A team of researchers from the United States and the Netherlands has identified mutations in three genes that are associated with high levels of uric acid in the blood, which is a risk factor for gout.  The team developed a genetic risk score composed of the number of uric acid-increasing mutations that each person carries (0 to 6), which was associated with up to a 40-fold increased risk for developing gout when comparing persons at lowest and highest risk.  The findings are published in the October 4 issue of The Lancet.

More than 3 million adults in the United States have gout.  Gout is a painful inflammation of the joints, which can occur with a build-up of uric acid in the blood (hyperuricaemia).  Besides a genetic disposition, obesity, a diet high in meat and cheese, as well as alcohol consumption and certain medications can increase the risk for developing the disease.

The researchers conducted genome-wide association studies of more than 20,000 people enrolled in three large population-based studies investigating cardiovascular disease risk factors: the Framingham Heart Study based at Boston University Medical Center; the Rotterdam Study based at Erasmus Medical Centre in Rotterdam, the Netherlands; and the Atherosclerosis Risk in Communities (ARIC) study based at Johns Hopkins University.  Of more than 500,000 genetic variations that were evaluated, the analysis identified two genes, ABCG2 and SLC17A3, as novel risk genes for gout and confirmed the association of a third gene, SLC2A9.

“This research gives us a better understanding of the underlying causes of gout, which could lead to better prevention and treatment.  Our evidence supports that a common pathway, the handling of uric acid by the kidney, is important in uric acid build-up and therefore for the development of gout,” said study author, Anna Köttgen, MD, MPH, an assistant scientist in the Johns Hopkins Bloomberg School of Public Health’s Department of Epidemiology.

“Genetic risk scores like the one we developed for gout can help alert people at a very early age, well before uric acid levels rise, that they are susceptible to gout.  The new insights are promising for drug development,” said Josef Coresh, MD, PhD, MHS, professor in the Bloomberg School’s departments of Epidemiology and Biostatistics.  “An important unanswered question is whether we can use genetic risk information to motivate people to change their behavior.  For gout, we know that moderate changes in diet and alcohol consumption can lower uric acid levels.  In the future, we will need to test if identification of high-risk individuals can lead to behavior change.”

In infancy, genes are the key influence on a child’s ability to deal with stress. But as early as 6 months of age, parenting plays an important role in changing the impact of genes that may put infants at risk for responding poorly to stress.That’s the message from a new study by researchers at the University of North Carolina-Chapel Hill, Pennsylvania State University, the University of North Carolina-Greensboro, and North Carolina State University. It appears in the September/October 2008 issue of the journal Child Development.

The researchers looked at 142 infants who had been placed in a stressful situation—being separated from their mothers—when they were 3, 6, and 12 months old. They measured infants’ heart rates while they were exposed to the stressor, isolating a cardiac response called vagal tone. Vagal tone acts like a brake on the heart when the body is in a calm state, but during a challenging situation, this brake is withdrawn, allowing heart rate to increase so the body can actively deal with the challenge.

They also collected DNA to determine which form of a dopamine receptor gene the infants carried; specific forms of this gene are related to problems in adolescence and adulthood including aggression, substance abuse, and other risky behaviors. To assess the mothers’ behavior as high or low in sensitivity, they also videotaped the mothers and their infants playing together for 10 minutes when the babies were 6 months old.

Both genes and parenting were found to be important to the infants’ development of the way in which the brain helps regulate cardiac responses to stress. At 3 and 6 months old, those infants with the form of the dopamine gene associated with later risky behaviors did not display an effective cardiac response to the stressor (a decrease in vagal tone which takes the brake off the heart so it can respond appropriately), while those infants with the non-risk version of the gene did. At these early ages, the researchers found, it didn’t appear to matter whether mothers were sensitive or not.

However, by the time the infants were 12 months old, the pattern changed. Infants with the risk form of the gene who also had mothers who were highly sensitive now showed the expected cardiac response while they were exposed to the stressful situation. Those infants with the risk form of the gene who had insensitive mothers continued to show the ineffective cardiac response to the stressor. These findings suggest that although genes play a role in the development of physiological responses to stress, environmental experience (such as mothers’ sensitive care-giving behavior) can have a strong influence, enough to change the effect that genes have on physiology very early in life. The researchers suggest this may be because of the cumulative effect on infants of exposure to their mothers’ behavior.

“Our findings provide further support for the notion that the development of complex behavioral and physiological responses is not the result of nature or nurture, but rather a combination of the two,” says Cathi Propper, research scientist at the University of North Carolina-Chapel Hill and the study’s lead author. “They also illustrate the importance of parenting not just for the development of children’s behavior, but for the underlying physiological mechanisms that support this behavior.

“Lastly, infancy is an important time for developing behavioral and biological processes. Although these processes will continue to change over time, parenting can have important positive effects even when children have inherited a genetic vulnerability to problematic behaviors.”

Breakthroughs in cytogenetic technologies, which focus on subtle alterations in genes and chromosomes, are enabling a new level of detail and accuracy in the diagnosis of complex and unexplained developmental problems in children.

The availability of this new information can help clinicians shift to a “genotype first” model of diagnosis, according to David H. Ledbetter, PhD, Woodruff professor of human genetics at Emory University and director of the Division of Medical Genetics.

Ledbetter’s editorial on “Cytogenetic Technology–Genotype and Phenotype,” is published online this week by the New England Journal of Medicine.  It accompanies an article by Heather Mefford and colleagues about using new cytogenetic technologies to identify microdeletions and microduplications in a specific region of chomosome 1q21.1 in patients with unexplained mental retardation, autism or congenital anomalies

Cytogenetic arrays that reveal DNA microdeletions and additions, including single-copy changes of a few hundred base pairs, beadchips that detect single-nucleotide polymorphisms (SNPs) and tests called comparative genomic hybridization have led to an exciting renaissance of genetics-based syndrome delineation, says Ledbetter in his editorial.

“In the early 1960s we began discovering the relationship between chromosome imbalance and diseases and syndromes, such as Down syndrome,” says Ledbetter.  “This was based on identifying multiple patients with the same cytogenetic abnormality and similar clinical symptoms.  Ever since then, technology breakthroughs have allowed us to identify new syndromes and ever more subtle genetic differences.”

The current proliferation of new genetic information has led researchers to discover that many small genetic variations are common and mostly benign in the human population.  This means the relationship between DNA variations and disease must be analyzed even more carefully in order to find accurate connections.  In order to prove that a genetic difference is directly related to a particular syndrome, notes Ledbetter, researchers must show that the difference is never found in normal control individuals or at least is found with significantly less frequency.

Also, researchers have found that a particular genetic variation may have only a mild effect in a parent but a much more severe effect in a child who inherits the same variant.  And a group of children may have a variety of different problems resulting from the same gene variation.  Whole-genome cytogenetic arrays are becoming much more common, however, which is bringing genetic testing to the level of everyday medicine.

“So many variations of developmental disorders and syndromes have been discovered that genetic testing has become essential for making a specific clinical diagnosis,” says Ledbetter.  “Although more information has made the job of a diagnostician even more challenging, it also is leading to more accurate diagnoses and should lead to much more effective treatments.”

New research identifies a few critical neurons that initiate sex-specific behaviors in fruit flies and, when masculinized, can elicit male-typical courtship behaviors from females.  The study, published by Cell Press in the September 11th issue of the journal Neuron, demonstrates a direct link between sexual dimorphism in the brain and gender differences in behavior.

In the fruit fly, Drosophila melanogaster, males display a series of complex and stereotypic behaviors when they are courting a female.  Males chase the female while vibrating their wings, producing a love song that has an aphrodisiac influence on the female, who would otherwise take action to escape the male’s advances.  Later steps in the male courtship behavior involve the initiation and completion of copulation.

“Although previous studies have identified a few key brain areas, such as the dorsal posterior brain, that appear to play a pivotal role in initiating male sexual behavior, nothing is known about the identity of neurons and their circuits in the brain sites which are central to the generation of male courtship behavior,” says lead study author Professor Ken-ichi Kimura of the Hokkaido University of Education in Japan.

Professor Kimura and colleagues made use of a sophisticated technique that allowed them to identify, manipulate, and study small groups of cells in the fruit fly brain.  The researchers focused on neurons that expressed a gene called fruitless (fru), a known sex-determination gene.  The male-specific Fru protein is expressed in the brains of male flies, but not females.  Studies have indicated that fru functions in parallel with another sex-determination gene called doublesex (dsx) and that fru may function as a kind of master control gene to direct organization of brain centers for sexual behavior.

A fru/dsx-expressing cell cluster, known as P1, was identified as an important site for initiating male courtship behavior.  P1 cells are fated to die in females through the action of a feminizing protein called DsxF.  Interestingly, genetic manipulation of females so that they possessed male P1 neurons effectively provoked male-typical courtship behavior in the females, even when other parts of the brain were not masculinized.

“P1 is located in the dorsal posterior brain and is composed of 20 neurons that have projections which communicate with the bilateral protocerebrum,” explains Professor Kimura.  “We found that the masculinizing protein Fru is required in the male brain for correct positioning of the projections from the P1 neurons.”

Taken together, these findings demonstrate that the coordinated action of sex-determination genes dsx and fru confer the unique ability to initiate male-typical sexual behavior on P1 neurons.  This research represents one of only a few examples presenting direct evidence for sexually dimorphic mechanisms that underlie gender-specific behavior and is the first to identify a specific cluster of cells that initiate courtship.

Some of the most challenging obstacles limiting the reprogramming of mature human cells into stem cells may not seem quite as daunting in the near future.  Two independent research papers, published by Cell Press in the September 11th issue of the journal Cell Stem Cell, describe new tools that provide invaluable platforms for elucidating the molecular, genetic, and biochemical mechanisms associated with reprogramming.  The new findings also offer considerable hope toward making the reprogramming process more therapeutically relevant.

Although scientists have successfully reprogrammed mature human skin cells into induced pluripotent stem (iPS) cells by expressing a few key transcription factors, the conversion has been extremely inefficient.  “Little is known about the mechanisms by which reprogramming occurs, in part because of the low efficiency,” says senior study author Dr. Konrad Hochedlinger from the Harvard Stem Cell Institute.  In addition, the iPS cells created thus far have been generated with retroviruses and noninducible lentiviruses, both of which have major limitations that are not compatible with clinical applications.

The Hochedlinger group created a drug-inducible viral system to generate human iPS cells that were molecularly and functionally similar to human embryonic stem cells.  This method was unique in that it allowed the researchers to create iPS cells by using the drug doxycycline to control expression of the necessary factors that had been delivered to the cells with viruses.

The researchers then found that when doxycycline was removed and these “primary” iPS cells differentiated to mature cells, another exposure to the drug reactivated the genes required for reprogramming and induced generation of “secondary” iPS cells at a frequency that was far greater that the initial “primary” conversion.  The idea of generating these secondary cells was conceived in previous experiments with mice performed in the lab of Dr. Rudolf Jaenisch from the Massachusetts Institute of Technology.

“The secondary system will enable chemical and genetic screening efforts to identify key molecular constituents of reprogramming, as well as important obstacles in this process, and will ultimately lend itself as a powerful tool in the development and optimization methods to produce human iPS cells,” explains Dr. Hochedlinger.

In a separate paper, Dr. Jaenisch’s group reports on their success in deriving human secondary iPS cells using doxycycline-inducible transgenes.  “The drug-inducible system we describe represents a novel, predictable, and highly reproducible platform to study the kinetics of iPS cell generation,” says Dr. Jaenisch.  “Further, the genetic homogeneity of secondary cells makes chemical and genetic screening approaches to enhance reprogramming efficiency or to replace any of the original reprogramming factors feasible.”

Both research teams found that generation of secondary human iPS cells required less time than the initial reprogramming.  Interestingly, the time required to generate iPS cells varied among the types of skin cells that were used.  For instance, human fibroblasts required several weeks, while keratinocytes required only about 10 days.  “The fast kinetics of reprogramming observed for keratinocytes suggests that these cells would be useful for development and optimization of methods to reprogram cells by transient delivery of factors,” suggests Dr. Hochedlinger.

The combined results from both research groups represent a major advance toward more efficient strategies for reprogramming differentiated human cells into iPS cells.  The methods described here will not only provide critical insight into the reprogramming process, but also, because of the abbreviated time frame, may lead to the generation of cells that will be amenable for therapies, as reprogramming might be achievable without the prohibitive viruses or genetic modifications.

Yeast, the essential microorganism for fermentation in the brewing of beer, converts carbohydrates into alcohol and other products that influence appearance, aroma, and taste.  In a study published online today in Genome Research, researchers have identified the genomic origins of the lager yeast Saccharomyces pastorianus, which could help brewers to better control the brewing process.

For thousands of years, ale-type beers have been brewed with Saccharomyces cerevisiae (brewer’s or baker’s yeast).  In contrast, lager beer, which utilizes fermentations carried out at much lower temperature than for ale, is a more recently developed alcoholic beverage, appearing in Bavaria near the end of the Middle Ages.  Lager beer gained worldwide popularity starting in the late 1800s, when the advent of refrigeration made year-round low-temperature fermentations possible.  Saccharomyces pastorianus, the yeast used in lager brewing, is a “hybrid” organism of two yeast species, Saccharomyces bayanus and S. cerevisiae.  It is thought that the contributions of both parent species resulted in an organism able to out-compete other yeasts during the cold lager fermentations.

Though early brewers understood that different brewing conditions would produce a unique beer, scientists are now unlocking the genetic differences between yeast strains that produce variation in flavor, color, and aroma.  By comparing the genomic properties of yeast strains sampled from breweries around the world, Drs.  Barbara Dunn and Gavin Sherlock of Stanford University have measured the genetic contribution of the parent yeasts to strains of S. pastorianus and revealed new insights into the events that brought about the evolution of lager yeast.

Surprisingly, the researchers found evidence that S. pastorianus strains used by brewers today may not have arisen from a single hybridization event, as was previously believed.  “There were two independent origins of today’s extant S. pastorianus strains,” said Sherlock.  “It is likely that each of these groups derived the S. cerevisiae portions of their genomes from distinct but related ale yeasts, and that these natural hybrids were then selected by brewers due to their abilities to ferment at cold temperatures.”

While this work identified two distinct groups of S. pastorianus, Sherlock noted that they observed significant genetic variation and flexibility within the groups as well.  Dunn and Sherlock speculated this genomic flexibility could have implications for the unique properties of each brewer’s beer.  “The fact that lager yeasts isolated from different breweries each seem to have a unique genomic make-up may indicate that the yeasts are adapting to the conditions specific to each brewery,” explained Dunn.

Furthermore, this work paves the way for the characterization of specific genetic features of each strain that could aid in the brewing process.  “Our discovery that unique genomic structures may be characteristic to each brewery and/or beer type could lead to insights on how to directly control flavor and aroma in beer,” said Dunn.

Individuals who have a genetic mutation associated with high body mass index (BMI) may be able to offset their increased risk for obesity through physical activity, according to a report in the September 8 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

There is a widely acknowledged genetic component to BMI and obesity, according to background information in the article.  Recently, a strong association has been shown between BMI and variants of one gene, known as the fat mass and obesity associated (FTO) gene.  The mutations associated with obesity are present in about 30 percent of European populations and are associated with a 1.75-kilogram (about 3.9 pounds) increase in body weight.  Lifestyle factors such as diet and physical activity are also important contributors to weight gain, but it is unknown exactly how they interact with genetics.

Evadnie Rampersaud, M.S.P.H., Ph.D., then of the University of Maryland School of Medicine in Baltimore and now of the University of Miami, and colleagues analyzed DNA samples of 704 healthy Amish adults (average age 43.6, 53 percent men and 47 percent women) recruited from 2003 to 2007.  Participants also underwent a series of physiological tests, including a seven-day measurement of physical activity using an instrument known as an accelerometer.

A total of 54 percent of the men and 63.7 percent of the women were overweight, and 10.1 percent of the men and 30.5 percent of the women were obese.  In the genetic analysis, 26 single-nucleotide polymorphisms (SNPs, or changes in a single base letter of DNA) in the FTO gene were associated with BMI.

The researchers then divided participants into two groups based on their physical activity levels and assessed the relationship between BMI and the two strongest SNPs.  Both SNPs were associated with BMI only in individuals who had low physical activity scores for their age and sex; they had no effect on those with above-average physical activity scores.

“Activity levels in the ‘high-activity’ stratum were approximately 900 calories [860 calories for women and 980 calories for men] higher than in the ‘low-activity’ stratum, which, depending on body size, corresponds to about three to four hours of moderately intensive physical activity, such as brisk walking, house cleaning or gardening,” the authors write.

“In conclusion, we have replicated the associations of common SNPs in the FTO gene with increased BMI and risk to obesity in the Old Order Amish,” they conclude.  “Furthermore, we provide quantitative data to show that the weight increase resulting from the presence of these SNPs is much smaller and not statistically significant in subjects who are very physically active.  This finding offers some clues to the mechanism by which FTO influences changes in BMI and may have important implications in targeting personalized lifestyle recommendations to prevent obesity in genetically susceptible individuals.”

Although every cell of our bodies contains the same genetic instructions, specific genes typically act only in specific cells at particular times. Other genes are “silenced” in a variety of ways. One mode of gene silencing depends upon the way DNA, the genetic material, is packed in the nucleus of cells.

When packed very tightly around complexes of proteins called histones, the DNA double helix is rendered physically inaccessible to molecules that mediate gene expression. Now, a research team that includes Michael Q. Zhang, Ph.D., a professor at Cold Spring Harbor Laboratory (CSHL), has published a comprehensive analysis of modification patterns in histones.

Using a new technology called ChIP-Seq, the team identified 39 histone modifications, including a “core set” of 17 modifications that tended to occur together and were associated with genes observed to be active.

Modification Patterns With Different “Personalities”

Scientists have long known that chemical changes at particular locations in histone complexes influence how tightly the DNA is wrapped around the histones. “But it is important to know whether particular modifications occur together in characteristic patterns, or if these patterns can predict gene activities,” Dr. Zhang explained.

At the heart of the team’s efforts to determine this, Keji Zhao, Ph.D., of the National Heart, Blood, and Lung Institute of the National Institutes of Health, and his colleagues developed a method to map modifications in human white blood cells known as CD4+ T cells. First they used an enzyme to cut the DNA into short segments, which remained attached to histone “spools.” For each of 39 distinct histone modifications, the scientists used an antibody to extract matching histone-DNA combinations. Finally, they used the ChIP-Seq DNA-sequencing technology to determine which parts of the genome were bound to each type of modified histone.

The team’s most recent research, published in the July 2008 issue of Nature Genetics, maps the DNA locations that bind to histones containing molecular configurations called acetyl groups at 18 different positions in the “tails” of the histone proteins. The scientists combined this information with earlier maps for 19 different changes called methylation modifications, and for replacement of one of the histone proteins with a well-known variant.

The various modifications showed distinctive “personalities,” each preferentially associating with particular regulatory regions of genes.

Looking for Patterns

Mapping many modifications enabled the researchers to explore whether different types tend to appear together in the same type of DNA regulatory regions. They found that some recurring combinations did occur frequently at “promoter” and “enhancer” regions in DNA, which are known to increase the activity of nearby genes. In particular, the team identified one combination of 17 modifications that was present in more than a quarter of the more than 12,000 promoter regions they examined.

On average, the genes corresponding to this “backbone” set were expressed more actively. That is to say, they were activated, setting the cellular machinery in motion to produce specific proteins, the workhorses of most life processes.

The rich relationships detected by the researchers among the various histone modifications suggests that specific combinations might carry specific meanings. Previous researchers have proposed a “histone code” hypothesis, which posits that a particular combination of modifications may be recognized by a particular protein module. Some scientists believe such histone code may determine the activity of a given gene.

But, cautions Dr. Zhang, while there are patterns, like the backbone, that are highly correlated, “none of them has exact predictive value.” He maintains “there must be something else” that also affects gene activity.

Since genes with higher or lower expression levels may have the same patterns of modification, and not all active genes share a common pattern, the reality is likely more complex than a universal histone code that predicts exact gene expression level. Nonetheless, the new research provides a rich data source for understanding how specific combinations of histone modifications modulate the effects of many genes, in turn helping to modify activity within and among cells. “Critical future research should focus on finding proteins that target histone modifications to genetic regions with particular sequences,” Dr. Zhang emphasized.

Research involving large Middle Eastern families, sophisticated genetic analysis and groundbreaking neuroscience has implicated a half-dozen new genes in autism.  More importantly, it strongly supports the emerging idea that autism stems from disruptions in the brain’s ability to form new connections in response to experience – consistent with autism’s onset during the first year of life, when many of these connections are normally made.

Interestingly, not all the affected genes were actually deleted, but only prevented from turning on – offering hope that therapies could be developed to reactivate the genes.  The study, led by researchers at Children’s Hospital Boston and members of the Boston-based Autism Consortium, is the cover article in the July 11 issue of Science.

Autism genes have been difficult to identify because the disorder is complex, with a variety of causes stemming from many possible genes or combinations of genes.  In addition, since people with autism tend not to have children, most of the genes identified thus far aren’t inherited from a parent, but instead are mutated during embryonic development, making them hard to track through traditional linkage studies in families.

Christopher Walsh, MD, PhD, chief of genetics at Children’s Hospital Boston, approached the problem by studying Middle Eastern families.  In traditional Arab societies, it is common for cousins to marry, increasing the likelihood that offspring will inherit rare mutations.  Middle Eastern families also tend to have many children, making them ideal for mapping genes.

“To map a gene for autism in American families, averaging two to three kids per family, you would need to pool many families,” says Walsh, who is also a Howard Hughes Medical Institute investigator at Beth Israel Deaconess Medical Center (BIDMC).  “In larger families, one family alone may be enough to definitively localize a gene.”

The Homozygosity Mapping Collaborative for Autism (HMCA) recruited 104 families with a high incidence of autism from the Arabic Middle East, Turkey and Pakistan; 88 of these families have cousin marriages.  Local clinicians were rigorously trained in administering standardized autism research assessments.  Walsh’s team later flew to sites in Turkey, Dubai, Kuwait and Saudi Arabia to confirm the diagnoses.

Using a technique called homozygosity mapping Walsh and colleagues compared the DNA of family members with and without autism, searching for recessive mutations—those that cause disease only when a child inherits two copies.

“We check each set of chromosomes from beginning to end, looking for one place where the child has two identical pieces of DNA on both chromosomes,” Walsh explains.  “Eventually we find a spot where all affected children have two identical chunks of DNA, and where unaffected children have something different.”

Just over 6 percent of the 88 families showed rare, inherited deletions within DNA regions linked to autism.  These affected DNA regions varied among families, further indication of autism’s large variety of genetic causes.  In all, the technique identified five chromosome deletions affecting at least six identifiable genes (C3orf58, NHE9, PCDH10, contactin-3 [CNTN3], RNF8, and genes encoding a cluster of cellular sodium channels).

One of the genes, NHE9, was also found to be mutated in European and American children with autism (particularly those with both autism and seizures).

Experience-dependent learning: A common thread

The genes discovered are diverse in function, but all seem to be part of a fundamental molecular network that orchestrates the refinement and maturation of brain connections, or synapses, in response to input from the outside world.  It is the refinement of these synaptic connections that is the basis of learning and memory, suggesting that autism at its heart may represent molecular defects of learning.

“This network can be disrupted in a myriad of ways, and may be one mechanism that people with a variety of autism-linked mutations share,” says Michael Greenberg, PhD, a coauthor on the paper and director of the Neurobiology Program at Children’s Hospital Boston.

Normally, as a neuron (brain cell) receives an incoming message at the synapse, a network of reactions is sparked that extends all the way to its nucleus.  Greenberg and his colleagues had long been mapping this network, and had previously found that it activates at least 300 genes.  These genes then communicate back to the neuron’s surface, telling the cell to make a new synapse, strengthen the synapse that’s already there, eliminate a synapse, or make a different kind of synapse.  This give-and-take system is how the brain builds its circuitry; neuroscientists call it “experience-dependent learning.”

Working independently of Walsh, Greenberg and his colleagues had already identified three of the same genes found in the Middle Eastern patients (c3orf58, NHE9, and PCDH10) while looking for genes that turn on or off in neurons as part of this network – either in response to synaptic activity or through so-called transcription factors that are activated by synaptic activity.

The work bolsters a growing body of evidence that autism may represent a disruption of the brain’s ability to modify its synaptic connections in response to experience.

“Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from the deregulation of any one of a number of genes that are part of the same signaling pathway,” Greenberg says.

Can normal function be revived?

Interestingly, only one chromosome deletion found in the Middle Eastern families actually removed a gene – in most cases, what was lost was a region adjacent to the gene that contains its “on/off” switches.  This has important implications for therapy, because it suggests that autism mutations don’t always remove a gene altogether, but only inhibit its activity in certain contexts, says Eric Morrow, MD, PhD, of Massachusetts General Hospital, who is co-first author of the paper with Seung-Yun Yoo, PhD.  “This means that we would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications,” says Morrow, who also holds appointments at BIDMC and Children’s.

The findings also support the use of behavioral therapies in autism, which expose children to a rich environment and highly repetitive activities that may help turn on the genes and strengthen synaptic connections, Morrow adds.

“This publication a big event in the world of autism research,” says Clarence Schutt, PhD, Scientific Advisor to the Nancy Lurie Marks Family Foundation, which funded work by both the Walsh and Greenberg labs.  “To have discovered a connection between autism and activity-related gene expression at the synapse will put this field at the center of neuroscience.”

Scientists have identified about two dozen genes that control embryonic stem cell fate.  The genes may either prod or restrain stem cells from drifting into a kind of limbo, they suspect.  The limbo lies between the embryonic stage and fully differentiated, or specialized, cells, such as bone, muscle or fat.

By knowing the genes and proteins that control a cell’s progress toward the differentiated form, researchers may be able to accelerate the process – a potential boon for the use of stem cells in therapy or the study of some degenerative diseases, the scientists say.

Their finding comes from the first large-scale search for genes crucial to embryonic stem cells.  The research was carried out by a team at the University of California, San Francisco and is reported in a paper in the July 11, 2008 issue of “Cell.”

“The genes we identified are necessary for embryonic stem cells to maintain a memory of who they are,” says Barbara Panning, PhD, associate professor of biochemistry and biophysics at UCSF, and senior author on the paper.  “Without them the cell doesn’t know whether it should remain a stem cell or differentiate into a specialized cell.”

The scientists used a powerful technique known as RNA interference, or RNAi, to screen more than 1,000 genes for their role in mouse embryonic stem cells.  The technique allows researchers to “knock down” individual genes, reducing their abundance in order to determine the gene’s normal role.

The research focused on proteins that help package DNA.  In the nucleus, DNA normally wraps around protein complexes called nucleosomes, forming a structure known as chromatin.  This is what makes up chromosomes.

They found 22 proteins, each of which is essential for embryonic stem cells to maintain their consistent shape, growth properties, and pattern of gene expression.

Most of the genes code for multi-protein complexes that physically rearrange, or “remodel” nucleosomes, changing the likelihood that the underlying genes will be expressed to make proteins.

The main player they identified is a 17-protein complex called Tip60-p400.  This complex is necessary for the cellular memory that maintains embryonic stem cell identity, Panning explains.  Without it, the embryonic stem cells turned into a different cell type, which had some features of a stem cell but many features of a differentiated cell.

The scientists believe that Tip60-p400 is necessary for embryonic stem cells to correctly read the signals that determine cell type.  These findings are not only important for understanding cellular memory in embryonic stem cells, but will also likely be relevant to other cell types, they say.

Inactivation of other genes disrupted embryonic stem cell proliferation.  These genes were already known to have only slight influence on viability of mature cells in the body.  This suggests that embryonic stem cells are “uniquely sensitive to certain perturbations of chromatin structure,” the scientists report.

If other types of stem cells are also found to be sensitive to these chromatin perturbations, this could lead to novel cancer therapies in the future, Panning says.

Common genetic variations affecting nicotine receptors in the nervous system can significantly increase the chance that European Americans who begin smoking by age 17 will struggle with life-long nicotine addiction.  Published July 11 in the open-access journal PloS Genetics, this research – led by scientists at the University of Utah together with colleagues from the University of Wisconsin – highlights the importance of preventing early exposure to tobacco through public health policies.

These common genetic variations, or single nucleotide polymorphisms (SNPs), are changes in a single unit of DNA.  A haplotype is a set of SNPs that are statistically linked.  The researchers found that one haplotype for the nicotine receptor put European American smokers at a greater risk of heavy nicotine dependence as adults, but only if they began daily smoking before the age of 17.  A second haplotype actually reduced the risk of adult heavy nicotine dependence for people who began smoking in their youth.

The researchers studied 2,827 long-term European American smokers, recruited in Utah and Wisconsin, and to the National Heart, Lung, and Blood Institute’s Lung Health Study.  They assessed the level of nicotine dependence for all smokers, recording the age they began smoking daily, the number of years they smoked, and the average number of cigarettes smoked per day.  DNA samples were taken from all smokers, and the researchers recorded the occurrence of common SNPs, grouped into four haplotypes, which had been identified earlier in a subset of participants.

They found that people who began smoking before the age of 17 and possessed two copies of the high-risk haplotype had from a 1.6-fold to almost 5-fold increase in risk of heavy smoking as an adult.  For people who began smoking at age 17 or older, presence of the high-risk haplotype did not significantly influence their risk of later addiction.

Although the authors caution that different haplotype frequencies would likely be observed in different ethnic populations, Robert Weiss, Ph.D., professor of human genetics at the University of Utah and lead author of the study, explains: “We know that people who begin smoking at a young age are more likely to face severe nicotine dependence later in life.  This finding suggests that genetic influences expressed during adolescence contribute to the risk of lifetime addiction severity produced from the early onset of tobacco use.”

“This study adds to recent advances in understanding how genetic variation can affect susceptibility to nicotine addiction, success or failure of smoking cessation treatments, and the risk of disease associated with tobacco use,” says National Institute on Drug Abuse (NIDA) Director Dr. Nora Volkow.  “As we learn more about how both genes and environment play a role in smoking, we will be able to better tailor both prevention and cessation programs to individuals.”  The study was funded in part by NIDA and the National Heart, Lung, and Blood Institute (NHLBI), parts of the National Institutes of Health (NIH).

In the wild, mammalian coat color is essential for camouflage and plays a role in social behavior.  Coat color also strongly influences the animals we choose to breed both as livestock and as pets.  Understanding the genetic determinants of coat color in livestock species such as sheep, specifically bred for their coat color, is critical for improving efficient selection of the desired trait.

Classical genetics has associated alternative forms, or alleles, of the agouti signaling protein gene (ASIP) with coat color variation in a number of mammals including mice, rats, dogs, cats, pigs, and sheep.  However, most research has been focused on the mouse, with little understood about the genetic basis for coat color in economically important livestock species such as sheep.

The wild-type coat color of sheep is typically dark-bodied with a pale belly, however sheep raisers have strongly selected for a uniformly white coat domestic sheep.  A problem for the sheep industry is a recessive black “non-agouti” allele of the ASIP gene carried by white sheep that cannot be distinguished within the flock, resulting in black coat color at a low, but persistent frequency.  Determining the exact genetic differences at the ASIP locus could assist in efficient selection for white coat color.

Scientists at the CSIRO Queensland Bioscience Precinct in Australia have now taken this step and identified the molecular mechanisms underlying white and black coat color in domestic sheep.  The researchers investigated the genetic architecture of the ASIP gene in several sheep breeds by sequencing the ASIP locus and measuring gene expression.  “Surprisingly what we found was in fact that the genetic cause of domestic white and black sheep involves a novel tandem duplication affecting the ovine agouti gene and two other neighboring genes, AHCY and ITCH,” explains Dr. Belinda Norris, lead author of the study.  “We discovered a novel mechanism in which the dominant white sheep is caused by the ubiquitous expression of a duplicated agouti coding sequence located immediately downstream of a duplicated ITCH gene promoter region.”  It was found that recessive black sheep harbor only poorly expressed non-duplicated agouti alleles, likely a result of a defective single-copy ancestral agouti gene promoter.  The researchers also studied the ASIP locus in Barbary sheep, an ancient species exhibiting a tan body and pale belly.  They confirmed in this ancient sheep that expression of a single-copy agouti gene determines coat color patterning, similarly to findings previously described in mice and pigs.

Norris notes that this work will aid in the development of gene copy number detection and analysis methods in the mapping and association of heritable traits in livestock animals.  For sheep raisers, this could ultimately mean a genetic test that would identify carriers of the black non-agouti allele.  Furthermore, these findings will help to unravel the events leading to the domestication of sheep, and future work may be able to pinpoint when the dominant Agouti mutation occurred, and whether it occurred as single or multiple events.

Many of the seemingly disparate mutations recently discovered in autism may share common underlying mechanisms, say researchers supported in part by the National Institute of Mental Health (NIMH), a part of the National Institutes of Health (NIH).  The mutations may disrupt specific genes that are vital to the developing brain, and which are turned on and off by experience-triggered neuronal activity.

A research team led by Christopher Walsh, M.D., Ph.D., and Eric Morrow, M.D., Ph.D., of Harvard University, found two large sections missing on chromosomes in people with autism and traced them to likely inherited mutations in such genes regulated by neuronal activity.  They report their findings in the July 11, 2008 issue of Science.  The study was also supported in part by the NIH’s National Center for Research Resources, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute of Child and Human Development, and the National Institute on Neurological Disorders and Stroke.

The study breaks new ground for complex disorders like autism, taking advantage of a shortcut to genetic discovery by sampling families in which parents are cousins.  The researchers found genes and mutations associated with autism in 88 families from the Middle East, Turkey and Pakistan in which cousins married and had children with the disorder.

“The emerging picture of the genetics of autism is quite surprising.  There appear to be many separate mutations involved, with each family having a different genetic cause,” explained NIMH Director Thomas R. Insel, M.D. “The one unifying observation from this new report is that all of the relevant mutations could disrupt the formation of vital neural connections during a critical period when experience is shaping the developing brain.”

Earlier studies had suggested that the individually rare mutations are present in at least 10 percent of sporadic cases of autism, which is the most common form.

The researchers used a technique that pinpoints from a relatively small group of families genes responsible for disorders that can be amplified by parenthood among relatives, which can increase transmission of recessive diseases.  Evidence had hinted at such transmission in autism, and the large amount of genetic information obtainable from such families reduced the need for a much larger sample including many families with multiple affected members.

The ratio of females to males with autism – normally one female to four males – was less lopsided in such families in which parents share a common recent ancestor.  This ratio equalized even more in a subset of these families with more than one affected member, suggesting a doubling of the rate of autism, due to recessive causes on non-sex-linked chromosomes.  Also, autism-linked spontaneous deletions and duplications of genetic material were relatively uncommon in these families, suggesting recessive inherited causes.

The researchers found multiple different genetic causes of autism in different individuals with little overlap between the families in which parents shared ancestry.  Yet a few large inherited autism-linked deletions, likely mutations, in a minority of families stood out.  The largest turned out to be in or near genes regulated, directly or indirectly, by neuronal activity.

“Autism symptoms emerge at an age when the developing brain is refining the connections between neurons in response to a child’s experience,” explained Walsh.  “Whether or not certain important genes turn on is thus dependent on experience-triggered neural activity.  Disruption of this refinement process may be a common mechanism of autism-associated mutations.”

Keeping the genome stable is a “sister act” of matched chromatids – the pairs of the double helix DNA molecule that exist during the chromosome duplication in the S phase of the cell cycle.

Maintaining the chromatids in their sister pairs rests with Eco1, a kind of enzyme known as an acetyltransferase.  Now researchers at Baylor College of Medicine, in a collaboration of two laboratories, have shown that Eco1 and its human homologue maintain sister chromatid cohesion and thus genome stability through a chemical process called acetylation that affects Smc3, one of the key components of the cohesion protein complex.  A report on their work appears in the current online issue of the journal Molecular Cell.

This activity is critical to maintaining the stability of the cell’s genome and its survival, said Dr. Jun Qin, associate professor of biochemistry and molecular biology and molecular and cellular biology at BCM and a senior author of the report.

“If a cell lacks this acetyltransferase activity, it’s dead,” said Dr. Xuewen Pan, assistant professor of biochemistry and molecular biology and molecular and human genetics at BCM and also a senior author.

“This is critical for genome stability, cell growth and organism survival,” said Qin.

“The collaboration in this work was important,” he said.  His laboratory carried out the work in human cells, and Pan’s did the work in yeast.

“We pooled the resources of our two laboratories and took advantage of the power of the genetics in yeast and the power of proteomics and cell biology in the human.  If a single labor had worked on this project, we would not have as complete a story,” Qin said.

The identification of five genes involve in the metastasis of breast tumours to the lung is the principal finding of a scientific team made up of two bodies from the University of Navarra, the Applied Medical Research Centre (CIMA) and the University Hospital of the University of Navarra.

Doctor Alfonso Calvo, researcher in the area of Oncology at the CIMA, led the work with the special collaboration of Doctor Ignacio Gil Bazo, cancer specialist from the University Hospital.  The study made up a significant part of Mr Raúl Catena’s PhD thesis.

For this research, recently published in the scientific journal Oncogene, a transgenic mouse model which presented a greater tendency for developing metastasis was employed.  The increase in what is known as the Vascular Endothelial Growth Factor (VEGF) in its mammary glands triggered profound changes in the tumoural structure, which enabled the malignant cells to leave the tumour and invade the lungs.

Finally, the pattern of genes responsible for this tumoural migration to the lungs was analysed and this was compared to that shown by women with breast tumours with pulmonary metastatic affectation.  It was shown that five of these genes were common to the animal model and patients with breast cancer.  Most effective ways of treatment

According to the results of this study, of the five genes identified, the Tenascina-C gene seems to be a good therapeutic target for the treatment of metastatic breast cancer.  In fact, the blocking of the expression of this gene in the animal model enabled a significant reduction, both in tumour growth and in the incidence of pulmonary metastasis.

This new discovery in the complex network that is the metastasis process of tumours provides key data on the knowledge of cancer and its spreading, at the same time identifying new targets for which new pharmaceutical medicines that contribute to more efficacious treatment of this disease can be designed.