Introns Nonsense DNA May Be More Important to Evolution of Genomes Than Thought

The sequences of nonsense DNA that interrupt genes could be far more important to the evolution of genomes than previously thought, according to a recent Sciencereport by Indiana University Bloomington and University of New Hampshire biologists.

Their study of the model organismDaphnia pulex (water flea) is the first to demonstrate the colonization of a single lineage by "introns," as the interrupting sequences are known. The scientists say introns are inserted into the genome far more frequently than current models predict. The scientists also found what appear to be "hot spots" for intron insertion -- areas of the genome where repeated insertions are more likely to occur. And surprisingly, the vast majority of intron DNA sequences the scientists examined were of unknown origin.

"The thinking has been that these insertion events are very rare because they always have bad effects," said postdoctoral fellow Abraham Tucker, a lead author of the Science paper.

Graduate student Wenli Li, whose participation in the research overlaps her dissertation work, was the paper's co-lead author. Li said she was particularly interested in the notion of hot spots that make it more likely for separate lineages of Daphnia to gain introns in the same place (or the same general area) within the water fleas' genomes. Four of the 23 different kinds of introns the scientists found were not unique with respect to position. If introns were always inserted in random places within genes, the scientists would have expected zero introns to have identical insertion points.

"The most intriguing finding for me is the multiple instances of parallel intron gains, because this means that Daphnia is in an active phase of intron proliferation," Li said. "This makesDaphnia an extraordinary system to study intron evolution. In addition, we believe our work facilitates a more accurate estimate of intron gain rates, and directly challenges the assumption that parallel intron gains are rare in many prior analyses."

Whether or not Daphnia is typical of eukaryotes with respect to intron gain (and loss), IU Bloomington evolutionary biologist Michael Lynch, the project's principal investigator, agreed that the discovery of parallelism will surprise his colleagues.

"Remarkably, we have found many cases of parallel intron gains at essentially the same sites in independent genotypes," Lynch said. "This strongly argues against the common assumption that when two species share introns at the same site, it is always due to inheritance from a common ancestor."

A unique and important aspect of the scientists' work is that they focused on one species (Daphnia pulex). Past studies have looked at a few introns shared by vastly different species. In doing so, geneticists have almost certainly missed the ephemeral appearance of new introns, and therefore would come to the wrong conclusions about how introns are gained, why they are lost, and how frequently either occurs.

That many introns are not acquired from a common ancestor but are the result of separate insertion events, the scientists say, means that the rates of intron gain in any species' lineage could be considerably higher than currently estimated.

Even if the rates of intron gain and loss of introns in Daphnia pulex are unlike those found in humans, sunflowers, and mushrooms, the Science report suggests geneticists and genome biologists take another look at introns, some of which could have been the result of hot spot insertion events in separate lines.

"The immediate question will be whether our findings can readily be extended to other species," Lynch said. "We are, in fact, doing that now. In addition, there is need for some solid molecular work to test our hypothesis about the mechanism of intron origin."

Intron is short for "intragenic region," a segment of DNA embedded within the coding portion of a gene. Introns are common in eukaryotic organisms -- animals, plants, fungi, and protists. When genes are expressed, special machinery within the cell nucleus usually removes the introns, thereby producing a transcript of the gene that is devoid of nonsense. Some introns are very small (20 DNA base pairs or fewer). A few introns are shockingly long (nearly 500,000 base pairs) long. Within a gene region, the total length of introns may dwarf the actual coding regions. There's a gene on humans' 22nd chromosome that is so riddled with introns, only 10 percent of it actually contains coding DNA. The rest is comprised of introns.

Scientists have generally assumed introns are so deleterious, their insertion almost always spells doom for the cell lines within individual organisms that produce offspring. With the exception of alternative splicing, introns serve no apparent function and consume needless energy when cells must duplicate all of their DNA. More importantly, the insertion of a new intron in a bad place can interfere with the cellular machinery's expression of an important gene. Experts have taken all of this to mean intron insertions are extremely rare events.

Almost all of the introns the IU Bloomington biologists located possessed a sequence of indeterminate origin. Only one of the 24 identified sequences bore a resemblance to a specific DNA sequences associated either with the Daphnia genome or its parasites. The other 23 introns had sequences that appear to have been improvised by the machinery responsible for DNA synthesis. "Our molecular analyses have enabled us to reject a number of hypotheses for the mechanism of intron origins, while clearly indicating an entirely unexpected pathway -- emergence as accidents arising during the repair of double-strand breaks," Lynch said.

Abraham Tucker, now at Indiana University Bloomington, and paper co-author Way Sung were both graduate students of William Kelley Thomas at the University of New Hampshire's Hubbard Center for Genome Studies when they did the bioinformatic analysis of the Daphnia genome that led to the findings of this paper. Drawing on longtime collaborations between Lynch's lab and the Hubbard Center on the Daphniagenome project, the two were able to access all Daphniagenome sequences.

"It was a very intense analysis, but it was obvious within a few days that there was some very interesting data," says Thomas, who is Hubbard Professor in Genomics and director of the Hubbard Center for Genome Studies. "This was a wonderful collaborative project."

This research was funded with grants from the National Science Foundation.

Female Fruit Flies Can Be 'Too Attractive' to Males, Scientists Show

Females can be too attractive to the opposite sex -- too attractive for their own good -- say biologists at UC Santa Barbara. They found that, among fruit flies, too much male attention directed toward attractive females leads to smaller families and, ultimately, to a reduced rate of population-wide adaptive evolution.

In an article published in the December 8 issue of Public Library of Science Biology, the authors described their experiments on the sex lives of fruit flies.

"Can females be too good looking?" asks William Rice, biology professor at UCSB. "Can there be disadvantages to being attractive? The answer is yes: If you are too attractive, you get too much male attention, and that interferes with your ability to function biologically."

The authors explain that the term "good looking," among fruit flies, refers to something, like a large body. From the perspective of a male fly, a desirable mate is a female that is larger and can therefore produce more offspring.

"These larger females are disproportionately courted and harassed by males attempting to obtain matings," said Tristan A. F. Long, the study's first author. "When these males are 'choosy' with their courtship, there may be negative consequences to the species' ability to adaptively evolve."

According to the scientists, too much mating is harmful to the females because seminal fluid from the male has toxic side effects. Too much courtship can also hinder the female's ability to forage effectively.

"When they court the females, the males sing to them; they do this by vibrating their wings," said Rice. "They dance and sing at the same time. This might sound romantic, and it would be if it only happened once. But males are doing it all the time. This courtship is unrelenting -- like mosquitoes on a warm summer night -- as the male fruit flies try to persuade females to mate. The males are so persistent that they get them to mate almost every day."

In many species, females are frequently subject to intense courtship "harassment" from males attempting to obtain additional matings, according to the researchers. These coercive activities can result in attractive females becoming less fit to reproduce -- a factor that has a major effect on the entire population.

"We found that when harmful courtship behaviors were directed predominantly toward larger females of greater fecundity potential -- and away from smaller females, of lesser fecundity potential -- this resulted in an overall reduction in the variation of lifetime reproductive success of females in the population," said Long.

The male-mediated, persistent courtship bias can have important consequences for the ability of a population to adaptively change over time. If, for example, a female acquires a mutation that increases metabolic efficiency, allowing her to grow larger, and produce more offspring over her lifetime, this mutation should rapidly spread through the population. However, if the males get in the way of the biological success of these more attractive females, the mutation won't spread through the population as well as it might if males courted females indiscriminately.

The experiments clearly showed that the evolutionary adaptation of fruit flies is hindered by this mating situation. "This change in the distribution of fitness represents a previously unappreciated aspect of sexual selection -- one with important implications for the ability of beneficial genetic variation to spread through the gene pool, and ultimately for a species' capacity to adaptively evolve," Long explained.

Long was a Natural Sciences and Engineering Research Council of Canada (NSERC) postdoctoral fellow at UCSB at the time that he carried out the experiments designed with Rice. Long is currently a postdoctoral fellow with the University of Toronto in the Department of Ecology and Evolutionary Biology. The other authors are Alison Pischedda, a graduate student, and Andrew D. Stewart, a postdoctoral fellow, both of UCSB.

Gaining Advantages From Childhood Experience

It often seems that certain aspects of our personalities are influenced by events that occurred in our childhoods. A recent study by Dr. Akaysha Tang's research team from the University of New Mexico Psychology Department and collaborators at Rockefeller University examined how early life experience influences social skills and ability to handle stressful situations using a rat model. The study will be published on July 30th in the online, open-access journal PLoS ONE.

In this study, Dr. Tang and colleagues examined whether rats that experienced greater novelty by spending three minutes a day away from their familiar home environment during infancy had a greater ability to compete against other rats for exclusive access to chocolate reward compared to their siblings that stayed in the home environment during infancy. They found that novelty-exposed rats were able to "beat out" their competitors more often than their home-staying siblings. They also found that across repeated sessions of competition, novelty-exposed rats decreased their release of stress hormones into the bloodstream, suggesting that they adapted faster to the stressful situation.

These findings were made among rats that were 24 months of age—considered old age for a rat. Perhaps most remarkably, the differences in early experience were induced by approximately 60 minutes of cumulative differential treatment carried out during the first 3 weeks of life. This means that very brief exposures to a novel environment during infancy can have a life-long influence on social competitive ability and the stress response.

Another question asked by Dr. Tang and colleagues was whether the differences between siblings depended on the care received from their mothers during infancy. They measured how much mother rats licked and groomed their pups after the novelty exposure procedure and how consistently they provided this care from day to day. They discovered that the mother rats that delivered more care to their pups on average were inconsistent in their amount of care from day to day. This led to the surprising finding that the novelty-exposed rats with the most adaptive stress responses had mothers that gave highly consistent, but lesser amounts, of care.

In translating possible significance of these findings to the human species, although it is sometimes assumed that the overall amount of care from the mother is one of the most important influences on her children's development, this study by Dr. Tang and colleagues provides a different view—that the consistency of maternal care may be more important than the amount of maternal care and that other sources of influences, such as environmental novelty can play an important role in shaping a child's development.

If You're Feeling Helpless, It May Be Best To Be Alone

If you're going to experience a period of helplessness, it's best to be alone. New research at the University of Haifa found that laboratory rats that were on their own when exposed to uncontrollable conditions, which create a feeling of helplessness, learned to avoid situations which create such feelings better than rats that were exposed to uncontrollable conditions in pairs.

The way laboratory rats react to uncontrollable situations in which their behaviors have no influence on subsequent events has been researched in the past. Results show that rats that are exposed to a situation in which they are powerless, for example, electric shocks that they can't possibly avoid, have a more difficult time learning how to avoid them in the future than rats that were never exposed to situations of helplessness -- a phenomenon known as "learned helplessness."

Researchers choose to experiment with rats because they are know as social animals and their brains work much the same way as human brains. However, most of the research done until now was done on rats exposed to uncontrollable conditions when they are alone.

In his doctoral dissertation, Dr. Qutaiba Agbaria, under the supervision of Dr. Richard Shuster, examined the differences in learned helplessness among rats that were exposed to uncontrollable conditions alone and in pairs. The researcher began with the hypothesis that rats would learn to be more adaptable in social situations, or in pairs, however, the research results revealed a very different picture. Rats that were exposed to uncontrollable conditions in pairs coped less well when they were no longer in uncontrollable situations than rats that were exposed to these situations alone.

The next phase of the research examined the influence of a rat that had never been exposed to an uncontrollable situation on a rat that had. These pairs of rats showed greater adaptability than pairs that had been exposed to helplessness as individuals or in pairs. In addition, the researchers did not find outstanding differences between the learning ability of these pairs of rats -- where one had been exposed to uncontrollable conditions and the other hadn't -- and pairs that were never exposed to uncontrollable conditions, which means that the effect of "learned helplessness" is effectively erased. "Now that we have see that "learned helplessness" can be "unlearned", we should continue to examine whether this change is a result of exposure to a rat that was not exposed to helplessness or rather that the social behavior between the two animals has another meaning," said Dr. Agbaria.

Social Scientists Build Case for 'Survival of the Kindest'

Researchers at the University of California, Berkeley, are challenging long-held beliefs that human beings are wired to be selfish. In a wide range of studies, social scientists are amassing a growing body of evidence to show we are evolving to become more compassionate and collaborative in our quest to survive and thrive.

In contrast to "every man for himself" interpretations of Charles Darwin's theory of evolution by natural selection, Dacher Keltner, a UC Berkeley psychologist and author of "Born to be Good: The Science of a Meaningful Life," and his fellow social scientists are building the case that humans are successful as a species precisely because of our nurturing, altruistic and compassionate traits.

They call it "survival of the kindest."

"Because of our very vulnerable offspring, the fundamental task for human survival and gene replication is to take care of others," said Keltner, co-director of UC Berkeley's Greater Good Science Center. "Human beings have survived as a species because we have evolved the capacities to care for those in need and to cooperate. As Darwin long ago surmised, sympathy is our strongest instinct."

Empathy in our genes

Keltner's team is looking into how the human capacity to care and cooperate is wired into particular regions of the brain and nervous system. One recent study found compelling evidence that many of us are genetically predisposed to be empathetic.

The study, led by UC Berkeley graduate student Laura Saslow and Sarina Rodrigues of Oregon State University, found that people with a particular variation of the oxytocin gene receptor are more adept at reading the emotional state of others, and get less stressed out under tense circumstances.

Informally known as the "cuddle hormone," oxytocin is secreted into the bloodstream and the brain, where it promotes social interaction, nurturing and romantic love, among other functions.

"The tendency to be more empathetic may be influenced by a single gene," Rodrigues said.

The more you give, the more respect you get

While studies show that bonding and making social connections can make for a healthier, more meaningful life, the larger question some UC Berkeley researchers are asking is, "How do these traits ensure our survival and raise our status among our peers?"

One answer, according to UC Berkeley social psychologist and sociologist Robb Willer is that the more generous we are, the more respect and influence we wield. In one recent study, Willer and his team gave participants each a modest amount of cash and directed them to play games of varying complexity that would benefit the "public good." The results, published in the journal American Sociological Review, showed that participants who acted more generously received more gifts, respect and cooperation from their peers and wielded more influence over them.

"The findings suggest that anyone who acts only in his or her narrow self-interest will be shunned, disrespected, even hated," Willer said. "But those who behave generously with others are held in high esteem by their peers and thus rise in status."

"Given how much is to be gained through generosity, social scientists increasingly wonder less why people are ever generous and more why they are ever selfish," he added.

Cultivating the greater good

Such results validate the findings of such "positive psychology" pioneers as Martin Seligman, a professor at the University of Pennsylvania whose research in the early 1990s shifted away from mental illness and dysfunction, delving instead into the mysteries of human resilience and optimism.

While much of the positive psychology being studied around the nation is focused on personal fulfillment and happiness, UC Berkeley researchers have narrowed their investigation into how it contributes to the greater societal good.

One outcome is the campus's Greater Good Science Center, a West Coast magnet for research on gratitude, compassion, altruism, awe and positive parenting, whose benefactors include the Metanexus Institute, Tom and Ruth Ann Hornaday and the Quality of Life Foundation.

Christine Carter, executive director of the Greater Good Science Center, is creator of the "Science for Raising Happy Kids" Web site, whose goal, among other things, is to assist in and promote the rearing of "emotionally literate" children. Carter translates rigorous research into practical parenting advice. She says many parents are turning away from materialistic or competitive activities, and rethinking what will bring their families true happiness and well-being.

"I've found that parents who start consciously cultivating gratitude and generosity in their children quickly see how much happier and more resilient their children become," said Carter, author of "Raising Happiness: 10 Simple Steps for More Joyful Kids and Happier Parents" which will be in bookstores in February 2010. "What is often surprising to parents is how much happier they themselves also become."

The sympathetic touch

As for college-goers, UC Berkeley psychologist Rodolfo Mendoza-Denton has found that cross-racial and cross-ethnic friendships can improve the social and academic experience on campuses. In one set of findings, published in the Journal of Personality and Social Psychology, he found that the cortisol levels of both white and Latino students dropped as they got to know each over a series of one-on-one get-togethers. Cortisol is a hormone triggered by stress and anxiety.

Meanwhile, in their investigation of the neurobiological roots of positive emotions, Keltner and his team are zeroing in on the aforementioned oxytocin as well as the vagus nerve, a uniquely mammalian system that connects to all the body's organs and regulates heart rate and breathing.

Both the vagus nerve and oxytocin play a role in communicating and calming. In one UC Berkeley study, for example, two people separated by a barrier took turns trying to communicate emotions to one another by touching one other through a hole in the barrier. For the most part, participants were able to successfully communicate sympathy, love and gratitude and even assuage major anxiety.

Researchers were able to see from activity in the threat response region of the brain that many of the female participants grew anxious as they waited to be touched. However, as soon as they felt a sympathetic touch, the vagus nerve was activated and oxytocin was released, calming them immediately.

"Sympathy is indeed wired into our brains and bodies; and it spreads from one person to another through touch," Keltner said.

The same goes for smaller mammals. UC Berkeley psychologist Darlene Francis and Michael Meaney, a professor of biological psychiatry and neurology at McGill University, found that rat pups whose mothers licked, groomed and generally nurtured them showed reduced levels of stress hormones, including cortisol, and had generally more robust immune systems.

Overall, these and other findings at UC Berkeley challenge the assumption that nice guys finish last, and instead support the hypothesis that humans, if adequately nurtured and supported, tend to err on the side of compassion.

"This new science of altruism and the physiological underpinnings of compassion is finally catching up with Darwin's observations nearly 130 years ago, that sympathy is our strongest instinct," Keltner said.

Are Angry Women More Like Men?

"Why is it that men can be bastards and women must wear pearls and smile?" wrote author Lynn Hecht Schafran. The answer, according to an article in the Journal of Vision, may lie in our interpretation of facial expressions.

In two studies, researchers asked subjects to identify the sex of a series of faces. In the first study, androgynous faces with lowered eyebrows and tight lips (angry expressions) were more likely to be identified as male, and faces with smiles and raised eyebrows (expressions of happiness and fear) were often labeled feminine.

The second study used male and female faces wearing expressions of happiness, anger, sadness, fear or a neutral expression. Overall, subjects were able to identify male faces more quickly than female faces, and female faces that expressed anger took the longest to identify.

"The present research shows that the association between anger and men and happiness and women is so strong that it can influence the decisions about the gender of another person when that person is viewed briefly," said Ursula Hess, PhD, from the Department of Psychology, University of Quebec at Montreal.

According to the report, the findings from this study as well as others lead to the idea that "the face is a complex social signaling system in which signals for emotion, behavioral intentions and sex all overlap."

Hess said that the same cues that make a face appear male -- a high forehead, a square jaw and thicker eyebrows -- have been linked to perceptions of dominance. Likewise, features that make a face appear female -- a rounded, baby face with large eyes -- have been linked to perceptions of the individual being approachable and warm.

"This difference in how the emotions and social traits of the two sexes are perceived could have significant implications for social interactions in a number of settings. Our research demonstrates that equivalent levels of anger are perceived as more intense when shown by men rather than women, and happiness as more intense when shown by women rather than men. It also suggests that it is less likely for men to be perceived as warm and caring and for women to be perceived as dominant."

First Evidence of Brain Rewiring in Children: Reading Remediation Positively Alters Brain Tissue

Carnegie Mellon University scientists Timothy Keller and Marcel Just have uncovered the first evidence that intensive instruction to improve reading skills in young children causes the brain to physically rewire itself, creating new white matter that improves communication within the brain.

As the researchers report today in the journal Neuron, brain imaging of children between the ages of 8 and 10 showed that the quality of white matter -- the brain tissue that carries signals between areas of grey matter, where information is processed -- improved substantially after the children received 100 hours of remedial training. After the training, imaging indicated that the capability of the white matter to transmit signals efficiently had increased, and testing showed the children could read better.

"Showing that it's possible to rewire a brain's white matter has important implications for treating reading disabilities and other developmental disorders, including autism," said Just, the D.O. Hebb Professor of Psychology and director of Carnegie Mellon's Center for Cognitive Brain Imaging (CCBI).

Dr. Thomas R. Insel, director of the National Institute of Mental Health, agreed. "We have known that behavioral training can enhance brain function. The exciting breakthrough here is detecting changes in brain connectivity with behavioral treatment. This finding with reading deficits suggests an exciting new approach to be tested in the treatment of mental disorders, which increasingly appear to be due to problems in specific brain circuits," Insel said.

Keller and Just's study was designed to discover what physically changes in the brains of poor readers who make the transition to good reading. They scanned the brains of 72 children before and after they went through a six-month remedial instruction program. Using diffusion tensor imaging (DTI), a new brain imaging technique that tracks water movement in order to reveal the microscopic structure of white matter, Keller and Just found a brain change involving the white matter cabling that wires different parts of the brain together.

"Water molecules that are inside nerve fibers tend to move or diffuse parallel to the nerve fibers," explained Keller, a CCBI research scientist and author of the first developmental study of compromised white matter in autism. "To track the nerve fibers, the scanner senses areas in which many water molecules are moving along in the same direction and produces a road-map of the brain's wiring."

Previous DTI studies had shown that both children and adults with reading difficulty displayed areas of compromised white matter. This new study shows that 100 hours of intensive reading instruction improved children's reading skills and also increased the quality of the compromised white matter to normal levels. More precisely, the DTI imaging illustrated that the consistency of water diffusion had increased in this region, indicating an improvement in the integrity of the white matter tracts.

"The improved integrity essentially increases communication bandwidth between the two brain areas that the white matter connects, by a factor of 10," Just said. "This opens a new era of being able to see the brain wiring change when an effective instructional treatment is applied. It lets us see educational interventions from a new perspective."

Out of the 72 children, 47 were poor readers and 25 were reading at a normal level. The good readers and a group of 12 poor readers did not receive the remedial instruction, and their brain scans did not show any changes. "The lack of change in the control groups demonstrates that the change in the treated group cannot be attributed to naturally occurring maturation during the study," Keller said.

Keller and Just also found that the amount of change in diffusion among the treated group was directly related to the amount of increase in phonological decoding ability. The children who showed the most white matter change also showed the most improvement in reading ability, confirming the link between the brain tissue alteration and reading progress.

Additional analyses indicated that the change resulted from a decrease in the movement of water perpendicular to the main axes of the underlying white matter fibers, a finding consistent with increased myelin content in the region. Although the authors caution that further research will be necessary to uncover the precise mechanism for the change in white matter, some previous findings indicate a role for electrical activity along axons in promoting the formation of myelin around them, providing a plausible physiological basis for intensive practice and instruction increasing the efficiency of communication among brain areas.

"We're excited about these results," Just said. "The indication that behavioral intervention can improve both cognitive performance and the microstructure of white matter tracts is a breakthrough for treating and understanding development problems."

Battle of the Sexes: Ovaries Must Suppress Their Inner Male

Is it a boy or a girl? Expecting parents may be accustomed to this question, but contrary to what they may think, the answer doesn't depend solely on their child's sex chromosomes.

Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany and the Medical Research Council's National Institute for Medical Research (NIMR) at Mill Hill, UK discovered that if a specific gene located on a non-sex chromosome is turned off, cells in the ovaries of adult female mice turn into cells typically found in testes. Their study, published in Cell, challenges the long-held assumption that the development of female traits is a default pathway. At the same time, it grants a valuable insight into how sex determination evolved.

In humans and most other mammals, an individual's sex is determined by its sex chromosomes: females have two X chromosomes, males have one X and one Y. Scientists had long assumed that the female pathway -- the development of ovaries and all the other traits that make a female -- was a kind of default: if it had a gene called Sry, which is located on the Y chromosome, an embryo would develop into a male, if not, then the result would be a female. But in adult animals it is the male pathway that needs to be actively suppressed, as Mathias Treier and his team at EMBL discovered.

A gene called Foxl2, which is located on an autosome -- a chromosome other than the sex chromosomes -- and therefore present in both sexes, was known to play an important role in the female pathway, but its precise function remained elusive. To elucidate the matter, Treier and colleagues ablated, or 'turned off', this gene in the ovaries of adult female mice.

"We were surprised by the results," says Treier, "We expected the mice to stop producing oocytes, but what happened was much more dramatic: somatic cells which support the developing egg took on the characteristics of the cells which usually support developing sperm, and the gender-specific hormone-producing cells also switched from a female to a male cell type."

Thus, the scientists discovered that Foxl2 plays a crucial role in keeping female mice female.

Teaming up with the group of Robin Lovell-Badge at the NIMR, they were able to decipher together the underlying molecular mechanism. They showed that FOXL2 and estrogen receptor act together by repressing a DNA element called TESCO that Lovell-Badge's group had previously identified to regulate expression of the testes-promoting gene Sox9. Sox9 was known to function in the embryo to make the early gonads become testes rather than ovaries, but the new studies suggest that it can perform the same task in the adult. FOXL2 is therefore critical to keep Sox9 turned off in ovaries throughout life.

"As most vertebrates have Foxl2, estrogen receptors and Sox9," Lovell-Badge explains, "this mechanism for maintaining female traits probably appeared early on in the evolution of vertebrates, while Sry and the mammalian Y chromosome are relatively new inventions."

These findings will have wide-ranging implications for reproductive medicine and may, for instance, help to treat sex differentiation disorders in children, for example where XY individuals develop as females or XX as males, and understand the masculinising effects of menopause on some women.

Why King Kong Failed to Impress: Humans, Apes Use Odor-Detecting Receptors Differently

Humans have the same receptors for detecting odors related to sex as do other primates. But each species uses them in different ways, stemming from the way the genes for these receptors have evolved over time, according to Duke University researchers.

Varying sensitivity to these sex-steroid odors may play a role in mate selection -- and perhaps prevent cross-species couplings, the researchers speculate.

The researchers analyzed the sequences and functions of the gene for the odorant receptor OR7D4 in terms of perceiving two steroid molecules related to testosterone, androstenone and androstadienone. The study did not try to examine how the receptors and odor perception might relate to behavior.

"There's variation in sensitivity of the odorant receptor from this gene (all primates) have," said Hiroaki Matsunami, associate professor of molecular genetics and microbiology and neurobiology at Duke University Medical Center. "Maybe these molecules operate in the process of reproduction. The fact that there is variation fits with this theory. Reproduction demands that an animal avoid attraction to other species, so variation in the receptor's sensitivity to these odors may prevent any cross-species attraction."

The study was published online Dec. 3 in the Early Edition of the Proceedings of the National Academy of Sciences.

Animals rely on olfactory signals to make all sorts of decisions about other animals, particularly in reproduction, said Christine Drea, Ph.D., an associate professor of Biology at Duke who was not involved with this study. "Beyond identifying members of the same species, odors help identify kin or nonkin, members of the opposite sex, even whether individuals are fertile or genetically appropriate as mates. How they do so is still largely unknown," she said. "By deciphering evolutionary changes in receptor function across species, Dr. Matsunami and his colleagues have brought us another step closer to unraveling the mysteries of olfactory signaling."

The odorant receptor gene, which the paper traces back to the mongoose lemur, evolved differently within the various primate species. Human receptors were found to be most closely related to the chimps and bonobo monkeys, as opposed to gorillas and other primates.

The findings support the evidence that primates have a common ancestor, but we are very different now. "One of the differences is in how well we are able to sense odors, which is exemplified by changes in the function of this odor receptor," Matsunami said.

Ultimately, the work will aim at discerning how smelling these chemicals might affect human social and sexual behavior. "We will begin working with a collaborator to examine chimpanzee behavior with regard to odor perception," Matsunami said.

However, the sense of smell also can vary from animal to animal and person to person, because of combinations of a number of odor receptors.

"The sex-steroid related odors act as pheromones in pigs," Matsunami said. "Pigs that are ovulating and that are exposed to the pheromones assume a mating posture. It's debatable whether these chemicals act similarly in humans. But there is evidence that smelling these odors can affect the mood and physiological state of both men and women. We have a lot more studying to do, but this finding and others in the future will create a picture of how smell may relate to sexual reproduction."

Matsunami added that there are likely other receptors and receptor variants that may also play roles in how these two chemicals are perceived. Because there are about 400 specific smell receptors and humans can detect more than 10,000 different odors, different combinations of receptor genes and variants must be involved in perceiving each odor, Matsunami said.

First Evidence of Brain Rewiring in Children: Reading Remediation Positively Alters Brain Tissue

Carnegie Mellon University scientists Timothy Keller and Marcel Just have uncovered the first evidence that intensive instruction to improve reading skills in young children causes the brain to physically rewire itself, creating new white matter that improves communication within the brain.

As the researchers report today in the journal Neuron, brain imaging of children between the ages of 8 and 10 showed that the quality of white matter -- the brain tissue that carries signals between areas of grey matter, where information is processed -- improved substantially after the children received 100 hours of remedial training. After the training, imaging indicated that the capability of the white matter to transmit signals efficiently had increased, and testing showed the children could read better.

"Showing that it's possible to rewire a brain's white matter has important implications for treating reading disabilities and other developmental disorders, including autism," said Just, the D.O. Hebb Professor of Psychology and director of Carnegie Mellon's Center for Cognitive Brain Imaging (CCBI).

Dr. Thomas R. Insel, director of the National Institute of Mental Health, agreed. "We have known that behavioral training can enhance brain function. The exciting breakthrough here is detecting changes in brain connectivity with behavioral treatment. This finding with reading deficits suggests an exciting new approach to be tested in the treatment of mental disorders, which increasingly appear to be due to problems in specific brain circuits," Insel said.

Keller and Just's study was designed to discover what physically changes in the brains of poor readers who make the transition to good reading. They scanned the brains of 72 children before and after they went through a six-month remedial instruction program. Using diffusion tensor imaging (DTI), a new brain imaging technique that tracks water movement in order to reveal the microscopic structure of white matter, Keller and Just found a brain change involving the white matter cabling that wires different parts of the brain together.

"Water molecules that are inside nerve fibers tend to move or diffuse parallel to the nerve fibers," explained Keller, a CCBI research scientist and author of the first developmental study of compromised white matter in autism. "To track the nerve fibers, the scanner senses areas in which many water molecules are moving along in the same direction and produces a road-map of the brain's wiring."

Previous DTI studies had shown that both children and adults with reading difficulty displayed areas of compromised white matter. This new study shows that 100 hours of intensive reading instruction improved children's reading skills and also increased the quality of the compromised white matter to normal levels. More precisely, the DTI imaging illustrated that the consistency of water diffusion had increased in this region, indicating an improvement in the integrity of the white matter tracts.

"The improved integrity essentially increases communication bandwidth between the two brain areas that the white matter connects, by a factor of 10," Just said. "This opens a new era of being able to see the brain wiring change when an effective instructional treatment is applied. It lets us see educational interventions from a new perspective."

Out of the 72 children, 47 were poor readers and 25 were reading at a normal level. The good readers and a group of 12 poor readers did not receive the remedial instruction, and their brain scans did not show any changes. "The lack of change in the control groups demonstrates that the change in the treated group cannot be attributed to naturally occurring maturation during the study," Keller said.

Keller and Just also found that the amount of change in diffusion among the treated group was directly related to the amount of increase in phonological decoding ability. The children who showed the most white matter change also showed the most improvement in reading ability, confirming the link between the brain tissue alteration and reading progress.

Additional analyses indicated that the change resulted from a decrease in the movement of water perpendicular to the main axes of the underlying white matter fibers, a finding consistent with increased myelin content in the region. Although the authors caution that further research will be necessary to uncover the precise mechanism for the change in white matter, some previous findings indicate a role for electrical activity along axons in promoting the formation of myelin around them, providing a plausible physiological basis for intensive practice and instruction increasing the efficiency of communication among brain areas.

"We're excited about these results," Just said. "The indication that behavioral intervention can improve both cognitive performance and the microstructure of white matter tracts is a breakthrough for treating and understanding development problems."

Spices Halt Growth of Breast Stem Cells, Study Finds

A new study finds that compounds derived from the spices turmeric and pepper could help prevent breast cancer by limiting the growth of stem cells, the small number of cells that fuel a tumor's growth.

Researchers at the University of Michigan Comprehensive Cancer Center have found that when the dietary compounds curcumin, which is derived from the Indian spice turmeric, and piperine, derived from black peppers, were applied to breast cells in culture, they decreased the number of stem cells while having no effect on normal differentiated cells.

"If we can limit the number of stem cells, we can limit the number of cells with potential to form tumors," says lead author Madhuri Kakarala, M.D., Ph.D., R.D., clinical lecturer in internal medicine at the U-M Medical School and a research investigator at the VA Ann Arbor Healthcare System.

Cancer stem cells are the small number of cells within a tumor that fuel the tumor's growth. Current chemotherapies do not work against these cells, which is why cancer recurs and spreads. Researchers believe that eliminating the cancer stem cells is key to controlling cancer. In addition, decreasing the number of normal stem cells -- unspecialized cells that can give rise to any type of cell in that organ -- can decrease the risk of cancer.

In this study, a solution of curcumin and piperine was applied to the cell cultures at the equivalent of about 20 times the potency of what could be consumed through diet. The compounds are available at this potency in a capsule form that could be taken by mouth. (Note: This work has not been tested in patients, and patients are not encouraged to add curcumin or piperine supplements to their diet at this time.)

The researchers applied a series of tests to the cells, looking at markers for breast stem cells and the effects of curcumin and piperine, both alone and combined, on the stem cell levels. They found that piperine enhanced the effects of curcumin, and that the compounds interrupted the self-renewal process that is the hallmark of cancer-initiating stem cells. At the same time, the compounds had no affect on cell differentiation, which is the normal process of cell development.

"This shows that these compounds are not toxic to normal breast tissue," Kakarala says. "Women at high risk of breast cancer right now can choose to take the drugs tamoxifen or raloxifene for prevention, but most women won't take these drugs because there is too much toxicity. The concept that dietary compounds can help is attractive, and curcumin and piperine appear to have very low toxicity."

Curcumin and piperine have been explored by other researchers as a potential cancer treatment. But this paper, published online in the journal Breast Cancer Research and Treatment, is the first to suggest these dietary compounds could prevent cancer by targeting stem cells.

In addition, tamoxifen or raloxifene are designed to affect estrogen, which is a factor in most, but not all breast cancers. In fact, the aggressive tumors that tend to occur more often in women with a family history or genetic susceptibility are typically not affected by estrogen. Because curcumin and piperine limit the self renewal of stem cells, they would impact cancers that are not estrogen sensitive as well as those that are.

Researchers are planning an initial Phase I clinical trial to determine what dose of curcumin or piperine can be tolerated in people. The trial is not expected to begin accruing participants until spring.

Breast cancer statistics: 194,280 Americans will be diagnosed with breast cancer this year and 40,610 will die from the disease, according to the American Cancer Society

Why Humans Outlive Apes: Human Genes Have Adapted to Inflammation, but We Are More Susceptible to Diseases of Aging

In spite of their genetic similarity to humans, chimpanzees and great apes have maximum lifespans that rarely exceed 50 years. The difference, explains USC Davis School of Gerontology Professor Caleb Finch, is that as humans evolved genes that enabled them to better adjust to levels of infection and inflammation and to the high cholesterol levels of their meat rich diets.

In the December issue ofProceedings of the National Academy of Sciences (Early Edition), Finch reveals that these evolutionary genetic advantages, caused by slight differences in DNA sequencing and improvements in diet, make humans uniquely susceptible to diseases of aging such as cancer, heart disease and dementia when compared to other primates.

Finch, the ARCO & William F. Kieschnick Professor in the Neurobiology of Aging and a distinguished University Professor, argues that a major contributor to longevity for humans is the genes that adapt to higher exposure to inflammation.

"Over time, ingestion of red meat, particularly raw meat infected with parasites in the era before cooking, stimulates chronic inflammation that leads to some of the common diseases of aging," Finch said.

In addition to differences in diets between species of primates, humans evolved unique variants in a cholesterol transporting gene, apolipoprotein E, which also regulates inflammation and many aspects of aging in the brain and arteries.

ApoE3 is unique to humans and may be what Finch calls "a meat-adaptive gene" that has increased the human lifespan.

However, the minor allele, apoE4, when expressed in humans, can impair neuronal development, as well as shorten human lifespan by about four years and increase the risk of heart disease and Alzheimer disease by several-fold. ApoE4 carriers have higher totals of blood cholesterol, more oxidized blood lipids and early onset of coronary heart disease and Alzheimer's disease.

"The chimpanzee apoE functions more like the "good" apoE3, which contributes to low levels of heart disease and Alzheimer's," Finch said. Correspondingly, chimpanzees in captivity have unusually low levels of heart disease and Alzheimer-like changes during aging.

Finch hypothesizes that the expression of ApoE4 could be the result of the antagonistic pleiotropy theory of aging, in which genes selected to fight diseases in early life have adverse affects in later life.

"ApoeE may be a prototype for other genes that enabled the huge changes in human lifespan, as well as brain size, despite our very unape-like meat-rich diets," Finch said. "Drugs being developed to alter activities of apoE4 may also enhance lifespan of apoE4 carriers."

Scientists Rescue Visual Function in Rats Using Induced Pluripotent Stem Cells

An international team of scientists has rescued visual function in laboratory rats with eye disease by using cells similar to stem cells. The research shows the potential for stem cell-based therapies to treat age-related macular degeneration in humans.

A team led by Dennis Clegg, of UC Santa Barbara, and Pete Coffey, of University College London (UCL), published their work in two papers, including one published the week of December 1 in the journal PloS One. The first paper was published in the October 27 issue of the journal Stem Cells.

The scientists worked with rats that have a mutation which causes a defect in retinal pigmented epithelial (RPE) cells and leads to photoreceptor death and subsequent blindness. Human RPE cells were derived from induced pluripotent stem cells -- embryonic stem cell-like cells that can be made from virtually any cell in the body, thus avoiding the controversy involved in using stem cells derived from embryos. Pluripotent means that the cells can become almost any cell in the body.

In experiments spearheaded by UCL's Amanda Carr, the team found that by surgically inserting stem cell-derived RPE into the retinas of the rats before photoreceptor degeneration, vision was retained. They found that the rats receiving the transplant tracked their visual focus in the direction of moving patterns more efficiently than control groups that did not receive a transplant.

"Although much work remains to be done, we believe our results underscore the potential for stem-cell based therapies in the treatment of age-related macular degeneration," said Sherry Hikita, an author on both papers and director of UCSB's Laboratory for Stem Cell Biology.

Dave Buchholz, first author of the article in Stem Cells, explained that by using induced stem cells that can be derived from patients, the scientists avoid immune rejection that might occur when using embryonic stem cells.

According to Buchholz, "RPE cells are essential for visual function. Without RPE, the rod and cone photoreceptors die, resulting in blindness. This is the basic progression in age-related macular degeneration. The hope is that by transplanting fresh RPE, derived from induced pluripotent stem cells, the photoreceptors will stay healthy, preventing vision loss."

Learning by Imagining: How Mental Imagery Training Aids Perceptual Learning

Practice makes perfect. But imaginary practice? Elisa Tartaglia of the Laboratory of Psychophysics at Switzerland's Ecole Polytechnique Federale de Lausanne (EPFL) and team show that perceptual learning -- learning by repeated exposure to a stimulus -- can occur by mental imagery as much as by the real thing. The results, published in Current Biology, suggest that thinking about something over and over again could actually be as good as doing it.

"When trained, radiologists are able to detect anomalies on medical images which are extremely hard to detect for untrained people," Tartaglia says. "The results of our study would predict that mental imagery training, hence, repeatedly mentally visualizing the anomalies that one wants to detect, would be sufficient to become able to detect them."

In a series of experiments, the scientists asked some participants to practice identifying which line, the right or the left in a series of parallel lines, a central line was closest to and to identify it by pushing the correct button. In follow-up, "post-training" exercises, these participants improved their baseline performance significantly. But so did another set of volunteers who, instead of practicing with all three lines in training, were instead asked to imagine the bisecting line's proximity based on an audio tone. This group also improved their performance significantly in further testing, meaning that "imagery training" was sufficient for perceptual learning.

Some experts question the relevance of mental imagery in this kind of learning, which is generally assumed to be driven by stimulus processing -- synapses firing in response to a physical cue. Here, the researchers show that perceptual learning can also occur by mental imagery, i.e., in the absence of physical stimulation. The results help shine a light on what has been an ongoing puzzle in the field and suggest an overlap in how -- and possibly where -- mental imagery affects perceptual learning.

New Therapy Targets for Amyloid Disease

A major discovery is challenging accepted thinking about amyloids -- the fibrous protein deposits associated with diseases such as Alzheimer's and Parkinson's -- and may open up a potential new area for therapeutics.

It was believed that amyloid fibrils -- rope-like structures made up of proteins sometimes known as fibres -- are inert, but that there may be toxic phases during their formation which can damage cells and cause disease.

But in a paper published December 4 2009 in the Journal of Biological Chemistry, scientists at the University of Leeds have shown that amyloid fibres are in fact toxic -- and that the shorter the fibre, the more toxic it becomes.

"This is a major step forward in our understanding of amyloid fibrils which play a role in such a large number of diseases," said Professor Sheena Radford of the Astbury Centre for Structural Molecular Biology and the Faculty of Biological Sciences.

"We've revisited an old suspect with very surprising results. Whilst we've only looked in detail at three of the 30 or so proteins that form amyloid in human disease, our results show that the fibres they produce are indeed toxic to cells especially when they are fragmented into shorter fibres. "

Amyloid deposits can accumulate at many different sites in the body or can remain localised to one particular organ or tissue, causing a range of different diseases. Amyloid deposits can be seen in the brain, in diseases such as Parkinson's and Alzheimer's, whereas in other amyloid diseases deposits can be found elsewhere in the body, in the joints, liver and many other organs. Amyloid deposits are also closely linked to the development of Type II diabetes.

Professor Radford said: "Problems in the self-assembly process that results in the formation of amyloid are a natural consequence of longer life. In fact 85 per cent of all cases of disease caused by amyloid deposits are seen in those over the age of sixty or so."

The study was funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC), supporting a team that included both cell biologists and biophysicists.

The next stage of this work is to look at a greater number of proteins that form amyloid fibres in order to consolidate these findings, says co-author and cell biologist Dr Eric Hewitt. "What we've discovered is fundamental and offers a whole new area for those working on therapeutics in this area. We anticipate that when we look at amyloid fibres formed from other proteins, they may well follow the same rules."

The team also hopes to discover why the shorter amyloid fibres are more toxic that their longer counterparts.

"It may be that because they're smaller it's easier for them to infiltrate cells," says Dr Hewitt. "We've observed them killing cells, but we're not sure yet exactly how they do it. Nor do we know whether these short fibres form naturally when amyloid fibres assemble or whether some molecular process makes them disassemble or fragment into shorter fibres.These are our next big challenges."

Newly Discovered Fat Molecule: An Undersea Killer With an Upside

A chemical culprit responsible for the rapid, mysterious death of phytoplankton in the North Atlantic Ocean has been found by collaborating scientists at Rutgers University and the Woods Hole Oceanographic Institution (WHOI). This same chemical may hold unexpected promise in cancer research.

The team discovered a previously unknown lipid, or fatty compound, in a virus that has been attacking and killing Emiliania huxleyi, a phytoplankton that plays a major role in the global carbon cycle.

"Emiliania huxleyi is the rock star of phytoplankton," explains Kay Bidle, Rutgers assistant professor of marine science in the Institute of Marine and Coastal Sciences. "It blooms all over the oceans, and we can easily see it by satellite. We know that these blooms are frequently infected with viruses, and this virus is specific to this phytoplankton."

The lipids are the key ingredient in the virus that causes the phytoplankton to die," says WHOI scientist Benjamin Van Mooy. "We have a completely different lipid molecule that, as far as we know, is unknown to science."

E. huxleyi grows rapidly in the North Atlantic, "in these big blooms that you can actually see from outer space," Van Mooy says.

"But," adds Van Mooy, "they die just almost as quickly as they start out, and we're not sure why. They die after a few days."

Bidle and Assaf Vardi, a postdoctoral investigator in his laboratory and the study's lead author, had been examining the interaction between the virus and the dying phytoplankton and had developed ideas for how this process works. After Vardi heard lipid expert Van Mooy give a talk in Santa Fe, N.M., he suggested the collaboration between WHOI and Rutgers.

"I saw Ben's talk on marine microbes and lipids…[and] I ran after him," said Vardi. "We told him about our ideas" involving the virus's effect on the phytoplankton.

"They studied the viruses and I study lipids," Van Mooy said. "It seemed like a good mix."

Their paper is published in the Nov. 6 issue of Science., E. huxleyi performs photosynthesis -- "just like plants," says Van Mooy. "They suck up carbon dioxide." In doing so, they reduce the amount of CO2 released into the atmosphere. They form a calcium carbonate shell, also helping to regulate the carbon cycle.

If viruses are killing off phytoplankton, this can increase greenhouse emissions, Van Mooy suggests. "That's important because if viruses infect a whole bunch of cells, then they can't perform photosynthesis, they can't take up carbon dioxide."

In April 2008, Van Mooy's team visited the sites of E. huxleyiblooms during a research cruise between Woods Hole and Bermuda and collected samples for lipid analysis back in the laboratory.

They immediately recognized lipids that were just like those in virally infected E. huxleyi cells grown by the Rutgers team. Helen Fredricks, a research associate with Van Mooy, carried out the lipid analyses at WHOI. "Seeing this viral lipid appear during the course of infection was amazing, and then we found it in the ocean too. We were celebrating in the lab that day."

Adds Vardi: "Viruses are really important players in regulating phytoplankton blooms. We zoom into the bloom and try to understand the interaction between the viruses and host, which is this really important, cosmopolitan, bloom-forming species."

After isolating the viral lipids, the team found that the lipids alone were able to bring about the symptoms of viral infection in the phytoplankton. "The lipids themselves act just like the virus," says Van Mooy. "We can cause the phytoplankton to die by just giving the lipids."

This alone was enough to excite the team. "Now we have a biological marker that we can go out on a ship and look for and identify where this [infection of phytoplankton] is happening and learn how to study it better," Van Mooy says.

But there may be other, even farther-reaching implications. Both the virus and the newly found lipid deal their deadly blow by causing the upper-ocean plants to commit cellular suicide. As a major focus of their research at Rutgers, Bidle's lab has found that "programmed cell death" is an important process in the fate of marine phytoplankton and in the demise of blooms in the oceans. Bidle's group had previously found that successful infection of E. huxleyi induced, and actually required, the programmed cell death pathway.

But programmed cell death is not unique to phytoplankton. It is a common and healthy process in all kinds of cells, including human cells.

According to Vardi, "These lipids can induce programmed cell death in many organisms, including animals and plants. They also enrich in plasma membrane, and they are the port of the cell, where pathogens get in and out of the cell. This is important in viral diseases."

There is also a potential connection with cancer. If a healthy cell is stressed or damaged, usually it will kill itself with programmed cell death. But cancer cells have a defect: "They don't kill themselves," says Bidle.

"It's a critical aspect of cancer research, because cancer cells have figured out a way to turn off the programmed cell death pathway," he says. "In cancer studies, they try to figure out ways to reactivate those pathways."

The lipid may help shed light on why cancer cells are unable to commit suicide. Someday, the researchers say, it might suggest ways to correct that defect. Right now, the lipid is only known to be effective in algae, but in the future, the team is hoping to test the effectiveness of their molecule in experiments with cancer cells.

"There's a long way to go between here and curing cancer," Van Mooy says, "but the potential exists that this molecule could have therapeutic applications in the treatment of human disease, including cancer. Hopefully this paper will pique the interest of other investigators."

More immediately, scientists hope to learn more about the central role phytoplankton -- and viruses -- play in regulating climate. Bidle says this is a particularly interesting virus. "It appears that the virus has…borrowed, copied actually, the genes for this lipid from the host," he says. "Similar genes are still on the host, but the virus has figured out a way to take those genes and put them into its own genome, and alter them enough to make them more toxic."

"We find the biosynthetic pathway for this unique lipid encoded in the virus genome, not only in the host, and this has never been described before in any other virus," Vardi says. "We knew that [lipids] were important, but we were really intrigued about why the virus contained these genes. And what is the role of the pathway in the co-evolution of programmed cell death in the host and virus."

Van Mooy sees it as a struggle between two mighty forces. "The phytoplankton are at one end of the boxing ring and they're taking up carbon dioxide, and the viruses are at the other end, and they're out to kill them. And how that works out controls how much carbon dioxide is taken up.

"We're very interested in understanding what controls these phytoplankton," he says. "I didn't know that much about viruses until I started working on this project and the Rutgers researchers didn't know that much about lipids. So now we're both really onto something here. We're continuing to collaborate. "We have found other interesting lipids from these viruses," says Van Mooy.

"There are probably more out there. And who knows what kind of activities they may be involved with. They may hold a cure for a human disease or they may play unknown role in…phytoplankton.