IQ loss linked to Schizophrenia genes

People at greater genetic risk of schizophrenia could see a fall in IQ as they age, study shows.

Scientists at the University say IQ decline in those at risk could happen even if they do not develop schizophrenia.

The findings could lead to new research into how different genes for schizophrenia affect brain function over time. Schizophrenia - a severe mental disorder characterised by delusions and by hallucinations - is in part caused by genetic factors.

The researchers used the latest genetic analysis techniques to reach their conclusion on how thinking skills change with age.

Retaining our thinking skills as we grow older is important for living well and independently. If nature has loaded a person’s genes towards schizophrenia, then there is a slight but detectable worsening in cognitive functions between childhood and old age. -Professor Ian Deary (Director of the University of Edinburgh’s Centre for Cognitive Ageing and Cognitive Epidemiology)

Historical data

They compared the IQ scores of more than 1,000 people from Edinburgh.

The people were tested for general cognitive functions in 1947, aged 11, and again when they were around 70 years old.

The researchers were able to examine people’s genes and calculate each subject’s genetic likelihood of developing schizophrenia, even though none of the group had ever developed the illness.

They then compared the IQ scores of people with a high and low risk of developing schizophrenia.

Scientists found that there was no difference at age 11, but people with a greater genetic risk of schizophrenia had slightly lower IQs at age 70.

Those people who had more genes linked to schizophrenia also had a greater estimated fall in IQ over their lifetime than those at lower risk.

Cognitive impact

With further research into how these genes affect the brain, it could become possible to understand how genes linked to schizophrenia affect people’s cognitive functions as they age. -Professor Andrew McIntosh (Centre for Clinical Brain Sciences)

Schizophrenia affects around 1 per cent of the population, often in the teenage or early adult years, and is associated with problems in mental ability and memory.

The study, which was funded by the BBSRC, Age UK, and the Chief Scientist Office, is published in the journal Biological Psychiatry.

Finding “Mr. Right,” How Insects Sniff Out the Perfect Mate

Unlike humans, most insects rely on their sense of smell when looking for a mate. Scientists have found that sex pheromones play an important role in finding a suitable partner of the same species; yet, little is known about the evolution and genetic basis of these alluring smells.

A team of researchers from Arizona State University and Germany found that one wasp species has evolved a specific scent, or pheromone, which keeps it from mating with other species. In addition, they discovered that the genetic basis of the new scent is simple, which allows the males to change an existing scent into a new one. Over time, the females recognize and use this new scent to distinguish their own species from others.

Scientists from ASU, the University of Regensburg, the Zoological Research Museum Alexander Koenig Bonn, and the Technical University Darmstadt in Germany, present their findings in an article published Feb. 13 online in the journal Nature.

Newt sequencing may set back efforts to regrow human limbs

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

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

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

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

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

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

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

Cellular renewal process may underlie benefits of omega fatty acids

A search for genes that change their levels of expression in response to nutrient deprivation has uncovered potential clues to the mechanism underlying the health benefits of omega fatty acids. In the Feb. 15 issue of Genes & Development, Massachusetts General Hospital (MGH) researchers describe finding that feeding omega-6 fatty acids to C. elegans roundworms or adding them to cultured human cells activates a cellular renewal process called autophagy, which may be deficient in several important diseases of aging. A process by which defective or worn-out cellular components and molecules are broken down for removal or recycling, autophagy is also activated in metabolically stressful situations, allowing cells to survive by self-digesting nonessential components.

"Enhanced autophagy implies improved clearance of old or damaged cellular components and a more efficient immune response," says Eyleen O’Rourke, PhD, of MGH Molecular Biology, lead author of the report. "It has been suggested that autophagy can extend lifespan by maintaining cellular function, and in humans a breakdown in autophagic function may involved in diseases including inflammatory bowel disease, Parkinson’s disease, and in a more complex way in cancer and metabolic syndrome."

O’Rourke is a research fellow in the laboratory of MGH investigator Gary Ruvkun, PhD, whose team investigates the development, longevity and metabolism of C.elegans. Ruvkun and other researchers have discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the lifespan of C. elegans and that similar mutations in the corresponding mammalian pathways also regulate lifespan. Many of these mutations also make animals resistant to starvation, suggesting that common molecular mechanisms may underlie both response to nutrient deprivation and the regulation of lifespan.

To find these mechanisms O’Rourke searched genomic databases covering many types of animals for shared genes that respond to fasting by changing their expression. She found that expression of the C. elegans gene lipl-4 increases up to seven times in worms not given access to nutrients. A transgenic strain that constantly expresses elevated levels of lipl-4, even when given full access to food, was found to have increased levels of arachidonic acid (AA), an omega-6, and eicosapentanoic acid (EPA), an omega-3 fatty acid and to resist the effects of starvation.

(Image: The Herman Lab, Kansas State University)

Why ‘Good Hair’ Matters: The first animal model of recent human evolution reveals that a mutation for thick hair does much more

The first animal model of recent human evolution reveals that a single mutation produced several traits common in East Asian peoples, from thicker hair to denser sweat glands, an international team of researchers reports.

The team, led by researchers from Harvard Medical School, Harvard University, the Broad Institute of MIT and Harvard, Massachusetts General Hospital, Fudan University and University College London, also modeled the spread of the gene mutation across Asia and North America, concluding that it most likely arose about 30,000 years ago in what is today central China. The findings are reported in the cover story of the Feb. 14 issue of Cell.

“This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans,” said Pardis Sabeti, associate professor in the Center for Systems Biology and Department of Organismic and Evolutionary Biology at Harvard University, and one of the paper’s senior authors. Sabeti is also a senior associate member at the Broad Institute.

“This paper tells a story about human evolution in three parts,” said Cliff Tabin, head of the HMS Department of Genetics and co-senior author. “The mouse model links multiple traits to a single mutation, the related association study finds these traits in humans, and computer models tell us where and when the mutation likely arose and spread.”

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Research update: Imaging fish in 3-D

Zebrafish larvae — tiny, transparent and fast-growing vertebrates — are widely used to study development and disease. However, visually examining the larvae for variations caused by drugs or genetic mutations is an imprecise, painstaking and time-consuming process.

Engineers at MIT have now built an automated system that can rapidly produce 3-D, micron-resolution images of thousands of zebrafish larvae and precisely analyze their physical traits. The system, described in the Feb. 12 edition of Nature Communications, offers a comprehensive view of how potential drugs affect vertebrates, says Mehmet Fatih Yanik, senior author of the paper.

“Complex processes involving organs cannot be accurately recapitulated in cell culture today. Existing 3-D tissue models are still far too simple to model live animals,” says Yanik, an MIT associate professor of electrical engineering and computer science and biological engineering. “In whole animals, the biology is far more complicated.”

Lead authors of the paper are MIT graduate student Carlos Pardo-Martin and Amin Allalou, a visiting student at MIT. Other authors are MIT senior research scientist Peter Eimon, MIT intern Jaime Medina, and Carolina Wahlby of the Broad Institute.

Zebrafish are genetically similar to humans and have many of the same developmental pathways, so scientists often use them to model human diseases including cancer, diabetes, Parkinson’s disease and autism.

Using the new technology, researchers can grow larvae in tiny wells and flow them through a channel to an imaging platform. Once there, the embryos are rotated and 320 images are taken from different angles, allowing 3-D reconstructions to be made using optical projection tomography (OPT). Getting larvae to the platform takes about 15 seconds, and the imaging takes only 2.5 seconds. This allows hundreds or thousands of larvae to be imaged within hours.

In a 2010 paper, Yanik’s team described the system that transports the embryos to the imaging platform, which they combined with high-resolution two-dimensional imaging. In the latest version, they developed a high-speed OPT imaging technique, which takes hundreds of two-dimensional images and subsequently generates a 3-D image, similar to a CT scan.

They also created a computer algorithm that can measure hundreds of traits and use that information to create a comprehensive phenotype map — the overall description of an organism’s characteristics — for each larva. This enables rapid and detailed studies of how different drugs affect those phenotypes.

“You could probably look at almost any organ or tissue that you’re interested in,” Eimon says. “It gives researchers a way to rapidly measure and quantify and put numbers on the kinds of phenotypes and gene-expression patterns that they’ve been looking at for years and years.”

In this study, the researchers focused on the craniofacial skeleton, which is analogous to the human skull. They measured the length and volume of each of the bones that make up this structure, as well as the angles between the bones.

Each embryo was imaged five days after being treated with one of nine different teratogens — drugs that cause developmental abnormalities. The researchers compared their results with the drugs’ known effects and found that they were very consistent. They also obtained high-resolution, 3-D images of the craniofacial skeletons, which are less than a millimeter long.

“Now that we’re able to load the animals, and we can image them really quickly, and we have a way to start looking at the information, the sky’s the limit,” Pardo-Martin says. “What we have to do now is ask the big questions, because the technology has advanced.”

This kind of analysis could be very valuable for drug developers who need to efficiently screen thousands of drug candidates. It could also be used to study hard-to-detect changes in phenotype caused by genetic mutations, says Joseph Fetcho, a professor of neurobiology and behavior at Cornell University.

“A really high-throughput way to assess phenotype is very important for measuring small effects on the development of an organism,” says Fetcho, who was not part of the research team. “You can see what the phenotype looks like in a large population and quantify it in a very rigorous way.”

Some Autism Behaviors Linked to Altered Gene

Scientists at Washington University School of Medicine in St. Louis have identified a genetic mutation that may underlie common behaviors seen in some people with autism, such as difficulty communicating and resistance to change.

An error in the gene, CELF6, leads to disturbances in serotonin, a chemical that relays messages in the brain and has long been suspected to be involved in autism.

The researchers identified the error in a child with autism and then, working in mice, showed that the same genetic alteration results in autism-related behaviors and a sharp drop in the level of serotonin circulating in the brain.

While the newly discovered mutation appears to be rare, it provides some of the first clues to the biological basis of the disease, the scientists report Feb. 13 in the Journal of Neuroscience.

“Genetically, autism looks very complicated, with many different genetic routes that lead to the disease,” says lead author Joseph D. Dougherty, PhD, an assistant professor of genetics at Washington University. “But it’s not possible to design a different drug for every child. The real key is to find the common biological pathways that link these different genetic routes and target those pathways for treatment.”

Autism is known to have a strong genetic component, but the handful of genes implicated in the condition so far explain only a small number of cases or make a small contribution to symptoms.

This led Dougherty and senior author Nathaniel Heintz, PhD, a Howard Hughes Medical Institute investigator at Rockefeller University, to speculate that some of the most common behavioral symptoms of autism may be caused by disruptions in a common biological pathway, like the one involved in serotonin signaling.

Putting Our Heads Together: Canines May Hold Clues to Human Skull Development

Man’s best friend may touch our hearts with their empathy, companionship, playfulness and loyalty, and they may also lead us to a deeper understanding of our heads.

In the article, “The Genetics of Canine Skull Shape Variation,” in the February issue of the Genetics Society of America’s journal, GENETICS, Jeffrey J. Schoenebeck, PhD, and Elaine A. Ostrander, PhD, researchers at the National Human Genome Research Institute (NHGRI), the National Institutes of Health (NIH), review progress in defining the genes and pathways that determine canine skull shape and development that have been made in the eight years since the dog genome was mapped.

The implications of this research extend beyond the interests of dog fanciers and breeders. “Dogs can serve as a model for skull growth and shape determination because the genetic conservation between dogs and humans makes it highly likely that craniofacial development is regulated similarly between both species,” Dr. Schoenebeck said. “These discoveries are important for human health and biology, especially for children born with craniofacial deformities,” Dr. Ostrander, added. In humans these deformities include Apert, Crouzon and Pfeiffer syndromes, where skull bones fuse prematurely causing facial malformations, such as wide-set bulging eyes and broad foreheads, resulting in dental, eye and other physiological problems.

Skull shape is a complex trait, involving multiple genes and their interactions. Thanks to standardized canine breeding, which documents more than 400 breeds worldwide, and their distinct morphological features, researchers can disentangle traits such as skull shape, which in many breeds is a breed-defining variation.

For example, researchers are beginning to identify which genes cause a Bulldog or a Pug to have short pushed-in faces, or brachycephaly, and those that cause Saluki’s or collies to have narrow, elongated snouts, or dolichocephaly. Between these two distinct canine cranium shapes are many variations that are also breed specific but can’t be neatly categorized as brachycephalic or dolichocephalic, such as the rounded skull of the Chihuahua or the downward pointing snout of the Bull terrier. Researchers now use genome-wide association studies (GWAS) to identify loci of interest that may be associated with these kinds of subtle differences.

The use of GWAS in determining genetic variation in dogs is in its infancy. What’s exciting said Dr. Schoenebeck is that with these studies and the tools researchers now have to map these variations “we may find new roles for genes, never before implicated in cranium development” and because similar genes and genetic pathways operate in humans, unexplained craniofacial developmental defects may become better understood.

Identifying the causative genetic mechanisms of these variations in canines offer researchers who study human cranial abnormalities “a way to figure out what sort of genetic variation matters and what doesn’t,” said Dr. Ostrander.

Drs. Schoenbeck and Ostrander clearly show there’s a lot more research to do on craniofacial development in dogs. It is also clear that the connection between us and our canine friends is in our heads as well as our hearts.

(Image: Villemarette)

What Causes Lou Gehrig’s Sticky Masses?

Globs of protein clustered in the neurons that control muscles have long been the hallmark of amyotrophic lateral sclerosis (ALS), the fatal neurodegenerative disease also commonly known as Lou Gehrig’s disease. Now, a study of the most commonly found mutant gene in people with ALS reveals an unexpected origin of some of those sticky masses, a finding that may offer drug developers a new target for treatments.

Located on the ninth chromosome, which explains part of its unwieldy name, the C9orf72 gene has a bit of a stutter. A typical version in healthy people contains a stretch of DNA where a string of six genetic letters—GGGGCC—repeats up to 25 times. Scientists have recently found that in a sizable share of people with ALS and frontotemporal dementia (FTD), a less common neurological disease characterized by language, memory, and emotional problems, this repeat occurs many more times; some people have thousands of copies.

Since these C9orf72 mutations were discovered in 2011, some researchers have speculated that the repeats interrupt production of the gene’s normal protein, which serves some as-yet unknown, but vital function in motor neurons or other brain cells. Others have hypothesized that the mutation spawns a large, misshapen strand of RNA that grabs on to proteins such as TDP-43, which normally help process RNA, creating protein tangles that starve the cell of the machinery it needs to function.

Molecular biologists at the Ludwig Maximilians University Munich in Germany and the University of Antwerp in Belgium, however, wondered whether the genetic stutters themselves coded for proteins that became tangled in the cell. Few scientists had considered this because the stutters don’t contain the “start signal” that allows proteins to be made. Still, in a few other diseases caused by genetic repeats, the cell manages to produce proteins from the abnormal gene despite lacking this signal. Sometimes these proteins are toxic and ultimately kill the cell.

Based on the DNA sequence of the GGGGCC-laden C9orf72 seen in ALS and FTD patients, the European team determined that if translated, the gene would produce various proteins containing strings of repeat amino acids. Dubbed dipeptide repeat (DPR) proteins, these molecules don’t normally appear in humans and should be prone to clumping, the scientists concluded. Indeed, when they began to search for DPR protein clusters in actual human brain tissues, they found them in tissue from FTD and ALS patients with the C9orf72 mutation. No such lumps showed up in the brain tissue of healthy controls or ALS and FTD patients without the C9orf72 mutation, increasing the likelihood that the mutation produced them, Dieter Edbauer, a molecular biologist at Ludwig Maximilians, and his co-authors report online today in Science.

Translation error tracked in the brain of dementia patients

In certain dementias silent areas of the genetic code are translated into highly unusual proteins by mistake. An international team of scientists including researchers from the German Center for Neurodegenerative Diseases (DZNE) in Munich and the Ludwig-Maximilians-Universität (LMU) present this finding in the online edition of “Science”. The proteins that have now been identified shouldn’t actually exist. Nevertheless, they build the core of cellular aggregates whose identity has been enigmatic until now. These aggregates are typically associated with hereditary neurodegenerative diseases including variants of frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). They are likely to be damaging and might be a target for therapy.

FTD and ALS are part of a group of neurodegenerative diseases that show a broad and overlapping variety of symptoms: Patients often suffer from dementia, personality changes and may also be affected by language abnormalities and movement disorders. The problems often arise before the age of 65 without a clear cause. However, about 30 percent of cases are linked to a genetic cause. In Europe approximately 10 percent of patients show a common genetic feature: In their DNA (the carrier of the genetic code) a particular short sequence appears in numerous copies one after another. Furthermore, proteins of unknown identity accumulate inside the brain of these patients. As it turns out both findings are directly related – that is what the team of researchers including molecular biologists Dieter Edbauer and Christian Haass has now been able to show.

“We have found that the proteins are linked to a genetic peculiarity which many patients have in common. At a certain location inside the gene C9orf72 there are several hundred repeats of the sequence GGGGCC, while healthy people display less than 20 such copies,” explains Prof. Edbauer, who researches at the DZNE and the LMU. “But it is surprising that these proteins are actually made, because these repeats fall into a region of the DNA that should not be translated into proteins.”

An area of DNA assumed to be silent

The DNA holds the blueprints for building proteins. In general, the beginning of such a blueprint is indicated by a certain molecular start signal, but the usual signal is missing in this case. The region of DNA comprising the numerous repeats should therefore not be translated into proteins. It seems that the process of protein synthesis is initiated in a non-textbook way. “Although quite rare there are two known alternatives to the common mechanism. Which procedure applies here, we don’t know yet,” says Prof. Haass, Site Speaker of the DZNE in Munich and chair of Metabolic Biochemistry at LMU.

Nevertheless, in cell culture experiments the researchers were able to show that long repeats of the sequence GGGGCC may in fact lead to the production of proteins, even though the usual start signal is missing. Furthermore, they identified the same proteins in the particles that typically accumulate in the brain of patients. The scientist could also identify their composition: They turned out to be dipeptid-repeat proteins, which comprise a very large number of identical building blocks.

“These are very extraordinary proteins that usually don’t show-up in the organism,” Edbauer notes. “As far as we know, they are completely useless and scarcely soluble. Therefore, they tend to aggregate and seem to damage the nerve cells. We haven’t formally proven toxicity, but there is ample evidence.” Because of their peculiarity these proteins might be an interesting target for new therapies. “As the mechanism of their production is so unusual, we may find ways to inhibit their synthesis without interfering with the formation of other proteins. One could also try to block their aggregation and accelerate their decomposition.”

The scientists have applied for a patent and are pursuing a major goal. “At the DZNE in Munich it is our dream to develop a therapy against these devastating diseases,“ Haass and Edbauer conclude.