Facial expressions of emotion are hardwired into our genes, according to a study published today in the Journal of Personality and Social Psychology.  The research suggests that facial expressions of emotion are innate rather than a product of cultural learning.  The study is the first of its kind to demonstrate that sighted and blind individuals use the same facial expressions, producing the same facial muscle movements in response to specific emotional stimuli.

The study also provides new insight into how humans manage emotional displays according to social context, suggesting that the ability to regulate emotional expressions is not learned through observation.

San Francisco State University Psychology Professor David Matsumoto compared the facial expressions of sighted and blind judo athletes at the 2004 Summer Olympics and Paralympic Games.  More than 4,800 photographs were captured and analyzed, including images of athletes from 23 countries.

“The statistical correlation between the facial expressions of sighted and blind individuals was almost perfect,” Matsumoto said.  “This suggests something genetically resident within us is the source of facial expressions of emotion.”

Matsumoto found that sighted and blind individuals manage their expressions of emotion in the same way according to social context.  For example, because of the social nature of the Olympic medal ceremonies, 85 percent of silver medalists who lost their medal matches produced “social smiles” during the ceremony.  Social smiles use only the mouth muscles whereas true smiles, known as Duchenne smiles, cause the eyes to twinkle and narrow and the cheeks to rise.

“Losers pushed their lower lip up as if to control the emotion on their face and many produced social smiles,” Matsumoto said.  “Individuals blind from birth could not have learned to control their emotions in this way through visual learning so there must be another mechanism.  It could be that our emotions, and the systems to regulate them, are vestiges of our evolutionary ancestry.  It’s possible that in response to negative emotions, humans have developed a system that closes the mouth so that they are prevented from yelling, biting or throwing insults.”

A new study in the October 31st issue of Cell, a Cell Press journal, has revealed the molecular and cellular underpinnings of one of the most common, single gene causes for learning disability in humans.  The findings made in learning disabled mice offer new insight into what happens in the brain when we learn and remember.

While most previous studies have focused on the role of brain cells that excite other brain cells in the process of learning, the current results suggest that inhibitory neurons and a careful balance between excitatory and inhibitory signals may be just as essential, according to the researchers.  They liken the role of those inhibitory and excitatory signals in the brain to the role of red and green stoplights in directing traffic.

” The significance of these findings is two-fold,” said Alcino Silva of the University of California, Los Angeles.  “First, we have in great detail the exact mechanism for one of the most common single gene causes for learning disability known.  It’s also a beachhead in our understanding of the balance between excitation and inhibition critical for learning.”

Learning disabilities are estimated to affect one in five people worldwide.  “It’s a huge problem and there is little known about their causes,” Silva said.

To begin to chip away at those underlying causes for conditions that often have complex causes, Silva’s team began a hunt several years ago to unravel the mechanisms responsible for a couple of single gene disorders that lead to learning disability.

In the new study, they examined mice with learning disabilities resulting from a condition called neurofibromatosis type 1.  The condition stems from a defect in the Nf1 gene encoding a protein called neurofibromin.  Earlier studies showed that neurofibromin controls a “Ras/Erk” signal that is involved in long-term potentiation (LTP) and learning in mice.  LTP is a process that strengthens the connections between neurons in the brain–the cellular basis for learning and memory.

Now, the researchers have found that the deficits in spatial learning experienced by mice with an abnormal version of the Nf1 gene stem from an increased release by inhibitory neurons of a chemical nerve messenger (or neurotransmitter) called GABA.  GABA is the chief inhibitory neurotransmitter in the central nervous systems of mammals.

That rise in GABA leads to deficits in the plasticity of neurons required for learning and memory.  Importantly, they also show that the learning deficits in the mice can be reversed with treatments that reign GABA levels back in.  They also show that GABA levels normally swell when mice learn, suggesting that a balance of GABA is the key.

Silva’s team notes another recent study implicating changes in GABA inhibition in the learning deficits exhibited by an animal model of Down’s syndrome.  Although learning disability—characterized by profound changes in one part of brain function—differs widely from mental retardation, that finding together with the new study suggest there may nevertheless be a common thread, Silva said.

Ultimately, these insights could lead to new ways to treat learning disabilities, although reaching that goal won’t be a simple proposition.

” It won’t be a single step from the mechanism to finding a drug,” Silva said.  As with other complex disorders like cancer, he said, it will likely take years of exploration to turn scientific advances into medical applications.  Nevertheless, “the more insight we have into the mechanisms responsible, the more likely it is that our treatment efforts will be effective.  ”

The new study is also representative of the exciting advances in the study of neuroscience more broadly.

” We are at the beginning of a wonderful journey into how the human mind works,” Silva said.  “We are developing a highly detailed view of what goes on in the brain when we learn and remember.  There is nothing more inspiring; it’s what makes us who we are.”

Researchers have put forward a simple model of development and gene regulation that is capable of explaining patterns observed in the distribution of morphologies and body plans (or, more generally, phenotypes). The study, by Elhanan Borenstein of the Santa Fe Institute and Stanford University and David Krakauer of the Santa Fe Institute was published in this month’s issue of PLoS Computational Biology.

Nature truly displays a bewildering variety of shapes and forms. Yet, with all its magnificence, this diversity still represents only a tiny fraction of the endless ’space’ of possibilities, and observed phenotypes actually occupy only small, dense patches in the abstract phenotypic space. Borenstein and Krakauer demonstrate that the sparseness of variety in nature can be attributed to the interactions between multiple genes and genetic controls involved in the development of organisms – a much simpler explanation than previously suggested.

Borenstein and Krakauer further integrated their model with phylogenetic dynamics, allowing developmental plans to evolve over time. They showed that this hybrid developmental-phylogenetic model reproduces patterns that are observed in the fossil record, including increasing variation between taxonomic groups, accompanied by decreasing variation within groups. This pattern is consistent with the Cambrian radiation associated with a rapid proliferation of highly disparate, multicellular animals, and suggests that much of the variation seen today is as a result of simpler genetic controls dating from much earlier in evolutionary time.

The findings presented in this study also bear directly on issues of convergence (when very different organisms independently evolve similar features). By including a model of development, rather different genotypes can produce very similar phenotypes. Consequently, convergent evolution, which the vast space of genotypes would suggest to be rare, is allowed to become much more common.

One of the paradoxical implications of this study has been to show how innovations in development that lead to an overall increase in the number of accessible phenotypes, can lead to a reduction in selective variance. In other words, while the potential for novel phenotypes increases, the fraction of space these phenotypes occupies tends to contract. They concluded that “The theory presented in our paper complements the view of development as a key component in the production of endless forms and highlights the crucial role of development in constraining (as well as generating) biotic diversity.”

Working as part of a multi-institutional collaboration, scientists at Washington University School of Medicine in St. Louis have assembled the most complete catalog to date of the genetic changes underlying the most common form of lung cancer.  The research, published Oct. 23 in Nature, helps lay the foundation for more personalized diagnosis and treatment of a disease that is the leading cause of U.S. cancer deaths.

The research team identified 26 genes that are frequently mutated in a type of cancer called lung adenocarcinoma, a finding that more than doubles the number of genes already known to be linked to the deadly disease.  What’s more, by casting a wide net in their search for genetic alterations, the scientists are now beginning to see intriguing relationships.  They found that some of the same genes associated with lung tumors are also defective in other cancers, that smokers and non-smokers with lung cancer have distinct genetic defects and that several molecular pathways underlie most of the mutations.

“This genomic approach has given us a completely different view of lung cancer,” says Richard K. Wilson, Ph.D., director of Washington University’s Genome Sequencing Center and one of the study’s lead authors.  “This broad view will allow scientists to more accurately categorize tumors, which should speed efforts to develop more targeted therapies to fight the disease.”

More than 1 million people worldwide die of lung cancer each year, including more than 160,000 in the United States.  About 40 percent of them are adenocarcinoma, a type of non-small cell lung cancer and one that is exceedingly difficult to treat.  Only about 15 percent of patients are still alive five years after diagnosis.

“By harnessing the power of genomic research, this pioneering work has painted the clearest and most complete portrait yet of lung cancer’s molecular complexities,” says Alan E. Guttmacher, M.D., acting director of the National Human Genome Research Institute, the agency that funded the research.

The Nature study was conducted as part of the Tumor Sequencing Project, a collaborative effort to assemble a genome-wide catalog of the genetic mutations in lung adenocarcinoma.  Like most cancers, lung adenocarcinoma arises from changes that accumulate in people’s DNA over the course of their lives.  However, little is known about the precise nature of these genetic alterations, how they occur and how they disrupt biological pathways to cause cancer’s unfettered cell growth.

Working with lung cancer samples donated by 188 patients from across the United States, the group sequenced 623 suspect genes and compared them to the same genes in healthy tissues from the same patients.  Initially, they found more than 1,000 mutations across the samples.  Looking more closely, the researchers identified 26 genes mutated in a significant number of samples.  Most of the genes had not previously been associated with lung cancer but are found in other tumors.

The new genes fingered in lung adenocarcinoma include:

* Neurofibromastosis 1: Mutations in this gene cause a rare inherited neurological disorder that increases the risk of tumors that form on nerve tissues, including the brain, spinal cord and individual nerves;

* Ataxia telangiectasia mutated (ATM): Mutations of this gene have been found in a rare inherited neurological disorder and in various types of leukemia and lymphoma;

* Retinoblastoma 1: Mutations in this gene have linked to a rare childhood cancer that begins in the retina;

* Adenomatosis polyposis coli (APC): Mutations of this gene are common in colon cancer.

The team also examined the effects of the genetic mutations on biological pathways and determined which of the pathways is most crucial to lung adenocarcinoma.  This line of discovery is essential to efforts to develop new and better treatments for cancer.

For example, the researchers discovered that more than 70 percent of the 188 tumors had at least one mutation affecting the mitogen-activated protein kinase (MAPK) pathway, indicating it plays a pivotal role in lung cancer.  Based on those findings, the researchers suggested new treatment strategies for some subtypes of lung adenocarcinoma might include compounds that affect this pathway.  One such group of compounds, the MEK inhibitors, has produced promising results in mouse models of lung cancer.

“Looking at the pathways helps simplify the picture,” Wilson explains.  “Generally, we found that each mutation only occurs in a small percentage of the tumor samples, but when we looked at all the mutations that intersect a particular signaling pathway, we were surprised to find a lot of overlap in only a handful of pathways.  This gives us a much better idea of what goes wrong in cells when they become cancerous.”

Additionally, the finding that more than 30 percent of tumors had mutations affecting the rapamycin (mTOR) pathway raises the possibility that the drug rapamycin might be tested in lung adenocarcinoma.  The drug, which inhibits mTOR, is approved for use in organ transplants and renal cancer.

The researchers also analyzed the patterns of genetic changes in both smokers and non-smokers with lung cancer.  About 90 percent of lung cancer is linked to smoking, but 10 percent of patients diagnosed with the disease have never smoked.  They found that the number of mutations detected in tumor samples from smokers was significantly higher than in tumors from never-smokers.  Smokers’ tumors contained as many as 49 mutations, while none of the never-smokers’ tumors had more than five.

More work is needed to determine the clinical significance of these differences.  However, doctors do know that in some other types of cancer, high mutation levels may cause a tumor to spread rapidly or be resistant to treatment.

The study also confirmed previous observations that indicated lung cancer in never-smokers may be triggered by different genetic mutations than those in smokers.  For example, mutations in the epidermal growth factor (EGFR) gene were prevalent in tumors from non-smokers, while mutations in the KRAS and Src tyrosine kinase 11 genes were common in tumors from smokers.

“Our findings underscore the value of systematic, large-scale genome studies for exploring cancer.  We now must move forward to apply this approach to even larger groups of samples and a wider range of cancers,” Wilson says.

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.”

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).

New data, generated by Hongbing Shen and colleagues, at the Cancer Center of Nanjing Medical University, People’s Republic of China, has identified a genetic variation that seems to help predict survival in individuals with non–small cell lung cancer (NSCLC).

A systematic screen of the DNA carrying the information for generating regulatory RNA molecules known as a microRNAs identified a specific genetic variant that was associated with decreased survival in individuals with NSCLC.  The specific genetic variation resulted in increased levels of expression of the functional miRNA molecule.  This was not because more of the miRNA was made but because more of the precursor form of the functional molecule was processed to become functional.  The functional miRNA molecule generated by the genetic variation also had different functional properties.  The authors hope that further characterization of genetic variations that modify miRNA expression and/or function will uncover other indicators of survival and opportunities for developing new therapeutics.

What are the genes implicated in upright walking of humans? The discovery of four families in which some members only walk on all fours (quadrupedality) may help us understand how humans, unlike other primates, are able to walk for long periods on only two legs, a scientist will tell the annual conference of the European Society of Human Genetics tomorrow (Monday 2 June).The quadrupedal families in Turkey previously attracted attention in 2005, when they were discovered. Now the Turkish team reports that they have found the first gene implicated in quadrupedal locomotion in these families.

Professor Tayfun Ozcelik, of Bilkent University, Ankara, Turkey, and colleagues, studied four unrelated families where some members were affected by the rare quadrupedic condition, Unertan syndrome, which is also associated with imperfect articulation of speech, mental retardation, and defects in the cerebellum, a part of the brain involved in motor control. They found that the affected individuals in two families had mutations in the gene responsible for the expression of very low density lipoprotein receptor (VLDLR), a protein which is known to be critical to the proper functioning of the cerebellum during development.

Although the families lived in isolated villages 200-300 km apart and reported no ancestral relationships, the scientists expected to find a single genetic mutation implicated in the condition. They were surprised to find that this was not the case.

“We carried out genome-wide screening on these families”, said Professor Ozcelik, “and found regions of DNA that were shared by all those family members who walk on all fours. However, we were surprised to find that genes on three different chromosomes are responsible for the condition in four different families.

“In families A and D there were mutations in VLDLR on chromosome 9, and in family B the phenotype maps to chromosome 17 to a region that contains at least 157 genes, and we are still looking for the precise mutation. Neither region appears to be implicated for family C.”

In all cases, the affected individuals were the offspring of consanguineous marriages, which suggests that if they had married outside the family they would not have had the condition. All of them had significant developmental delay in infancy. “Whereas normal infants make the transition to walking on two legs in a relatively short period”, said Professor Ozcelik, “these individuals continued to move on their palms and feet and never walked upright. Although they can stand from a sitting position and maintain this upright position with flexed hips and knees, they virtually never initiate bipedal walking on their own.”

It has been suggested in the past that lack of access to medical care exacerbated the effects of an under-developed cerebellum, and that this led to quadrupedality. “Although it may be true that family B lacked proper medical care, families A and D had consistent access to good medical attention, and both families sought a correction of quadrupedality in their affected children”, said Professor Ozcelik. “Indeed, an unaffected member of family A is a physician, who has been actively involved in the medical interventions. In addition, the parents in family A also discouraged their affected children from walking on all fours, to no avail. We think that social factors are unlikely to be involved in the development of quadrupedal locomotion.”

Mutations causing VLDLR deficiency are also found in Hutterites, a group of Anabaptists who live in colonies of North America. There, however, most of the affected individuals cannot walk at all. The neurological characteristics of the affected members of the Turkish families and the Hutterites seem similar, with the most striking difference being that the Turkish individuals are able to walk on all fours, said the scientists. They hypothesize that the Hutterites may be more profoundly affected due to the deficiency in VLDLR and a neighbouring gene, and therefore lack the motor skills even for quadrupedal locomotion.

Along with brain enlargement, speech, and the ability to make tools, upright walking has long been regarded as one of the key traits that have led to modern humans. Professor Ozcelik’s team have opened a window on how mutations in VLDLR affect brain development and influence gait in humans.

“It will be interesting to see if the VLDLR gene is involved in other types of cerebellar ataxias. In addition, we hope to identify the defective genes associated with quadrupedal locomotion in families B and C”, he says.

Researchers from the University of Melbourne, Australia, and the University of Texas, USA, have extracted genes from the extinct Tasmanian tiger (thylacine), inserted it into a mouse and observed a biological function – this is a world first for the use of the DNA of an extinct species to induce a functional response in another living organism.

The results, published in the international scientific journal PLoS ONE this week, showed that the thylacine Col2a1 gene has a similar function in developing cartilage and bone development as the Col2a1 gene does in the mouse.

“This is the first time that DNA from an extinct species has been used to induce a functional response in another living organism,” said Dr Andrew Pask, RD Wright Fellow at the University of Melbourne’s Department of Zoology who led the research.

“As more and more species of animals become extinct, we are continuing to lose critical knowledge of gene function and their potential.”

“Up until now we have only been able to examine gene sequences from extinct animals. This research was developed to go one step further to examine extinct gene function in a whole organism,” he said.

“This research has enormous potential for many applications including the development of new biomedicines and gaining a better understanding of the biology of extinct animals,” said Professor Richard Behringer, Deputy Head of the Department of Molecular Genetics, M.D. Anderson Cancer Center, at the University of Texas, who is the corresponding author on the paper.

The last known Tasmanian tiger died in captivity in the Hobart Zoo in 1936. This enigmatic marsupial carnivore was hunted to extinction in the wild in the early 1900s.

Researchers say fortunately some thylacine pouch young and adult tissues were preserved in alcohol in several museum collections around the world.

The research team used thylacine specimens from Museum Victoria in Melbourne Australia to examine how the thylacine genome functioned.

The research team isolated DNA from 100 year old ethanol fixed specimens. After authenticating this DNA as truly thylacine, it was inserted into mouse embryos and its function examined.

The thylacine DNA was resurrected, showing a function in the developing mouse cartilage, which will later form the bone.

“At a time when extinction rates are increasing at an alarming rate, especially of mammals, this research discovery is critical,” says Professor Marilyn Renfree, Federation Fellow and Laureate Professor in the University of Melbourne’s Department of Zoology, the senior author on the paper.

“For those species that have already become extinct, our method shows that access to their genetic biodiversity may not be completely lost.”