks?” asks Kirk Czymmek, as he points to the video on his computer screen of a highly magnified heart cell in action. Tiny fireworks flash across the screen with every pulsation of the cell.

“That's calcium,” Czymmek notes. “Scientists have discovered that there is a large release of calcium with every heartbeat. If we don't see those sparks,” he notes, “you have a major problem--perhaps even heart failure.”
Czymmek has a bird's-eye view into the fascinating and rarely seen world of the microscopic, as director of the University of Delaware's Bio-imaging Center.
The center, a component of UD's Delaware Biotechnology Institute, is equipped with the latest technology for microscopic explorations into a diversity of intriguing subjects under investigation by University researchers, from plants that can decontaminate soils of toxic metal pollutants, to carbon nano-bombs for destroying cancer cells.
Czymmek, who also is an associate professor of biological sciences at UD, recently showcased the latest addition to the University's suite of high-tech imaging tools--a state-of-the-art laser-scanning confocal microscope. UD is among a handful of universities that own one of the million-dollar instruments.
The device, known as the LSM 510 DUO, manufactured by Carl Zeiss MicroImaging Inc., typically uses a laser beam to observe a single focal point at a time on its subject--acquiring over a quarter-million picture elements, or pixels, in a single scan, which takes about one second. However, if the laser beam is shaped into a line and swept across the sample, it can scan an image over 100 times faster.
The microscope is particularly useful in examining thick samples such as muscle tissue at high resolution, Czymmek says, because a series of scans may be made at different depths within the sample and assembled automatically in minutes, yielding breathtakingly detailed, three-dimensional images, much like an MRI of the human body reveals.
“It has been my experience, that advances in analytical science often open the door to new scientific inventions and innovations,” said David Weir, director of the Delaware Biotechnology Institute. “The capability we now have with this new microscope, which allows us to observe natural processes as they occur and in great detail, will surely result in new, important discoveries.”
Currently, Czymmek and his staff--associate scientist Liz Adams and research associates Deborah Powell and Shannon Modla--are assisting UD researchers with a broad range of scientific projects on plants and fungi, vocal cords, bone health, biofilms, DNA repair, and gel-like synthetic polymers, among others.
An average of 175 users per year have been served at the center since it opened in 2001, according to Czymmek. UD faculty, staff and students, as well as research collaborators from industry and governmental agency partners, have all been trained in the safe and proper operation of the center's sophisticated “eyes.”
UD's Bio-Imaging Center also is an important resource for scientists beyond Delaware's borders, with colleagues from the National Institutes of Health, Johns Hopkins University, DuPont, Georgetown University, Merck and Virginia Commonwealth University attending microscopy training workshops hosted by Czymmek and his staff.
Czymmek, who refers to himself as a “jack of all trades,” has been using confocal microscopes on almost a daily basis since 1990 when they helped illuminate his doctoral studies of plant diseases and fungi.
One of the things he most likes about his position at UD is its cross-disciplinary focus. He has assisted scientists in examining the hard exoskeleton of an insect, for example, to learn how to make new and improved materials.
“I like being able to help tie together the biology and engineering and help people figure out the best way to solve a problem,” he says.
With each new and improved tool for revealing hidden worlds, Czymmek and his staff gain a front-row seat into the formerly unknown and help put dozens of UD research studies literally into sharper focus.
“It's kind of like going out in space,” Czymmek says with a smile. “We get to see things that no one else has ever seen before.”
Adapted from materials provided by University of Delaware.

Fausto Intilla

www.oloscience.com

Scientists Melt Million-year-old Ice In Search Of Ancient Microbes

Source:

http://www.sciencedaily.com/releases/2007/11/071126115305.htm

ScienceDaily (Nov. 26, 2007) — Researchers from the University of Delaware and the University of California at Riverside have thawed ice estimated to be at least a million years old from above Lake Vostok, an ancient lake that lies hidden more than two miles beneath the frozen surface of Antarctica.

The scientists will now examine the eons-old water for microorganisms, and then through novel genomic techniques, try to figure out how these tiny, living “time capsules” survived the ages in total darkness, in freezing cold and without food and energy from the sun.
The research is designed to provide insight into how organisms adapted to live in extreme environments.
“It's some of the coolest stuff I have ever worked on,” said Craig Cary, professor of marine biosciences at UD. “We are going to gain access to the genetics of organisms isolated for possibly as long as 15 million years.”
The collaborative research team includes Cary and doctoral student Julie Smith from UD's College of Marine and Earth Studies; project leader Brian Lanoil, assistant professor of environmental sciences at the University of California at Riverside, and doctoral student James Gosses; and Philip Hugenholtz and postdoctoral fellows Victor Kunin and Brian Rabkin at the U.S. Department of Energy's Joint Genome Institute.
Last week in Lanoil's laboratory in California, segments of a tube-like ice core were thawed under meticulous, “clean lab” conditions to prevent accidental contamination, a process that required nearly a year of preparation.
“It was very exciting to see the Vostok ice, knowing how old it is and how much it took to get that ice to the lab,” Smith said. “The ice core itself was incredibly clear and glasslike, reflecting the light like a prism.”
The segments of ice were cut from an 11,866-foot ice core drilled in 1998 through a joint effort involving Russia, France and the United States. The core was taken from approximately two miles below the surface of Antarctica and 656 feet (200 meters) above the surface of Lake Vostok and has since been stored at -35 degrees C at the National Ice Core Laboratory in Denver.
“This ice was once water in the lake that refroze onto the bottom of the ice sheet,” Cary explained. “We have no direct samples of the lake itself, only this indirect sampling of the refrozen ice above it because drilling into the lake without taking extensive precautions could lead to the lake's contamination. The borehole made to collect the ice is filled with a mixture of jet fuel, kerosene, and CFCs to keep it from closing,” Cary noted. “Since the lake has not had direct contact with the surface world for at least 15 million years, this would be a contamination of one of the most pristine environments on Earth,” he said.
Cary said the decontamination procedure was “the most complicated and complete ever attempted,” requiring the use of an isolation chamber for the actual melting, concentration of the meltwater through a special filtering system, use of bleaching solutions for the destruction of any contaminating bacteria or DNA from the outside of the core, and the wearing of sterile jump suits for all of the laboratory personnel, among other measures.
Although other scientific projects have identified the microorganisms living in the Vostok water, they have not revealed what these little one-celled organisms do or how they have become adapted to an environment that is eternally dark, cold and so isolated that food and energy sources are likely rare and hard to come by.
“This research is important because it will give us insight into how microbes can survive in a very energy-limited system,” Smith said. She intends to pursue a career in academia after she completes her doctorate at UD's College of Marine and Earth Studies.
“Most of our planet is permanently cold and dark, so it makes sense that we should study how life exists under these conditions. In addition, enzymes produced by these microorganisms may be useful in industrial applications down the road,” Smith noted.
The Vostok water contains only between 10-100 microbes per milliliter compared to approximately 1 million microbes per milliliter for most lakes, Cary said.
Novel “whole genome amplification” techniques will be applied, which provide insight into the genetic diversity of a community of organisms when only small numbers of organisms are available.
A veteran of research expeditions around the globe, Cary is an expert on “extremophiles”--organisms that thrive in the harshest environments on the planet, ranging from the dry, frigid desert of Antarctica, to geyser-like hydrothermal vents spewing toxic chemicals from the ocean floor.
In the case of Lake Vostok, scientists speculate that it stays in a liquid state underneath miles of ice due to one of the Earth's natural “furnaces”--hydrothermal vents. Superheated water erupts from these cracks in the seafloor which form where the plates that form the Earth's crust pull apart.
“We hope that by being so isolated for millions of years, these microorganisms from Vostok will be able to tell us about their life and conditions through the ages,” Cary said.
This research is sponsored by the National Science Foundation and is part of the International Polar Year.
Adapted from materials provided by University of Delaware.

Fausto Intilla

www.oloscience.com

Flip-flopping Gene Expression Can Be Advantageous

Source:

http://www.sciencedaily.com/releases/2007/11/071126103616.htm

ScienceDaily (Nov. 26, 2007) — One gene for pea pod color generates green pods while a variant of that gene gives rise to the yellow-pod phenotype, a feature that helped Gregor Mendel, the 19th century Austrian priest and scientist, first describe genetic inheritance. However, many modern-day geneticists are focused on the strange ability of some genes to be expressed spontaneously in either of two possible ways.

In order to better understand this phenomenon of epigenetic multistability, a major complication for Mendelian genetics, scientists at UC San Diego grew virtual bacterial cells in a computer experiment. They created a two-phenotype model system programmed to grow in ways that matched natural growth. In a deceptively simple experiment, they then recorded the degree to which the two phenotypes varied over time in individual cells, and then repeated the experiment over and over. They reported in the Nov. 19 online edition of Proceedings of the National Academy of Sciences that variability due to epigenetic multistability is larger and persists much longer than they had expected.
While the phenomenon is yet to be discovered in the human genome, the new results suggest that researchers studying bacteria should carefully design their experiments to measure variability due to epigenetic multistability. Even in human cells, multistability may play a role in genes can alternate between “on” and “off” settings.
“Scientists studying bacteria have simply not had the tools to understand phenotypic variability,” said Ting Lu, lead author of the study who was a physics graduate student in the lab of bioengineering professor Jeff Hasty. (Lu is currently a postdoctoral fellow at Princeton University.) “We’ve arrived at a theoretical framework that allows experimenters to measure the ephemeral nature of epigenetics.”
Epigenetic multistability may be vital to cells that are outwardly different, but genetically identical. Only one of the two phenotypes might thrive in a given environmental condition; however, the less advantageous phenotype could come in handy if the environmental conditions unexpectedly changed. By having both phenotypes, the chances would be better that the best one will be present when needed.
Researchers in many labs recently have demonstrated that gene expression can be surprisingly random. The framework established in the UCSD study evaluates how such noisy gene expression affects the properties of developing cellular colonies, such as the progression of bacterial infections or the growth of a population of cancerous cells.
The PNAS paper also documented that the time it takes for a population of cells to reach a stable variance depends on the initial growth conditions and how easily those conditions support cell growth.
“Different results can emerge depending on how cells are grown,” said Jeff Hasty, a professor of bioengineering at UCSD and senior author of the paper. “Our results should allow all researchers studying bacteria to better understand the variability they routinely see from one experiment to the next."
This work is supported by the National Institutes of Health. While a student at UCSD, Lu was affiliated with the Center for Theoretical Biological Physics, a $10 million National Science Foundation-financed center designed to apply the mathematical tools of theoretical physics to biology.
Adapted from materials provided by University of California - San Diego.

Fausto Intilla

www.oloscience.com

Key Nerve Navigation Pathway Identified

Source:

http://www.sciencedaily.com/releases/2007/11/071121145008.htm

ScienceDaily (Nov. 26, 2007) — Newly launched nerve cells in a growing embryo must chart their course to distant destinations, and many of the means they use to navigate have yet to surface. In a study published in the current issue of the journal Neuron, scientists at the Salk Institute for Biological Studies have recovered a key signal that guides motor neurons -- the nascent cells that extend from the spinal cord and must find their way down the length of limbs such as arms, wings and legs.

The Salk study, led by Samuel Pfaff, Ph.D, a professor in the Gene Expression Laboratory, identifies a mutation they christened Magellan, after the Portuguese mariner whose ship Victoria was first to circumnavigate the globe. The Magellan mutation occurs in a gene that normally pilots motor neurons on the correct course employing a newly discovered mechanism, their results demonstrate.
In the mutants, growing neurons can be seen leaving the spinal cord normally but then appear to lose direction. The elongating cells develop "kinks" and sometimes fold back on themselves or become entwined in a spiral, forming coils outside the spinal cord. "They appear to become lost in a traffic roundabout," described Pfaff, who observed the growing neurons with fluorescent technology.
Understanding how motor neurons reach the appropriate targets is necessary for the implementation of novel therapies, including embryonic stem cell replacement for the treatment of presently incurable disorders such as Lou Gehrig's disease, in which motor neurons undergo irreversible decay.
"Embryonic studies provide useful insights on how to replicate the system in an adult," said Pfaff. And, as he also pointed out, the mechanisms used by motor neurons are likely to be similar to those used in other parts of the central nervous system, such as the brain. The Magellan mutation discovered by Pfaff's group was found in mice, but the affected gene, called Phr1, has also been identified in other model systems, including fruit flies and the worm species C. elegans.
A growing nerve bears at its bow a structure called the growth cone, a region rich in the receptor molecules whose job is to receive cues from the environment, much as ancient mariners who observed the stars and set their course accordingly. During development, the growth cone continuously pushes forward, while the lengthening neuron behind it matures into the part of the cell called the axon. Once the growing cell "lands" at its target in a muscle cell, it is the axon that will relay the messages that allow an animal to control and move its limbs at will.
In Magellan mutants, Pfaff's team discovered that the growth cone becomes disordered. Rather than forming a distinct "cap" on the developing neuron, the cone is dispersed in pieces along both the forward end and the axon extending behind it.
"The defect is found in the structure of the neuron itself," said Pfaff, noting that the fundamental pieces, such as the receptors capable of reading cues, all seem to be present. Without the correct orientation of receptors, however, signals cannot be read accurately, resulting in growth going off course.
"A precise gradient normally exists across the cone," said Pfaff, "which is disrupted in the Magellan mutants." As a result, cells lose their polarity. They literally do not know the front end from the back end, according to Pfaff. This sense of polarity is a universal feature common to all growing neurons. Therefore, "Phr1 is likely to play a role in most growing neurons to ensure their structure is retained at the same time they are growing larger," he said.
Pfaff and his group identified Magellan using a novel system they had developed, in which individual motor neurons and axons can be visualized fluorescently. They were able to screen more than a quarter of a million mutations, and the mutations of interest were rapidly mapped to known genes as a result of the availability of the sequenced mouse genome -- a byproduct of the effort to sequence entire genomes such as that in the human.
The Magellan mutation is located in a gene known as Phr1, which is also active in other parts of the nervous system, indicating that it most likely functions to steer other types of neurons, such as those that enervate sensory organs or connect different regions of the brain. Studies of Magellan may therefore shed light on how a variety of neurological disorders might be treated with cell replacement strategies.
Lead author on the study is Joseph W. Lewcock, formerly a postdoctoral fellow in Pfaff's laboratory and currently at Genentech, Inc. Additional Salk authors include postdoctoral fellow Nicolas Genoud and senior research assistant Karen Lettieri.
The study, titled "The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics," was supported by the National Institute for Neurological Disorders and Stroke.
Adapted from materials provided by Salk Institute.

Fausto Intilla

www.oloscience.com

Bioclocks Work By Controlling Chromosome Coiling

Source:

http://www.sciencedaily.com/releases/2007/11/071121144914.htm

ScienceDaily (Nov. 23, 2007) — There is a new twist on the question of how biological clocks work.

In recent years, scientists have discovered that biological clocks help organize a dizzying array of biochemical processes in the body. Despite a number of hypotheses, exactly how the microscopic pacemakers in every cell in the body exert such a widespread influence has remained a mystery. Now, a new study provides direct evidence that biological clocks can influence the activity of a large number of different genes in an ingenious fashion, simply by causing chromosomes to coil more tightly during the day and to relax at night.
"The idea that the whole genome is oscillating is really cool," enthuses Vanderbilt Professor of Biological Sciences Carl Johnson, who headed the research that was published online Nov. 13 in the Proceedings of the National Academy of Sciences. "The fact that oscillations can act as a regulatory mechanism is telling us something important about how DNA works: It is something DNA jockeys really need to think about."
Johnson's team, which consisted of Senior Lecturer Mark A Woelfle, Assistant Research Professor Yao Xu and graduate student Ximing Qin, performed the study with cyanobacteria (blue-green algae), the simplest organism known to possess a biological clock. The chromosomes in cyanobacteria are organized in circular molecules of DNA. In their relaxed state, they form a single loop. But, within the cell, they are usually "supercoiled" into a series of small helical loops. There are even two families of special enzymes, called gyrases and topoisomerases, whose function is coiling and uncoiling DNA.
The researchers focused on small, non-essential pieces of DNA in the cyanobacteria called plasmids that occur naturally in the cyanobacteria. Because a plasmid should behave in the same fashion as the larger and more unwieldy chromosome, the scientists consider it to be a good proxy of the behavior of the chromosome itself.
When the plasmid is relaxed, it is open and uncoiled and, when it is supercoiled, it is twisted into a smaller, more condensed state. So, the researchers used a standard method, called gel electrophoresis, to measure the extent of a plasmid's supercoiling during different points in the day/night cycle.
The researchers found a distinct day/night cycle: The plasmid is smaller and more tightly wound during periods of light than they are during periods of darkness. They also found that this rhythmic condensation disappears when the cyanobacteria are kept in constant darkness.
"This is one of the first pieces of evidence that the biological clock exerts its effect on DNA structure through the coiling of the chromosome and that this, in turn, allows it to regulate all the genes in the organism," says Woelfle.
Some cyanobacteria use their biological clocks to control two basic processes. During the day, they use photosynthesis to turn sunlight into chemical energy. During the night, they remove nitrogen from the atmosphere and incorporate it into a chemical compound that they can use to make proteins.
According to the Johnson lab's "oscilloid model," the genes that are involved in photosynthesis should be located in regions of the chromosome that are "turned on" by the tighter coiling in the DNA during the day and "turned off" during the night when the DNA is more relaxed. By the same token, the genes that are involved in nitrogen fixation should be located in regions of the chromosome that are "turned off" during the day when the DNA is tightly coiled and "turned on" during the night when it is more relaxed.
The researchers see no reason why the bioclocks in higher organisms, including humans, do not operate in a similar fashion. "This could be a universal theme that we are just starting to decipher," says Woelfle.
The DNA in higher organisms is much larger than that in cyanobacteria and it is linear, not circular. Stretched end-to-end, the genome in a mammalian cell is about six feet long. In order to fit into a microscopic cell, the DNA must be tightly packed into a series of small coils, something like microscopic Slinkies.
Previous studies have shown that in higher organisms between 5 to 10 percent of genes in the genome are controlled by the bioclock, compared to 100 percent of genes in the cyanobacteria. In the case of the higher organisms, the bioclock's control is likely to be local rather than the global situation in cyanobacteria.
With a circular chromosome (as in cyanobacteria), twisting it at any point affects the entire molecule. When you twist a linear chromosome at a certain point, however, the effect only extends for a limited distance in either direction because the ends are not connected. That fits neatly with the idea that the bioclock's influence on linear chromosomes is limited to certain specific regions, regions where the specific genes that it regulates are located.
Adapted from materials provided by Vanderbilt University.

Fausto Intilla

www.oloscience.com

Evolutionary Comparison Finds New Human Genes

Source:

http://www.sciencedaily.com/releases/2007/11/071120111538.htm

ScienceDaily (Nov. 23, 2007) — Using supercomputers to compare portions of the human genome with those of other mammals, researchers at Cornell have discovered some 300 previously unidentified human genes, and found extensions of several hundred genes already known.
The discovery is based on the idea that as organisms evolve, sections of genetic code that do something useful for the organism change in different ways.
The research is reported by Adam Siepel, Cornell assistant professor of biological statistics and computational biology, Cornell postdoctoral researcher Brona Brejova and colleagues at several other institutions in the online version of the journal Genome Research, and it will appear in the December print edition.
The complete human genome was sequenced several years ago, but that simply means that the order of the 3 billion or so chemical units, called bases, that make up the genetic code is known. What remains is the identification of the exact location of all the short sections that code for proteins or perform regulatory or other functions.
More than 20,000 protein-coding genes have been identified, so the Cornell contribution, while significant, doesn't dramatically change the number of known genes. What's important, the researchers say, is that their discovery shows there still could be many more genes that have been missed using current biological methods. These methods are very effective at finding genes that are widely expressed but may miss those that are expressed only in certain tissues or at early stages of embryonic development, Siepel said.
"What's exciting is using evolution to identify these genes," Siepel said. "Evolution has been doing this experiment for millions of years. The computer is our microscope to observe the results."
Four different bases -- commonly referred to by the letters G, C, A and T -- make up DNA. Three bases in a row can code for an amino acid (the building blocks of proteins), and a string of these three-letter codes can be a gene, coding for a string of amino acids that a cell can make into a protein.
Siepel and colleagues set out to find genes that have been "conserved" -- that are fundamental to all life and that have stayed the same, or nearly so, over millions of years of evolution.
The researchers started with "alignments" discovered by other workers -- stretches up to several thousand bases long that are mostly alike across two or more species. Using large-scale computer clusters, including an 850-node cluster at the Cornell Center for Advanced Computing, the researchers ran three different algorithms, or computing designs -- one of which Siepel created -- to compare these alignments between human, mouse, rat and chicken in various combinations.
Over millions of years, individual bases can be swapped -- C to G, T to A, for example -- by damage or miscopying. Changes that alter the structure of a protein can kill the organism or send it down a dead-end evolutionary path. But conserved genes contain only minor changes that leave the protein able to do its job. The computer looked for regions with those sorts of changes by creating a mathematical model of how the gene might have changed, then looking for matches to this model.
After eliminating predictions that matched already known genes, the researchers tested the remainder in the laboratory, proving that many of the genes could in fact be found in samples of human tissue and could code for proteins. The researchers were sometimes able to identify the proteins by comparison with databases of known proteins. The discovered genes mainly have to do with motor activity, cell adhesion, connective tissue and central nervous system development, functions that might be expected to be common to many different creatures.
The entire project, from building and testing the mathematical models to running final laboratory tests, took about three years, Siepel said. The work was supported by the National Cancer Institute, a National Science Foundation Early Career Development Grant and a University of California graduate research fellowship.
Adapted from materials provided by Cornell University.

Fausto Intilla
www.oloscience.com

Tiny DNA Molecules Show Liquid Crystal Phases, Pointing Up New Scenario For First Life On Earth

Source:

http://www.sciencedaily.com/releases/2007/11/071122151148.htm

ScienceDaily (Nov. 23, 2007) — A team led by the University of Colorado at Boulder and the University of Milan has discovered some unexpected forms of liquid crystals of ultrashort DNA molecules immersed in water, providing a new scenario for a key step in the emergence of life on Earth.

CU-Boulder physics Professor Noel Clark said the team found that surprisingly short segments of DNA, life's molecular carrier of genetic information, could assemble into several distinct liquid crystal phases that "self-orient" parallel to one another and stack into columns when placed in a water solution. Life is widely believed to have emerged as segments of DNA- or RNA-like molecules in a prebiotic "soup" solution of ancient organic molecules.
Since the formation of molecular chains as uniform as DNA by random chemistry is essentially impossible, Clark said, scientists have been seeking effective ways for simple molecules to spontaneously self-select, "chain-up" and self-replicate. The new study shows that in a mixture of tiny fragments of DNA, those molecules capable of forming liquid crystals selectively condense into droplets in which conditions are favorable for them to be chemically linked into longer molecules with enhanced liquid crystal-forming tendencies, he said.
"We found that even tiny fragments of double helix DNA can spontaneously self-assemble into columns that contain many molecules," Clark said. "Our vision is that from the collection of ancient molecules, short RNA pieces or some structurally related precursor emerged as the molecular fragments most capable of condensing into liquid crystal droplets, selectively developing into long molecules."
Liquid crystals -- organic materials related to soap that exhibit both solid and liquid properties -- are commonly used for information displays in computers, flat-panel televisions, cell phones, calculators and watches. Most liquid crystal phase molecules are rod-shaped and have the ability to spontaneously form large domains of a common orientation, which makes them particularly sensitive to stimuli like changes in temperature or applied voltage.
RNA and DNA are chain-like polymers with side groups known as nucleotides, or bases, that selectively adhere only to specific bases on a second chain. Matching, or complementary base sequences enable the chains to pair up and form the widely recognized double helix structure. Genetic information is encoded in sequences of thousands to millions of bases along the chains, which can be microns to millimeters in length.
Such DNA polynucleotides had previously been shown to organize into liquid crystal phases in which the chains spontaneously oriented parallel to each other, he said. Researchers understand the liquid crystal organization to be a result of DNA's elongated molecular shape, making parallel alignment easier, much like spaghetti thrown in a box and shaken would be prone to line up in parallel, Clark said.
A paper on the subject was published in the Nov. 23 issue of Science. The paper was authored by Clark, Michi Nakata and Christopher Jones from CU-Boulder, Giuliano Zanchetta and Tommaso Bellini of the University of Milan, Brandon Chapman and Ronald Pindak of Brookhaven National Laboratory and Julie Cross of Argonne National Laboratory. Nakata died in September 2006.
The CU-Boulder and University of Milan team began a series of experiments to see how short the DNA segments could be and still show liquid crystal ordering, said Clark. The team found that even a DNA segment as short as six bases, when paired with a complementary segment that together measured just two nanometers long and two nanometers in diameter, could still assemble itself into the liquid crystal phases, in spite of having almost no elongation in shape.
Structural analysis of the liquid crystal phases showed that they appeared because such short DNA duplex pairs were able to stick together "end-to-end," forming rod-shaped aggregates that could then behave like much longer segments of DNA. The sticking was a result of small, oily patches found on the ends of the short DNA segments that help them adhere to each other in a reversible way -- much like magnetic buttons -- as they expelled water in between them, Clark said.
A key characterization technique employed was X-ray microbeam diffraction combined with in-situ optical microscopy, carried out with researchers from Argonne and Brookhaven National Laboratories. The team using a machine called the Argonne Advanced Photon Source synchrotron that enabled probing of the "nano DNA" molecular organization in single liquid crystal orientation domains only a few microns in size. The experiments provided direct evidence for the columnar stacking of the nano DNA pieces in a fluid liquid crystal phase.
"The key observation with respect to early life is that this aggregation of nano DNA strands is possible only if they form duplexes," Clark said. "In a sample of chains in which the bases don't match and the chains can't form helical duplexes, we did not observe liquid crystal ordering."
Subsequent tests by the team involved mixed solutions of complementary and noncomplementary DNA segments, said Clark. The results indicated that essentially all of the complementary DNA bits condensed out in the form of liquid crystal droplets, physically separating them from the noncomplementary DNA segments.
"We found this to be a remarkable result," Clark said. "It means that small molecules with the ability to pair up the right way can seek each other out and collect together into drops that are internally self-organized to facilitate the growth of larger pairable molecules.
"In essence, the liquid crystal phase condensation selects the appropriate molecular components, and with the right chemistry would evolve larger molecules tuned to stabilize the liquid crystal phase. If this is correct, the linear polymer shape of DNA itself is a vestige of formation by liquid crystal order."
Adapted from materials provided by University of Colorado at Boulder.

Fausto Intilla

www.oloscience.com

Scientists Guide Human Skin Cells To Embryonic State

Source:

http://www.sciencedaily.com/releases/2007/11/071120092709.htm

ScienceDaily (Nov. 21, 2007) — In a paper to be published Nov. 22 in the online edition of the journal Science, a team of University of Wisconsin-Madison researchers reports the genetic reprogramming of human skin cells to create cells indistinguishable from embryonic stem cells.

The finding is not only a critical scientific accomplishment, but potentially remakes the tumultuous political and ethical landscape of stem cell biology as human embryos may no longer be needed to obtain the blank slate stem cells capable of becoming any of the 220 types of cells in the human body. Perfected, the new technique would bring stem cells within easy reach of many more scientists as they could be easily made in labs of moderate sophistication, and without the ethical and legal constraints that now hamper their use by scientists.
The new study was conducted in the laboratory of UW-Madison biologist James Thomson, the scientist who first coaxed stem cells from human embryos in 1998. It was led by Junying Yu of the Genome Center of Wisconsin and the Wisconsin National Primate Research Center.
"The induced cells do all the things embryonic stem cells do," explains Thomson, a professor of anatomy in the University of Wisconsin School of Medicine and Public Health. "It's going to completely change the field."
In addition to exorcising the ethical and political dimensions of the stem cell debate, the advantage of using reprogrammed skin cells is that any cells developed for therapeutic purposes can be customized to the patient.
"They are probably more clinically relevant than embryonic stem cells," Thomson explains. "Immune rejection should not be a problem using these cells."
An important caveat, Thomson notes, is that more study of the newly-made cells is required to ensure that the "cells do not differ from embryonic stem cells in a clinically significant or unexpected way, so it is hardly time to discontinue embryonic stem cell research."
The successful isolation and culturing of human embryonic stem cells in 1998 sparked a huge amount of scientific and public interest, as stem cells are capable of becoming any of the cells or tissues that make up the human body.
The potential for transplant medicine was immediately recognized, as was their promise as a window to the earliest stages of human development, and for novel drug discovery schemes. The capacity to generate cells that could be used to treat diseases such as Parkinson's, diabetes and spinal cord injuries, among others, garnered much interest by patients and patient advocacy groups.
But embryonic stem cells also sparked significant controversy as embryos were destroyed in the process of obtaining them, and they became a potent national political issue beginning with the 2000 presidential campaign. Since 2001, a national policy has permitted only limited use of some embryonic stem cell lines by scientists receiving public funding.
In the new study, to induce the skin cells to what scientists call a pluripotent state, a condition that is essentially the same as that of embryonic stem cells, Yu, Thomson and their colleagues introduced a set of four genes into human fibroblasts, skin cells that are easy to obtain and grow in culture.
Finding a combination of genes capable of transforming differentiated skin cells to undifferentiated stem cells helps resolve a critical question posed by Dolly, the famous sheep cloned in 1996. Dolly was the result of the nucleus of an adult cell transferred to an oocyte, an unfertilized egg. An unknown combination of factors in the egg caused the adult cell nucleus to be reprogrammed and, when implanted in a surrogate mother, develop into a fully formed animal.
The new study by Yu and Thomson reveal some of those genetic factors. The ability to reprogram human cells through well defined factors would permit the generation of patient-specific stem cell lines without use of the cloning techniques employed by the creators of Dolly.
"These are embryonic stem cell-specific genes which we identified through a combinatorial screen," Thomson says. "Getting rid of the oocyte means that any lab with standard molecular biology can do reprogramming without difficulty to obtain oocytes."
Although Thomson is encouraged that the new cells will speed new cell-based therapies to treat disease, more work is required, he says, to refine the techniques through which the cells were generated to prevent the incorporation of the introduced genes into the genome of the cells. In addition, to ensure their safety for therapy, methods to remove the vectors, the viruses used to ferry the genes into the skin cells, need to be developed.
Using the new reprogramming techniques, the Wisconsin group has developed eight new stem cell lines. As of the writing of the new Science paper, which will appear in the Dec. 21, 2007 print edition of the journal Science, some of the new cell lines have been growing continuously in culture for as long as 22 weeks.
The new work was funded by grants from the Charlotte Geyer Foundation and the National Institutes of Health. In addition to Yu and Thomson, authors of the new study include Maxim A. Vodyanik, Kim Smuga-Otto, Jessica Antosiewicz-Bourget, Jennifer L. Frane and Igor I. Slukvin, all of UW-Madison; and Shulan Tian, Jeff Nie, Gudrun A. Jonsdottir, Victor Ruotti and Ron Stewart, all of the WiCell Research Institute.
Adapted from materials provided by University of Wisconsin-Madison.

Fausto Intilla

www.oloscience.com

New Nanoparticle Technique Captures Chemical Reactions In Single Living Cell With Amazing Clarity

Source:

http://www.sciencedaily.com/releases/2007/11/071119170147.htm

ScienceDaily (Nov. 19, 2007) — Bioengineers at the University of California, Berkeley, have discovered a technique that for the first time enables the detection of biomolecules' dynamic reactions in a single living cell.

By taking advantage of the signature frequency by which organic and inorganic molecules absorb light, the team of researchers, led by Luke Lee, professor of bioengineering and director of UC Berkeley's Biomolecular Nanotechnology Center, can determine in real time whether specific enzymes are activated or particular genes are expressed, all with unprecedented resolution within a single living cell.
The technique could lead to a new era in molecular imaging with implications for cell-based drug discovery and biomedical diagnostics.
The researchers point out that other techniques, such as nuclear magnetic resonance, can at best provide information about a cluster of cells. But to determine the earliest signs of disease progression or of stem cell proliferation, it's necessary to drill down deeper to the molecular dynamics within a single cell.
To study the biochemical processes of a cell, scientists currently cut through its outer membrane to separate and analyze the cellular components. That method can never provide a real-time view of how components function together because the cell is killed in the process of extracting its components.
"Until now, there has been no non-invasive method that exists that can capture the chemical fingerprints of molecules with nanoscale spatial resolution within a single living cell," said Lee, who is also a faculty affiliate of the California Institute for Quantitative Biosciences and the co-director of the Berkeley Sensor and Actuator Center. "There is great hope that stem cells can one day be used to treat diseases, but one of the biggest challenges in this field is understanding exactly how individual cells differentiate. What is happening inside a stem cell as it develops into a heart muscle instead of a tooth or a strand of hair? To find out, we need to look at the telltale chemical signals involved as proteins and genes function together within a cell."
The researchers tackled this challenge by improving upon conventional optical absorption spectroscopy, a technique by which light is passed through a solution of molecules to determine which wavelengths are absorbed. Cytochrome c, for instance, is a protein involved in cell metabolism and cell death that has several optical absorption peaks of around 550 nanometers.
The absorption spectra of a molecule can change based upon the chemical changes that occur as it interacts with other molecules, such as oxygen.
"For conventional optical absorption spectroscopy to work, a relatively high concentration of biomolecules and a large volume of solution is needed in order to detect these subtle changes in frequencies and absorption peaks," said Lee. "That's because optical absorption signals from a single biomolecule are very weak, so you need to kill hundreds to millions of cells to fish out enough of the target molecule for detection."
The researchers came up with a novel solution to this problem by coupling biomolecules, the protein cytochrome c in this study, with tiny particles of gold measuring 20-30 nanometers long. The electrons on the surface of metal particles such as gold and silver are known to oscillate at specific frequencies in response to light, a phenomenon known as plasmon resonance. The resonant frequencies of the gold nanoparticles are much easier to detect than the weak optical signals of cytochrome c, giving the researchers an easier target.
Gold nanoparticles were chosen because they have a plasmon resonance wavelength ranging from 530 to 580 nanometers, corresponding to the absorption peak of cytochrome c.
"When the absorption peak of the biomolecule overlaps with the plasmon resonance frequency of the gold particle, you can see whether they are exchanging energy," said study co-lead author Gang Logan Liu, who conducted the research as a UC Berkeley Ph.D. student in bioengineering. "This energy transfer shows up as small dips, something we call 'quenching,' in the characteristic absorption peak of the gold particle."
A relatively small concentration of the molecule is needed to create these quenching dips, so instead of a concentration of millions of molecules, researchers can get by with hundreds or even dozens of molecules. The sensitivity and selectivity of the quenching dips will improve the molecular diagnosis of diseases and be instrumental in the development of personalized medicine, the researchers said.
The researchers repeated the experiment matching the protein hemoglobin with silver nanoparticles and achieved similar results.
"Our technique kills two birds with one stone," Lee said. "We're reducing the spatial resolution required to detect the molecule at the same time we're able to obtain chemical information about molecules while they are in a living cell. In a way, these gold particles are like 'nano-stars' because they illuminate the inner life of a cellular galaxy."
Other researchers on the UC Berkeley team are Yi-Tao Long, co-lead author and postdoctoral scholar in bioengineering; Yeonho Choi, a Ph.D. student in mechanical engineering; and Taewook Kang, a postdoctoral scholar in bioengineering.
This research is described in the Nov. 18 issue of the journal Nature Methods. The Ministry of Science and Technology in Korea helped support this research.
Adapted from materials provided by University of California - Berkeley.

Fausto Intilla

www.oloscience.com

Evolution Is Deterministic, Not Random, Biologists Conclude From Multi-species Study

Source:

http://www.sciencedaily.com/releases/2007/11/071119123929.htm

ScienceDaily (Nov. 19, 2007) — A multi-national team of biologists has concluded that developmental evolution is deterministic and orderly, rather than random, based on a study of different species of roundworms.

The researchers were interested in how development evolves in organs which themselves do not change. To do so, they examined the vulva -- the female's copulatory and egg-laying organ -- in nearly 50 species of roundworms. Because the vulva does not significantly change across species, one might predict that there would be little variation in vulva development. However, the researchers found an astonishing amount of developmental variation. They then reasoned that this variation, since it did not affect the final adult vulva, should have evolved in a stochastic, or random, fashion.
In executing the study, the research team analyzed more than 40 characteristics of vulva development, including cell death, cell division patterns, and related aspects of gonad development. They plotted the evolution of these traits on a new phylogenetic tree, which illustrates how species are related to one another and provides a map as to how evolutionary changes are occurring.
Their results showed an even greater number of evolutionary changes in vulva development than the researchers had expected. In addition, they found that evolutionary changes among these species were unidirectional in nearly all instances.
For example, they concluded that the number of cell divisions needed in vulva development declined over time -- instead of randomly increasing and decreasing. In addition, the team noted that the number of rings used to form the vulva consistently declined during the evolutionary process. These results demonstrate that, even where we might expect evolution to be random, it is not.
The leading author is Karin Kiontke, a post-doctoral fellow in New York University's Department of Biology. The research team included NYU Biology Professor David Fitch as well as researchers from the University of Paris, the Israel Institute of Technology, and the Max-Planck Institute for Developmental Biology in Germany.
The findings are reported in the latest issue of the journal Current Biology.
The study was supported, in part, by a grant from the National Science Foundation.
Adapted from materials provided by New York University.

Fausto Intilla

www.oloscience.com

Hormone Of Darkness: Melatonin Could Hurt Memory Formation At Night

Source:

http://www.sciencedaily.com/releases/2007/11/071115164438.htm

ScienceDaily (Nov. 17, 2007) — What do you do when a naturally occurring hormone in your body turns against you? What do you do when that same hormone – melatonin – is a popular supplement you take to help you sleep? A University of Houston professor and his team of researchers may have some answers.

Gregg W. Roman, assistant professor in the department of biology and biochemistry at UH, describes his team’s findings in Science.
Frequently called “the hormone of darkness,” melatonin is a hormone the body produces that may regulate patterns of sleeping and awakening in humans. In almost all organisms tested, this antioxidant’s natural levels are high during the night and low during the day. In addition to what the body produces naturally, many people also take melatonin supplements to fight jet lag, balance out seasonal affect disorder and regulate nighttime dementia.
Roman says, however, that melatonin could actually be hurting you at night, finding in a study with zebrafish (Danio rerio) that melatonin directly inhibits memory formation.
“This work is about the mechanism by which the biological clock controls the formation of new memories,” Roman said. “We were interested in the circadian control – the day-night cycle control – of learning and memory formation. We found zebrafish are capable of learning very well during their active phase during the day, but learn very poorly at night during their sleep or quiet phase.”
The experiments were performed using zebrafish for several reasons. They’re small and breed in large numbers (thereby being less expensive to use), and they are diurnal, having the same activity rhythms as people. Zebrafish are most active during the day and less active at night, whereas many other vertebrate model systems, such as rodents, are nocturnal. Roman reasons that if you are interested in how the biological clock regulates cognitive function in humans, you should use a model system that reacts to the clock the same way people do.
More than two years worth of work, including the discovery that the ability to learn and remember was controlled by an endogenous (or internal) clock originating within the zebrafish, led Roman and his colleagues to hypothesize that melatonin may be responsible for poor learning and memory formation during the night. In order to test whether melatonin was involved in inhibiting nighttime learning and memory formation, they treated the zebrafish during the day with this hormone to see how the fish performed. Interestingly, melatonin failed to affect learning, but dramatically inhibited the formation of new memories, with the melatonin-treated fish resembling fish trained during the night in a test for 24-hour memory.
“The next step was to inhibit melatonin signaling during the night with a melatonin receptor antagonist and test for effects on memory formation,” Roman said. “It was tremendous – the results were, excuse the expression, like night and day. We saw dramatic improvements in nighttime memory formation by inhibiting melatonin signaling, indicating that the reason the zebrafish did not form memories at night was because of the melatonin hormone.”
Next, with the pineal gland being the primary source of melatonin in fish and in people, Roman’s student Oliver Rawashdeh removed this gland from the fish and found they could now form memories at high levels even during the night. Removing this melatonin-producing gland allowed the researchers to alleviate the hormone’s negative side effects, further demonstrating that melatonin inhibits the formation of new memories during the night.
With these findings, Roman hopes to be able to retain the beneficial effects of melatonin’s antioxidant properties. Such benefits include fighting free radical damage to slow some forms of neurodegeneration, such as in Parkinson’s and Alzheimer’s diseases, and stopping DNA damage, which has potential to act as a preventative against cancer. And, since the positive antioxidant effect is direct and independent of receptor signaling, there is hope that removing the melatonin receptor signaling will combat only this hormone’s negative effects on cognitive function.
Additionally, Roman said that inhibiting melatonin signaling with receptor antagonists may help with a large number of nighttime cognitive tasks, helping such people as students studying for finals, airplane pilots, ER physicians and night-shift workers. Roman also thinks that a natural role of melatonin may be to facilitate the storage of memories made during the day and that more studies are required to understand the ultimate role melatonin has in memory formation.
“The value of melatonin as a supplement is largely due to its antioxidant properties,” Roman said. “The use of melatonin receptor antagonists will not affect this attribute, but may alleviate an important side effect on nighttime cognitive function.”
In other words, a ‘best of both worlds’ scenario could result, taking advantage of melatonin’s antioxidant benefits while improving nighttime memory formation that is now inhibited by it.
Roman’s team at UH for this breakthrough study includes Gregory M. Cahill, associate professor of biology and biochemistry, and two of their students and research assistants, Oliver Rawashdeh and Nancy Hernandez de Borsetti.
The Science article is entitled “Melatonin Suppresses Nighttime Memory Formation in Zebrafish,” and will be published Nov. 16.
Adapted from materials provided by University of Houston.

Fausto Intilla

www.oloscience.com

Imaging Neural Progenitor Cells In The Living Human Brain

Source:

http://www.sciencedaily.com/releases/2007/11/071108141511.htm

ScienceDaily (Nov. 17, 2007) — For the first time, investigators have identified a way to detect neural progenitor cells (NPCs), which can develop into neurons and other nervous system cells, in the living human brain using a type of imaging called magnetic resonance spectroscopy (MRS). The finding may lead to improved diagnosis and treatment for depression, Parkinson's disease, brain tumors, and a host of other disorders.

Research has shown that, in select brain regions, NPCs persist into adulthood and may give rise to new neurons. Studies have suggested that the development of new neurons from NPCs, called neurogenesis, is disrupted in disorders ranging from depression and schizophrenia to Parkinson's disease, epilepsy, and cancer. Until now, however, there has been no way to monitor neurogenesis in the living human brain.
"The recent finding that neural progenitor cells exist in adult human brain has opened a whole new field in neuroscience. The ability to track these cells in living people would be a major breakthrough in understanding brain development in children and continued maturation of the adult brain. It could also be a very useful tool for research aimed at influencing NPCs to restore or maintain brain health," says Walter J. Koroshetz, M.D., deputy director of the NIH's National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the work. The study was also funded by the NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
"This is the first noninvasive approach to identify neural progenitor cells in the human brain," says Grigori Enikolopov, Ph.D., of Cold Spring Harbor Laboratory in New York, who conducted the new study along with co-corresponding author Mirjana Maletic-Savatic, M.D., Ph.D., of the State University of New York, Stony Brook and their colleagues at SUNY Stony Brook and Brookhaven National Laboratory. MRS is an imaging technique that can be used to detect proteins and other compounds normally present in body fluids or tissues. The study results are published in the November 9, 2007, issue of Science.*
Previously developed techniques using positron emission tomography and other types of brain imaging allow investigators to identify NPCs in animals. However, those techniques require pre-labeling the cells with radioactive agents or magnetic nanoparticles -- strategies that are not practical in people. In the new study, the researchers identified an innate property of NPCs that can be detected by MRS. This enables them to image NPCs without introducing drugs or other agents.
The researchers used a technique related to MRS to compare the signals of NPCs from embryonic mice to those of neurons, astrocytes, and oligodendrocytes. Astrocytes and oligodendrocytes are non-neuronal cells that are very common in the brain. The investigators found that NPCs showed a specific signal, or marker, that was not as common in other cell types.
Next, the researchers studied NPCs at various points as they differentiated into other cell types in the laboratory. The level of the NPC signal decreased over time, while the levels of other markers common in neurons and astrocytes rose. The newly identified marker was more common in brain cells from embryonic mice than in those from adult mice. It also was more common in cells from the mouse hippocampus, a region where neurogenesis occurs constantly, than in cells from the brain's cortex, where new neurons are not normally formed.
Dr. Maletic-Savatic, Dr. Enikolopov and their colleagues then gave adult mice a form of electrical stimulation that increases the amount of neurogenesis in the brain. They found that the marker they had identified increased significantly after the stimulation. Additional results indicated that the marker is probably a mixture of lipids (fatty acids), although the exact identity of the lipids, and how they function in NPCs, is still undetermined.
The researchers then developed a signal processing method that allowed them to separate the marker from other signals in the living brain. They transplanted NPCs into the cortex of the adult rat brain and found that they could clearly detect the marker in the area where the NPCs were injected. They also found that it increased after stimulation.
Finally, the investigators tested their MRS imaging technique in healthy people. They found major differences in the concentration of the marker between the hippocampus and the cortex. They also imaged the brains of pre-adolescents, adolescents, and adults and found that the marker decreased with age.
The findings suggest that the marker identified in these experiments can be used to detect NPCs and neurogenesis in the live human brain using MRS. They also show that NPCs decrease during brain development. Previous research had shown that neurogenesis decreases with age in animals, but this is the first study to demonstrate that it also decreases in the living human brain.
"This study identifies a novel biomarker and shows that we can use it to see progenitor cells in the live brain," Dr. Enikolopov says. "This protocol can now be used to study a variety of problems." For example, researchers might study people with depression to see if neurogenesis correlates with alterations in depression or schizophrenia. The technique might also be used to study changes that occur in neurological diseases such as traumatic brain injury, stroke, epilepsy, and Parkinson's disease. It might even be useful for detecting cancer, because researchers believe some brain tumors are associated with aberrant proliferation of NPCs, Dr. Enikolopov adds.
The researchers are now planning studies that will test the usefulness of the new imaging technique in people with disease. They also hope to improve their understanding of how the lipids they detected function in NPCs and to refine the sensitivity of their technique.
This research was supported by the National Institutes of Health (NIH).
*Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, Wagshul ME, Henn F, Benveniste H, Djuric PM, Enikolopov G, Maletic-Savatic M. "Magnetic Resonance Spectroscopy Identifies Neural Progenitor Cells in the Live Human Brain." Science, November 9, 2007, Vol. 318, No. 5852, p. 980.
Adapted from materials provided by NIH/National Institute of Neurological Disorders and Stroke.

Fausto Intilla

www.oloscience.com

Are There Rearrangement Hot Spots In The Human Genome?

Source:

http://www.sciencedaily.com/releases/2007/11/071109100207.htm

ScienceDaily (Nov. 13, 2007) — The debate over the validity of genomic rearrangement “hotspots” has its most recent addition in a new theory put forth by researchers at the University of California San Diego. The study, published on November 9 in PLoS Computational Biology, holds that there are indeed rearrangement hotspots in the human genome.
Doctors Max Alekseyev and Pavel Pevzner developed a theory for analyzing complex rearrangements (including transpositions) which demonstrates that even if transpositions were a dominant evolutionary force, there are still rearrangement hotspots in mammalian genomes.
In 1970 the random breakage model (RBM) was proposed by Susumo Ohno, and later formalized by Nadeau and Taylor in 1984. This model postulates that rearrangements are “random,” and thus there are no rearrangement hotspots in mammalian genomes. Biologists largely embraced the model as it held such predictive powers.
However, in 2003 the model was refuted by Pevzner and Tesler, who suggested an alternative fragile breakage model (FBM) of chromosome evolution. FBM implies that the human genome is a mosaic of solid regions with low propensity for rearrangements and fragile regions where rearrangement hotspots reside. The rebuttal of RBM resulted in a rebuttal of the rebuttal, and a scientific divide was begun.
Most recent studies support the existence of rearrangement hotspots, but some researchers still uphold the RBM model. This study represents a major advance in the debate.
CITATION: Alekseyev MA, Pevzner PA (2007) Are there rearrangement hotspots in the human genome? PLoS Comput Biol 3(11): e209. doi:10.1371/journal.pcbi.0030209 (http://dx.doi.org/10.1371/journal.pcbi.0030209)
Adapted from materials provided by Public Library of Science.

Fausto Intilla
www.oloscience.com

In DNA Era, New Worries About Prejudice

Source:

http://www.nytimes.com/2007/11/11/us/11dna.html?_r=1&ref=science&oref=slogin

By AMY HARMON
Published: November 11, 2007

When scientists first decoded the human genome in 2000, they were quick to portray it as proof of humankind’s remarkable similarity. The DNA of any two people, they emphasized, is at least 99 percent identical.
But new research is exploring the remaining fraction to explain differences between people of different continental origins.
Scientists, for instance, have recently identified small changes in DNA that account for the pale skin of Europeans, the tendency of Asians to sweat less and West Africans’ resistance to certain diseases.
At the same time, genetic information is slipping out of the laboratory and into everyday life, carrying with it the inescapable message that people of different races have different DNA. Ancestry tests tell customers what percentage of their genes are from Asia, Europe, Africa and the Americas. The heart-disease drug BiDil is marketed exclusively to African-Americans, who seem genetically predisposed to respond to it. Jews are offered prenatal tests for genetic disorders rarely found in other ethnic groups.
Such developments are providing some of the first tangible benefits of the genetic revolution. Yet some social critics fear they may also be giving long-discredited racial prejudices a new potency. The notion that race is more than skin deep, they fear, could undermine principles of equal treatment and opportunity that have relied on the presumption that we are all fundamentally equal.
“We are living through an era of the ascendance of biology, and we have to be very careful,” said Henry Louis Gates Jr., director of the W. E. B. Du Bois Institute for African and African American Research at Harvard University. “We will all be walking a fine line between using biology and allowing it to be abused.”
Certain superficial traits like skin pigmentation have long been presumed to be genetic. But the ability to pinpoint their DNA source makes the link between genes and race more palpable. And on mainstream blogs, in college classrooms and among the growing community of ancestry test-takers, it is prompting the question of whether more profound differences may also be attributed to DNA.
Nonscientists are already beginning to stitch together highly speculative conclusions about the historically charged subject of race and intelligence from the new biological data. Last month, a blogger in Manhattan described a recently published study that linked several snippets of DNA to high I.Q. An online genetic database used by medical researchers, he told readers, showed that two of the snippets were found more often in Europeans and Asians than in Africans.
No matter that the link between I.Q. and those particular bits of DNA was unconfirmed, or that other high I.Q. snippets are more common in Africans, or that hundreds or thousands of others may also affect intelligence, or that their combined influence might be dwarfed by environmental factors. Just the existence of such genetic differences between races, proclaimed the author of the Half Sigma blog, a 40-year-old software developer, means “the egalitarian theory,” that all races are equal, “is proven false.”
Though few of the bits of human genetic code that vary between individuals have yet to be tied to physical or behavioral traits, scientists have found that roughly 10 percent of them are more common in certain continental groups and can be used to distinguish people of different races. They say that studying the differences, which arose during the tens of thousands of years that human populations evolved on separate continents after their ancestors dispersed from humanity’s birthplace in East Africa, is crucial to mapping the genetic basis for disease.
But many geneticists, wary of fueling discrimination and worried that speaking openly about race could endanger support for their research, are loath to discuss the social implications of their findings. Still, some acknowledge that as their data and methods are extended to nonmedical traits, the field is at what one leading researcher recently called “a very delicate time, and a dangerous time.”
“There are clear differences between people of different continental ancestries,” said Marcus W. Feldman, a professor of biological sciences at Stanford University. “It’s not there yet for things like I.Q., but I can see it coming. And it has the potential to spark a new era of racism if we do not start explaining it better.”
Dr. Feldman said any finding on intelligence was likely to be exceedingly hard to pin down. But given that some may emerge, he said he wanted to create “ready response teams” of geneticists to put such socially fraught discoveries in perspective.
The authority that DNA has earned through its use in freeing falsely convicted inmates, preventing disease and reconstructing family ties leads people to wrongly elevate genetics over other explanations for differences between groups.
“I’ve spent the last 10 years of my life researching how much genetic variability there is between populations,” said Dr. David Altshuler, director of the Program in Medical and Population Genetics at the Broad Institute in Cambridge, Mass. “But living in America, it is so clear that the economic and social and educational differences have so much more influence than genes. People just somehow fixate on genetics, even if the influence is very small.”
But on the Half Sigma blog and elsewhere, the conversation is already flashing forward to what might happen if genetically encoded racial differences in socially desirable — or undesirable — traits are identified.
“If I were to believe the ‘facts’ in this post, what should I do?” one reader responded on Half Sigma. “Should I advocate discrimination against blacks because they are less smart? Should I not hire them to my company because odds are I could find a smarter white person? Stop trying to prove that one group of people are genetically inferior to your group. Just stop.”
Renata McGriff, 52, a health care consultant who had been encouraging black clients to volunteer genetic information to scientists, said she and other African-Americans have lately been discussing “opting out of genetic research until it’s clear we’re not going to use science to validate prejudices.”
“I don’t want the children in my family to be born thinking they are less than someone else based on their DNA,” added Ms. McGriff, of Manhattan.
Such discussions are among thousands that followed the geneticist James D. Watson’s assertion last month that Africans are innately less intelligent than other races. Dr. Watson, a Nobel Prize winner, subsequently apologized and quit his post at the Cold Spring Harbor Laboratory on Long Island.
But the incident has added to uneasiness about whether society is prepared to handle the consequences of science that may eventually reveal appreciable differences between races in the genes that influence socially important traits.
New genetic information, some liberal critics say, could become the latest rallying point for a conservative political camp that objects to social policies like affirmative action, as happened with “The Bell Curve,” the controversial 1994 book that examined the relationship between race and I.Q.
Yet even some self-described liberals argue that accepting that there may be genetic differences between races is important in preparing to address them politically.
“Let’s say the genetic data says we’ll have to spend two times as much for every black child to close the achievement gap,” said Jason Malloy, 28, an artist in Madison, Wis., who wrote a defense of Dr. Watson for the widely read science blog Gene Expression. Society, he said, would need to consider how individuals “can be given educational and occupational opportunities that work best for their unique talents and limitations.”
Others hope that the genetic data may overturn preconceived notions of racial superiority by, for example, showing that Africans are innately more intelligent than other groups. But either way, the increased outpouring of conversation on the normally taboo subject of race and genetics has prompted some to suggest that innate differences should be accepted but, at some level, ignored.
“Regardless of any such genetic variation, it is our moral duty to treat all as equal before God and before the law,” Perry Clark, 44, wrote on a New York Times blog. It is not necessary, argued Dr. Clark, a retired neonatologist in Leawood, Kan., who is white, to maintain the pretense that inborn racial differences do not exist.
“When was the last time a nonblack sprinter won the Olympic 100 meters?” he asked.
“To say that such differences aren’t real,” Dr. Clark later said in an interview, “is to stick your head in the sand and go blah blah blah blah blah until the band marches by.”
Race, many sociologists and anthropologists have argued for decades, is a social invention historically used to justify prejudice and persecution. But when Samuel M. Richards gave his students at Pennsylvania State University genetic ancestry tests to establish the imprecision of socially constructed racial categories, he found the exercise reinforced them instead.
One white-skinned student, told she was 9 percent West African, went to a Kwanzaa celebration, for instance, but would not dream of going to an Asian cultural event because her DNA did not match, Dr. Richards said. Preconceived notions of race seemed all the more authentic when quantified by DNA.
“Before, it was, ‘I’m white because I have white skin and grew up in white culture,’ ” Dr. Richards said. “Now it’s, ‘I really know I’m white, so white is this big neon sign hanging over my head.’ It’s like, oh, no, come on. That wasn’t the point.”

Fausto Intilla
www.oloscience.com

Breastfeeding Boosts IQ In Infants With 'Helpful' Genetic Variant

Source:

http://www.sciencedaily.com/releases/2007/11/071105171949.htm

ScienceDaily (Nov. 6, 2007) — The known association between breast feeding and slightly higher IQ in children has been shown to relate to a particular gene in the babies, according to a report in the Proceedings of the National Academy of Sciences.

In two studies of breast-fed infants involving more than 3,000 children in Britain and New Zealand, breastfeeding was found to raise intelligence an average of nearly 7 IQ points if the children had a particular version of a gene called FADS2.
"It is this genetic variant in FADS2, a gene involved in the control of fatty acid pathways, that may help the children make better use of the breast milk and promote the brain development that is associated with a higher IQ score," said Julia Kim-Cohen, assistant professor of psychology at Yale and a member of the research team.
"Children who do not carry the 'helpful' genetic variant have normal average IQ scores," Kim-Cohen said. "Being breastfed for them is not associated with an IQ advantage."
"There has been some criticism of earlier studies about breastfeeding and IQ that they didn't control for socioeconomic status, or the mother's IQ or other factors, but our findings take an end-run around those arguments by showing the physiological mechanism that accounts for the difference," said Terrie Moffitt, a professor of psychological and brain sciences in Duke University's Institute for Genome Sciences and Policy.
The intelligence quotient (IQ) has long been at the heart of debates about nature versus nurture. Twin studies document both strong genetic influences and nongenetic environmental influences on IQ, particularly for young children.
Moffitt, who performed the research with her husband and co-author Avshalom Caspi at King's College in London, found that the baby's intellectual development is influenced by both genes and environment or, more specifically, by the interaction of its genes with its environment.
"The argument about intelligence has been about nature versus nurture for at least a century," Moffitt said. "We're finding that nature and nurture work together."
Ninety percent of the children in the two study groups had at least one copy of the "C" version of FADS2, which yielded higher IQ if they were breast-fed. The other 10 percent, with only the "G" versions of the gene, showed no IQ advantage or disadvantage from breastfeeding.
The gene was singled out for the researchers' attention because it produces an enzyme that helps convert dietary fatty acids into the polyunsaturated fatty acids DHA (docosahexaenoic acid) and AA (arachidonic acid) that have been shown to accumulate in the human brain during the first months after birth.
Since the first findings about breastfeeding and IQ appeared a decade ago, many formula makers have added DHA and AA fatty acids to their products. The children in these studies however were born in 1972-73 in New Zealand and 1994-95 in England, before fatty acid supplementation in formula began.
Though the jury is still out on whether such supplementation has made a difference in humans, laboratory studies in which rodents and primates were fed supplemental fatty acids have shown increased brain DHA concentrations and enhanced abilities in tests of learning, memory and problem-solving.
"Our findings support the idea that the nutritional content of breast milk accounts for the differences seen in human IQ," Moffitt said. "But it's not a simple all-or-none connection: it depends to some extent on the genetic makeup of each infant."
Moffitt and Caspi joined the Duke faculty in August, but are finishing up their research in London before moving to Durham in December.
Moffitt noted that the researchers aren't particularly interested in IQ or breastfeeding, per se. Rather, this study fits into a body of work they have done on gene-environment interactions and the brain.
"We're more interested in proving to the psychiatric community that genes usually have a physiological effect," Moffitt said. "When looking at depression or intelligence, the key bit that's often left out here is the environmental effects."
Journal reference: PNAS Early Edition: doi/10.1073/pnas.0704292104
The research was supported by the National Institute of Mental Health (US), the Medical Research Council (UK), and the Health Research Council (New Zealand).
Adapted from materials provided by Duke University.

Fausto Intilla

www.oloscience.com