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James Sutcliffe, Ph.D.

By Bill Snyder | Vanderbilt Medical Center

Vanderbilt University is participating in a multi-center project, funded by a $17 million federal stimulus grant, to identify the “genetic architecture” of autism.

The researchers will scan the DNA sequences of thousands of people for rare genetic variations associated with autism risk. The project will generate a huge amount of data to “really get at the biological questions,” said James Sutcliffe, Ph.D., who will lead the Vanderbilt contribution.

Autism is a spectrum of developmental disorders characterized by impairments in communication and social interaction, and patterns of repetitive, restricted and stereotyped behaviors. It occurs in up to one in every 150 children in the United States, mainly boys.

Both common and rare variations in many different genes may increase autism risk. Most studies to date have focused on common genetic variation, which causes only slight increases in risk. Emerging data implicate rare variants and specific genes in which they are found, although mutations in these genes may affect only a small number of families.

The level of complexity is “extraordinary,” Sutcliffe said, but at the same time the scientific challenge is “absolutely fascinating.”

Nationally known for his contributions to autism genetics, Sutcliffe is associate professor of Molecular Physiology and Biophysics and of Psychiatry. He is an investigator in the Vanderbilt Kennedy Center for Research on Human Development and in the Vanderbilt Centers for Human Genetics Research and Molecular Neuroscience.

The “genetic architecture” project, supported by a two-year stimulus grant awarded last fall through the National Institute of Mental Health, will be conducted in two phases.

In the first phase, genetic sequences from DNA samples collected from people with autism will be compared to control samples at Baylor College of Medicine and at the Broad Institute of MIT and Harvard.

Approximately 1,000 different genes will be deeply sequenced and compared using “next generation sequencing” techniques. The goal is to identify previously unrecognized gene variants that are associated with autism.

In the second, verification phase, DNA samples from 2,500 “trios” — children with autism and their parents — and from an additional 2,000 controls will be sequenced and scanned for the top 50 genes identified in the first phase.

This work will be done by Sutcliffe and his colleagues at Vanderbilt, and by researchers at Mount Sinai School of Medicine, the University of Pennsylvania, the Broad Institute and University of Pittsburgh.

Additionally, the Rutgers University DNA and Cell Repository will create a new repository of DNA, cell lines and clinical data from the families studied in this project.

Sutcliffe said the project should create a huge opportunity for scientists to study the effect of genetic variation on the function of specific brain proteins and the biological networks in which they play a role.

But, he cautioned, “this is one step in a long story.”

Source: http://www.mc.vanderbilt.edu/reporter/index.html?ID=8151

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“Autism could have 100 different causes,” says Kennedy Krieger neuroscientist Jonathan Pevsner, who’s encouraged by DNA sequencing studies of autistic patients’ genomes. (Baltimore Sun photo by Jed Kirschbaum / December 23, 2009)

Researchers suspect multiple genetic roles, environmental triggers

By Kelly Brewington | Baltimore Sun

At 22 months old, identical twins John and Sam Fetters couldn’t speak a word. By their second birthday, the Gaithersburg boys had both beendiagnosed with autism, leaving their parents wondering if they got a double stroke of bad luck, or if genetics could be responsible.

Researchers have known for years that when one identical twin has autism, the other is also likely to be diagnosed with it – evidence that autism likely has a genetic component.

Recent studies support that theory. Researchers at Kennedy Krieger Institute studied 277 pairs of twins and found that when one identical twin had the disorder, the other developed it 88 percent of the time; for fraternal twins, that figure was 31 percent.

In another recent study, an international team led by Johns Hopkins researchers identified a gene that could play a role in developing autism.

Despite this progress in unlocking the mysteries of autism, scientists have simply confirmed that there are likely numerous genetic links to autism. Pinpointing those links and how they work is exceedingly complex and may take years to unravel, let alone counteract.

Each discovery explains just a tiny fraction of autism’s causes. Researchers think the great majority – 90 percent – of autism cases have a genetic cause, but they’ve found fewer than 10 percent of the triggers.

The need for answers is huge. Federal researchers reported last month that nearly 1 percent of 8-year-olds nationwide struggle with the puzzling neurobiological disorder – indicating autism might be more common than previously thought. The causes of autism have bedeviled researchers for years, but the findings are fueling a push among experts to redouble their efforts to hunt for possible genetic and environmental explanations.

When scientists first delved into genetic research on autism, they hoped to find one or two genes to explain the disorder, said Dr. Gary Goldstein, president and chief executive of Kennedy Krieger Institute, which specializes in children’s developmental disabilities. Instead, researchers have found about 50 genes so far that might be tied to autism, which explain very few cases, he said.

Autism isn’t one disease; it’s too individual to locate just one genetic cause. It’s not like cystic fibrosis, a disorder for which researchers have identified one gene – and tests to diagnose it.

Instead, autism researchers envision that a wide variety of gene defects are responsible for the symptoms collectively known as autism spectrum disorders. The disabilities, different in each child, range from the mild Asperger syndrome to more severe impairments in social interaction and communication.

“Autism could have 100 different causes,” said Jonathan Pevsner, a Kennedy Krieger neuroscientist who is studying a genetic basis for a form of autism in which children have such extreme behavior problems that they injure themselves.

Still, Pevsner is hopeful scientists will make great strides.

“I feel that we should be very hopeful – at the same time realistic – about how difficult it is to untangle all the different causes of autism,” he said. With recent breakthroughs in DNA sequencing, researchers can analyze the genomes of people with autism faster and cheaper. “This provides a far more detailed look at possible genetic causes than ever before.”

Still, as far as tracking those genes down, scientists are just at the beginning, said Aravinda Chakravarti, a professor of molecular biology and genetics at McKusick-Nathans Institute of Genetic Medicine at Hopkins, who led the Hopkins research.

“It’s going to take some work before we understand the true causes of autism,” he said. “We need to make much more headway to ever have enough understanding so that patient management and therapies can be improved.”

His goal: to understand what’s happening with autism on the molecular level and identify causes that can lead to effective treatment that millions of parents so desperately hope for.

Disorders like autism are not only perplexing to scientists, they’re frustrating, Chakravarti said.

“We attach much more meaning to them than to other disorders, because they have to do with the basic aspects that make us human – our ability to feel, to think, to speak,” he said. “It destroys, often, the sense of self that we have.”

The twins study came from findings from Kennedy Krieger’s Interactive Autism Network. The project, set up two years ago, has 32,000 participants and is known as the largest worldwide clearinghouse of data from people such as Kim Leaird and Mike Fetters, the parents of identical twins John and Sam. Scientists use that data to investigate genetic and environmental links to autism.

At Hopkins, Chakravarti studied the genes of 1,000 families and some 1,500 autistic children and concluded that one gene could play a key role. The gene, Semaphorin 5A, helps guide growing neurons and connects them to the right points during fetal development. The activity of this gene is lower in autistic children, researchers found. More research is needed to better understand how the gene might be responsible for autism.

None of the new findings explains why more children are being diagnosed with autism. Genes, said Goldstein, tell only part of the story.

“The idea is there is an environmental interaction with the genetic component,” he said.

But no one knows what the environmental triggers are, and Goldstein suggests they might be different in every patient.

“This does not rule out that you are born with a powerful propensity to have autism, but the severity of that autism, or whether you might actually show it, might depend on something in the environment,” he said.

Autism may be inherited to some degree, but even twin studies show that not all sets of identical twins have autism. And when they do, they don’t always have the same severity of the disorder.

That connection between genes and the environment, called epigenetics, might explain these distinctions, said Dr. Walter Kaufmann, director of the Center for Genetic Disorders of Cognition and Behavior at Kennedy Krieger. Kaufmann is studying identical twins to better understand how certain genes may be “turned on and off” by environmental factors.

“No matter how similar the environment of twins, no two humans are exposed to the exact same conditions,” he said. “There are differences and they appear to accumulate over time.”

That’s of huge interest to Leaird and Fetters, whose twins, now 5, were diagnosed with different types of autism.

While John is mostly nonverbal, flaps his hands and is often fixated with putting his toy blocks in a perfect line, Sam talks nonstop and is a social butterfly in his mainstream kindergarten classroom, said Leaird.

“They’ve always been polar opposites in ways,” she said. “It was really hard for me to believe they both had autism.”

Since their diagnosis, the boys received the same types of speech and occupational therapy. But early on, they led drastically different lives. John was diagnosed with a heart defect at 2 months old, and spent his early months in the hospital having major heart surgery and being pumped with antibiotics.

“I always thought maybe that environment had something to do with turning on his autism – but who knows,” Leaird said.

Leaird and Fetters don’t have any scientific insight into the disorder – they didn’t even know a child with autism before their children were diagnosed. While they have always wondered why one son is more affected than the other, they think genes could be at work.

“While neither one of us have family on the spectrum, I just find it hard not to believe with identical twins,” Leaird said. “Both are affected by autism differently, but both are affected. Right there, it is a clear indicator.”

Source: http://www.baltimoresun.com/health/bal-md.hs.autism04jan04,0,7145703.story

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Randy Jirtle, a Duke University researcher, with mice whose epigenomes were altered to produce differing size and color. (Duke University)

Research on mice might have meaning for many human illnesses

By Rachel Saslow | The Washington Post

Two mice. One weighs 20 grams and has brown fur. The other is a hefty 60 grams with yellow fur and is prone to diabetes and cancer. They’re identical twins, with identical DNA.

So what accounts for the differences?

It turns out that their varying traits are controlled by a mediator between nature and nurture known as epigenetics. A group of molecules that sit atop our DNA, the epigenome ( which means “above the genome” )  tells genes when to turn on and off. Duke University’s Randy Jirtle made one of the mice brown and one yellow by altering their epigenetics in utero through diet. The mother of the brown, thin mouse was given a dietary supplement of folic acid, vitamin B12 and other nutrients while pregnant, and the mother of the obese mouse was not. (Though the mice had different mothers, they’re genetically identical as a result of inbreeding.) The supplement “turned off” the agouti gene, which gives mice yellow coats and insatiable appetites.

“If you look at these animals and realize they’re genetically identical but at 100 days old some of them are yellow, obese and have diabetes and you don’t appreciate the importance of epigenetics in disease, there’s frankly no hope for you,” Jirtle says.

He offers this analogy: The genome is a computer’s hardware, and the epigenome is the software that tells it what to do.

Epigenomes vary greatly among species, Jirtle explains, so we cannot assume that obesity in humans is preventable with prenatal vitamins. But his experiment is part of a growing body of research that has some scientists rethinking humans’ genetic destinies. Is our hereditary fate — bipolar disorder or cancer at age 70, for example — sealed upon the formation of our double helices, or are there things we can do to change it? Are we recipients of our DNA, or caretakers of it?

Last year, the National Institutes of Health announced that it would invest $190 million to accelerate epigenetic research. The list of illnesses to be studied in the resulting grants reveals the scope of the emerging field: cancer, Alzheimer’s disease, autism, bipolar disorder, schizophrenia, asthma, kidney disease, glaucoma, muscular dystrophy and more.

When Jirtle planned his first epigenetics conference in 1998 in Raleigh, N.C., epigenetics was such a small field that he worried nobody would come. About 160 people attended. Jirtle hosted another conference in 2005; it attracted 470.

“It’s the flavor of the month,” says Michael Meaney, a brain researcher at McGill University in Montreal.

When a gene is turned off epigenetically, the DNA has usually been “methylated.” Biologists have known for decades that methylation is involved in cell differentiation in utero, making one cell a skin cell, another cell a liver cell, and so on. Cell differentiation is also what happens when scientists prompt an embryonic stem cell to grow into a specific type of cell. But five years ago, when Meaney submitted a paper suggesting that DNA methylation happens throughout life in response to environmental changes, he was told, “This just can’t happen.” (Most DNA methylation occurs prenatally and during infancy, puberty and old age, Jirtle says. Research suggests that epigenetically, humans are pretty stable during adulthood.)

Duke Department of Medicine researcher Simon Gregory described the link between DNA methylation and autism in a paper published in October in the journal BMC Medicine.

Most genetic studies of autism focus on variations in the DNA sequence itself, especially on genes that are missing. Gregory and his colleagues looked at an oxytocin receptor gene, called OXTR, and found that about 70 percent of the 119 autistic people in his study had a methylated OXTR; in a control group of people without autism, the rate was about 40 percent. Oxytocin is a hormone that affects social interaction; difficulty relating to others is common for those with autism spectrum disorders.

Because this was only a pilot study, more research is necessary. But Gregory says methylation-modifying drugs might be a new avenue for treatments. He also hopes that his findings will provide a new tool for doctors to diagnose autism.

“Methylation has been very hot in the cancer field for a number of years,” Gregory says. “To find something like this associated with autism is very exciting.”

Epigenetic therapy is still very inexact — “a pretty broad brush,” says Jirtle. But oncologists have seen some success in using it against leukemia. Azacitidine, sold as Vidaza and used to treat bone-marrow cancer and blood disorders, became the first FDA-approved epigenetic drug in 2004. When tumor-suppressing genes aren’t doing their job, due to a genetic mutation or hypermethylation, cancer cells can replicate uncontrollably. But by manipulating the epigenetic marks, doctors can get tumor-suppressing genes to work again. Toxicologists also have a big stake in epigenetics. A 2005 study by Washington State University molecular biologist Michael Skinner generated buzz with his finding that when a pregnant rat was exposed to high doses of pesticides, her offspring plus the next three generations suffered from high rates of infertility. (Some scientists have challenged Skinner’s work because they have not been able to reproduce his results in their labs.)

The potential human implications — do the chemicals we ingest today affect our great-grandchildren? — are tremendous. In addition to pesticides, toxicologists are studying chemicals in plastics, such as phthalates and bisphenol A, to see if they could enhance our risk of disease by altering the epigenome.

Jirtle says that he and his fellow researchers usually discuss epigenetics only on the microscopic level, but when he pulls back and looks at the big picture, he is awed.

“I’ve got goose bumps right now talking about it,” he says. “You’re looking at the book of life, how it’s read and how you can change it.”

Source: http://www.washingtonpost.com/wp-dyn/content/article/2009/12/14/AR2009121402894.html

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By EmpowHer

While scientists have long known autism is highly hereditary, their challenge has been identifying the genetic factors associated with it. In a recent study, researchers took an important step toward developing a better understanding of this complex neurodevelopmental disorder.

The study uncovered a simple change in the genetic code that is associated with autism, implicating a neuronal gene that has not previously been tied to the disorder. The genetic code is a long chain of four letters (A, C, G and T) in varying sequences that specify genetic information, and researchers found that a particular single-letter change, or mutation, in this code could play an important role in autism. The research highlighted two other regions of the genome which are likely to contain rare genetic differences that may also influence autism risk.

The study was a large multinational collaboration led by researchers at the Broad Institute of Harvard and MIT in Cambridge, Massachusetts, founded in 2003 to use new genome-based knowledge in medical research. Other participants included Massachusetts General Hospital and Johns Hopkins University.

“These genetic findings give us important new leads to understand what’s different in the developing autistic brain compared with typical neurodevelopment,” said Lauren Weiss, the co-lead author of the study’s results, which were published in the October 8 issue of the journal Nature. Weiss, a former postdoctoral fellow at MGH and the Broad Institute, is currently an assistant professor of psychiatry and human genetics at University of California, San Francisco. “We can now begin to explore the pathways in which this novel gene acts, expanding our knowledge of autism’s biology.”

Support for the study was provided by the Autism Consortium, the Nancy Lurie Marks Family Foundation, NARSAD, the National Center for Research Resources, the National Institute of Mental Health, the Simons Foundation, and others.

Using a Two-Pronged Approach

In order to better understand the complex genetics behind autism, the researchers devised a two-pronged approach that looked at the entire genome, which is all of an organism’s hereditary information. The first prong analyzed DNA from autism patients and their family members.

The goal of this family-based method was detecting portions of the genome that harbor rare but large-effect DNA variants.

The second prong, a population-based method known as “association,” examined DNA from unrelated individuals. This step is useful for exposing common genetic variants that are associated with autism and tend to exert more modest effects.

“The biggest challenge to finding the genes that contribute to autism is having a large and well studied group of patients and their family members, both for primary discovery of genes and to test and verify the discovery candidates,” said Aravinda Chakravarti, professor of medicine, pediatrics and molecular biology and genetics at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, and one of the study’s senior authors. He also notes the study would not have been possible without genomic scanning technologies.

Identifying the Relevant Genomic Regions

The researchers’ results highlight three regions of the human genome. These include parts of chromosomes 6 and 20, the top-scoring regions to emerge from the family-based linkage studies.

Although further research is needed to localize the exact causal changes and genes within these regions that contribute to autism, these findings can help guide future work.

“The genomic regions we’ve identified help shed additional light on the biology of autism and point to areas that should be prioritized for further study,” said Mark Daly, one of the study’s senior authors, a senior associate member at the Broad Institute and an associate professor at the Center for Human Genetic Research at MGH. “Given the genetic complexity of autism, it’s unlikely that a single method or type of genomic variation is going to provide us with a complete picture. Our approach of combining multiple complementary methods aims to meet this critical challenge.”

Although the Nature paper identifies a handful of new genomic regions, the researchers emphasize that the findings are just one piece of a very large – and mostly unfinished – puzzle. Future studies involving larger patient cohorts and higher resolution genomic technologies, such as next-generation DNA sequencing, promise to yield a deeper understanding of autism and its complex genetic roots.

Source: http://www.empowher.com/news/herarticle/2009/12/01/broad-genome-study-increases-understanding-autism

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By Science Daily

Researchers at Duke University Medical Center have uncovered a new genetic signature that correlates strongly with autism and which doesn’t involve changes to the DNA sequence itself. Rather, the changes are in the way the genes are turned on and off. The finding may suggest new approaches to diagnosis and treatment of autism.

The researchers found higher-than-usual numbers of gene-regulating molecules called methyl groups in a region of the genome that regulates oxytocin receptor expression in people with autism.

“In both blood samples and brain tissue, the methylation status of specific nucleotides in the oxytocin receptor gene is significantly higher in someone with autism, about 70 percent, compared to the control population, where it is about 40 percent,” said co-lead author Simon G. Gregory, Ph.D., assistant professor in the Duke Department of Medicine. The work appears in BMC Medicine journal online.

Oxytocin is a hormone secreted into the bloodstream from the brain, and also released within the brain, where it has a bearing on social interaction. Previous studies have shown that giving oxytocin can improve an autistic person’s social engagement behavior and it is being explored as a potential treatment of the disorder. Higher methylation of the oxytocin receptor gene may make a person less sensitive to the hormone.

The findings by Dr. Gregory and his colleagues will potentially provide information about which individuals will respond better to treatment with oxytocin.

“We are excited about our findings because they represent one of the few occasions in which a mechanism other than genetic susceptibility or genome instability is implicated in the development of autism, Gregory said.

“These results provide a possible explanation of why social isolation forms part of the autism spectrum — because an autistic individual’s ability to respond to oxytocin may be limited,” Gregory said. ” Oxytocin has been tied to levels of trust and ability to read social cues.”

Although the methylation status of the OXTR gene is not a definitive diagnosis of autism by itself, a test for methylation might be used along with other clinical tests for diagnosing autism. Gregory said that methylation-modifying drugs also may be a new avenue for treatments.

Though not a change to the DNA sequence itself, methylation status can be inherited, by what is known as epigenetics — inherited changes in gene regulation.

“The epigenetic link to autism is extremely exciting as it provides another opportunity for us to explore the heritability of this disorder and argues the importance of exploring epigenetic markers in complex disease,” said co-lead author Jessica J. Connelly, Ph.D., assistant professor in the Department of Medicine at the University of Virginia.

The identification of differences in methylation status of OXTR in people with and without autism was discovered through a genome-wide study of genomic instability.

The researchers examined 119 individuals with autism to identify genomic rearrangements. One of these individuals had a DNA deletion of a region containing the OXTR gene. The group then examined the genomic make-up of the individual’s family members and established that the boy with the deletion had a brother with autism who didn’t have the deletion. (Their mother had symptoms of an obsessive-compulsive disorder, but not autism; autism and OCD share the symptom of intensely repetitive thoughts and behaviors).

The researchers examined the brother’s genome and found instances of elevated methylation. With this discovery, they looked again at independent collections of blood samples and brain tissue from a repository of specimens, and found consistent differences in OXTR methylation.

This research was supported by the JP Hussman Foundation and National Institutes of Health grants.

Other authors include co-lead-author Jessica J. Connelly, now with the University of Virginia and formerly of the Duke Center for Human Genetics; Aaron Towers, J. Johnson, D Biscocho, and Christina Markunas of the Duke Center for Human Genetics; G.R. Delong of the Duke Department of Medicine; S.K. Murphy of the Duke Departments of Obstetrics and Gynecology, and Pathology; Carla Lintas and Antonio. Persico of the Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, and the Department of Experimental Neurosciences, IRCCS “Fondazione Santa Lucia,” both in Rome; R.K. Abramson and H.H. Wright of the Department of Neuropsychiatry, SOM-USC in Columbia, S.C.; P. Ellis and C.F. Langford of Wellcome Trust Sanger Institute in Hinxton, U.K.; and Michael L. Cuccaro and Margaret A. Pericak-Vance of the John P. Hussman Institute for Human Genomics of the University of Miami Miller School of Medicine in Miami, Fla.

Source: http://www.sciencedaily.com/releases/2009/10/091021212247.htm

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By Science Daily

In one of the first studies of its kind, an international team of researchers has uncovered a single-letter change in the genetic code that is associated with autism. The finding, published in the journal Nature, implicates a neuronal gene not previously tied to the disorder and more broadly, underscores a role for common DNA variation. In addition, the new research highlights two other regions of the genome, which are likely to contain rare genetic differences that may also influence autism risk.

“These discoveries are an important step forward, but just one of many that are needed to fully dissect the complex genetics of this disorder, ” said Mark Daly, one of the study’s senior authors, a senior associate member at the Broad Institute of Harvard and MIT and an associate professor at the Center for Human Genetic Research at Massachusetts General Hospital (MGH). “The genomic regions we’ve identified help shed additional light on the biology of autism and point to areas that should be prioritized for further study.”

“The biggest challenge to finding the genes that contribute to autism is having a large and well studied group of patients and their family members, both for primary discovery of genes and to test and verify the discovery candidates,” said Aravinda Chakravarti, professor of medicine, pediatrics and molecular biology and genetics at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, and one of the study’s senior authors. “This latest finding would not have been possible without these many research groups and consortia pooling together their patient resources. Of course, they would not have been possible without the genomic scanning technologies either.”

Autism is a common neurodevelopmental disorder characterized by impaired social, behavioral and communication abilities. Compared to other complex diseases, which are caused by a complicated mix of genetic, environmental and other factors, autism is highly heritable — roughly 90% of the disorder is thought to be genetic in origin. Yet the majority of autism cases cannot be attributed to known inherited causes.

Modern approaches that harness genome-scale technologies have begun to yield some insights into autism and its genetic underpinnings. However, the relative importance of common genetic variants, which are generally present in the human population at a frequency of about 5%, as well as other forms of genetic variation, remains an unresolved question.

To more deeply probe autism’s complex genetic architecture, a large multinational collaboration led by researchers at the Broad Institute of Harvard and MIT, Massachusetts General Hospital, Johns Hopkins University and elsewhere devised a two-pronged, genome-scale approach. The first component makes use of a family-based method (called “linkage” ) that analyzes DNA from autism patients and their family members to detect portions of the genome that harbor rare but high-impact DNA variants. The second harnesses a population-based method (known as “association” ) that examines DNA from unrelated individuals and can expose common genetic variants associated with autism and which tend to exert more modest effects.

“Given the genetic complexity of autism, it’s unlikely that a single method or type of genomic variation is going to provide us with a complete picture,” said Daly. “Our approach of combining multiple complementary methods aims to meet this critical challenge.”

For their initial studies, the researchers examined roughly half a million genetic markers in more than 1,000 families from the Autism Genetic Resource Exchange (AGRE) and the US National Institute of Mental Health (NIMH) repositories. Follow-up analyses were conducted in collaboration with the Autism Genome Project as well as other international groups. “We are deeply grateful to all of the patients and their families who made this work possible,” said Daly.

The researchers’ results highlight three regions of the human genome. These include parts of chromosomes 6 and 20, the top-scoring regions to emerge from the family-based linkage studies. Although further research is needed localize the exact causal changes and genes within these regions that contribute to autism, these findings can help guide future work.

The other major result, this one flowing from the population-based analyses, is a single-letter change in the genetic code known as a single nucleotide polymorphism, or SNP (pronounced “snip” ). This common variant lies on chromosome 5 near a gene known as semaphorin 5A, which is thought to help guide the growth of neurons and their long projections called axons. Notably, the activity or “expression” of this gene appears to be reduced in the brains of autism patients compared to those without the disorder.

“These genetic findings give us important new leads to understand what’s different in the developing autistic brain compared with typical neurodevelopment. We can now begin to explore the pathways in which this novel gene acts, expanding our knowledge of autism’s biology,” said co-lead author Lauren Weiss, a former postdoctoral fellow who collaborated with Daly and his colleagues at MGH and the Broad Institute. Weiss is now an assistant professor of psychiatry and human genetics at University of California, San Francisco (UCSF).

Although the Nature paper identifies a handful of new genes and genomic regions, the researchers emphasize that the findings are just one piece of a very large — and mostly unfinished — puzzle. Future studies involving larger patient cohorts and higher resolution genomic technologies, such as next-generation DNA sequencing, promise to yield a deeper understanding of autism and its complex genetic roots.

This work was supported by the Autism Consortium, the Nancy Lurie Marks Family Foundation, NARSAD, the National Center for Research Resources, the National Institute of Mental Health, the Simons Foundation as well as other funding agencies.

Source: http://www.sciencedaily.com/releases/2009/10/091007131210.htm

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Celine Dion, 41, and her husband Rene Angelil, 67, recently announced they are having a baby. Some experts are calling for more awareness of the risks of older men fathering children. (Photograph by: Valery Hache, AFP/Getty Images)

By Dr. Tom Keenan | The Calgary Herald

Evidence is piling up that men, or at least our reproductive parts, have a “best before” date. Not only is it harder to create a pregnancy after the age of 35 or 40, researchers are finding that our sperm quality decreases with age. This can result in a higher-than-normal incidence of offspring with schizophrenia, autism and low IQ, as well as an increased chance of miscarriage.

Quite a few experts are calling for more awareness of this problem, partly to balance out the “grandpa-daddy” trend among high-profile celebrities. Yes, Celine Dion, 41, is pregnant and her husband Rene is 67. Sure, actor Anthony Quinn became a father at age 81 and Charlie Chaplin was able to mock his biological clock at age 73. Pierre Trudeau’s last child was born when he was 72.

Still, for most of us, baby making is a game best played by the young. A study of more than 12,000 couples treated at the Eylau Centre for Assisted Reproduction in Paris found a man’s fertility drops off in his late 30s and plummets after 40. The researchers also found if the father was over the age of 44, almost a third of the pregnancies ended in miscarriage.

They attribute this at least in part to a kind of “sperm decay,” marked by DNA fragmentation and other abnormalities. Unlike women, who are born with all their eggs, men do not make any sperm until they reach puberty. Then we make up for it by generating up to 100 million new ones per day. Because of all this sperm-copying, mutations can accumulate with age.

Writing on healthline.com,fertility specialist Dr. Carl Herbert likens the process to photocopying a cake recipe over and over until the “3 cups of flour” looks like “2 cups” and the recipe doesn’t work any more.

“These subtle copying defects cause a long list of diseases in the children of older fathers,” he writes. “Lesch Nyhan syndrome, polycystic kidney disease and hemophilia A are among the most well known. For fathers over age 40, the risk of having a child with a disease-causing mutation is similar to the risk the mother has for a child with Down syndrome.” Other factors, ranging from high or low body weight to diabetes, can also adversely affect sperm quality.

Columbia University urologist Dr. Harry Fisch is one of the high-profile experts speaking out about the risks of geriatric fatherhood. He’s appeared on the Today show and written a book called The Male Biological Clock, as well as an article in the medical journal Geriatrics. There he warns “couples are waiting longer to have children, and advances in reproductive technology are allowing older men and women to consider having children. The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome.”

Since there’s no turning back our biological clocks, Fisch advises older dad-wannabes to “have a thorough history and physical examination focused on their sexual and reproductive capacity. Such examination should entail disclosure of any sexual dysfunction and the use of medications, drugs, or lifestyle factors that might impair fertility or sexual response.”

Other experts suggest older couples trying for a baby should at least consider an assisted reproductive technology such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI.) IVF is the classic “test tube baby,” fertilized outside the body and implanted in a uterus.

ICSI is a fancier technique that involves injecting a specific sperm into an egg, again outside the woman’s body. While there’s no guarantee that a spermatozoon that looks good during this procedure will be genetically sound, at least the duds with two heads or two tails can be eliminated. Contrarians argue that piercing the egg with a needle might allow a sperm that should never succeed to penetrate the egg. With these procedures, you pay thousands of dollars and you still take your chances.

One cheerful bit of sperm news was presented in July at the European Society of Human Reproduction and Embryology meeting. Australian researcher Dr. David Greening reported that having sex (or at least ejaculating) every day improved sperm DNA quality.

He studied 118 men with higher-than-normal sperm DNA damage and instructed them to ejaculate daily for seven days. He found this somewhat pleasant prescription produced a significant reduction in DNA-damaged sperm. Asked why this happened, he suggested the sperm spent less time in the male plumbing system, where they can be exposed to DNA damage.

A blurb on the back cover of Harry Fisch’s book notes “male sexuality is a topic discussed far more by standup comics than by responsible physicians.” Which, of course, leads to the classic “Why does it take millions of sperm to fertilize one egg? Because they won’t ask for directions.”

Now it seems that, as we get older, this little jest becomes even more appropriate!

Source: http://www.canada.com/health/biological+clocks+ticking/1958635/story.html

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The Autism News English aging, autism, autistic, biological clock, Celine Dion, dna, having a baby, low IQ, men, miscarriage, Rene Angelil, Schizophrenia

The Autism News | English

By Science Daily

An international group of researchers is the first to show that common variations in a gene – previously shown to be associated with Retts Syndrome, autism, and mental retardation – are associated with differences in brain structure in both healthy individuals and patients with neurological and psychiatric disorders.

Their findings will be published in the early online edition of the Proceedings of the National Academy of Sciences the week of August 17.

“We studied not only the gene itself – a gene called MECP2, which is known to have a big effect on brain development – but also the regions surrounding the gene, sometimes known as junk DNA,” said principle investigator Anders M. Dale, PhD, professor of Neurosciences and Radiology at the University of California, San Diego School of Medicine. “Looking at this ‘bigger window’ of genetic data, we discovered that common variations in the MECP2 region result in changes to brain structure, even in healthy individuals.” Anders explained that these effects do not seem to be population or disease-specific.

The link between genetics and brain structure is a hotly debated area of research. According to the research team, past studies investigating the link between gene variations and human brain structure haven’t used the types of refined brain measurements provided by the structural MRI scans and software developed at UC San Diego, or the and full genetic coverage included in the PNAS study.

A team led by Ole A. Andreassen at Ullelvål University Hospital and Institute of Psychiatry in Oslo, Norway, provided data on one cohort – a sample from the Thematic Organized Psychosis (TOP) research group. This data was compared to a sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the largest Alzheimer’s disease study ever funded by the National Institutes of Health, in studies conducted at UC San Diego. The researchers looked at 289 healthy and psychotic subjects from the TOP study, and 655 healthy and demented patients, largely with Alzheimer’s disease, from the ADNI study.

“The most statistically significant association between the two groups involved a minor allele of a single polymorphism, an inherited genetic variation that is found in more than one percent of the population,” said co-author Nicholas J. Schork, PhD, of the Scripps Translational Science Institute. “This variation resulted in structural brain changes, such as reduced surface area in the brain’s cortex, the area that plays a key role in memory, attention, perceptual awareness, thought and language.” Although expressed in all cells, the MECP2 gene is developmentally regulated and exists in two different genetic transcripts within the brain’s neuronal cells. Changes in brain structure caused by this gene are specific to males, since the variation is found on the X chromosome, but the functional, cognitive consequences aren’t yet known.

The fact that broader, common variations in the area surrounding the MECP2 gene also resulted in changes to the brain structure suggests that this gene may be a promising candidate gene for further study, according to Dale. “Since each individual genetic mutation causes only small changes, the so-called ‘junk DNA’ may be where the action is,” he said. These regions may not change the gene or the protein it encodes, but change the regulation of the gene, he added.

Additional contributors include Alexander H. Joyner, of UC San Diego and Scripps Translational Science Institute; J. Cooper Roddey, of UC San Diego; Cinnamon S. Bloss, of Scripps Translational Science Institute; Trygve E. Bakken, of Scripps Translational Science Institute and UC San Diego; Lars M. Rimol, of the University of Oslo, Norway; Ingrid Melle, of the University of Oslo, Norway; Ingrid Agartz, of the University of Oslo, Norway; Srdjan Djurovic, of UC San Diego; and Eric J. Topol, of UC San Diego.

Funding for this study was provided in part by the National Institutes of Health, Eastern Norway Health Authority and Research Council of Norway.

Source: http://www.sciencedaily.com/releases/2009/08/090817190752.htm

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The Autism News | English

By The Times of India

WASHINGTON: A collaborative team of geneticists from The Children’s Hospital of Philadelphia, the University of Pennsylvania School of Medicine, and several other institutions say that they have found more autism susceptibility genes.

The researchers said that they identified 27 different genetic regions where rare copy number variations – missing or extra copies of DNA segments – were found in the genes of children with autism spectrum disorders (ASDs), but not in the healthy controls.

The complex combination of multiple genetic duplications and deletions is thought to interfere with gene function, which can disrupt the production of proteins necessary for normal neurological development.

“We focused on changes in the exons of DNA–protein-coding areas in which deletions or duplications are more likely to directly disrupt biological functions,” said study leader Dr. Hakon Hakonarson, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia and associate professor of Pediatrics at the University of Pennsylvania School of Medicine.

“We identified additional autism susceptibility genes, many of which, as we previously found, belong to the neuronal cell adhesion molecule family involved in the development of brain circuitry in early childhood,” he added.

According to him, the study also revealed many “private” gene mutations, those found only in one or a few individuals or families–an indication of genetic complexity, in which many different gene changes may contribute to an autism spectrum disorder.

“We are finding that both inherited and new, or de novo, genetic mutations are scattered throughout the genome and we suspect that different combinations of these variations contribute to autism susceptibility,” said Dr. Maja Bucan, professor of Genetics at the University of Pennsylvania School of Medicine and Chair of the Steering committee for Autism Speaks’ Autism Genetic Resource Exchange (AGRE).

“We are grateful to families of children with autism spectrum disorders for their willingness to participate in genetic studies because family-based studies have many advantages. We have learned a lot both from genetic analyses of children with autism as well as analyses of their patents and their unaffected siblings,” the researcher added.

During the study, the researchers compared genetic samples of 3,832 individuals from 912 families with multiple children with ASDs from the AGRE cohort against genetic samples of 1,070 disease-free children from The Children’s Hospital of Philadelphia.

They said that their research also unveiled two novel genes in which variations were found, BZRAP1 and MDGA2. According to them, they were thought to be important in synaptic function and neurological development, respectively.

Key variants of these genes, say the researchers, were transmitted in some, but not all, of the affected individuals in families.

A research article on the findings has been published in the journal PloS Genetics.

Source: http://timesofindia.indiatimes.com/Health–Science/Science/Gene-mutations-linked-to-autism-risk-/articleshow/4705909.cms

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The Autism News | English

Findings show that many autistic people have a deviation in a portion of their DNA that affects the way brain cells connect with one another. The discovery may lead to treatments.

Reporting from Chicago — Researchers have found that many people with autism share common genetic variations, a discovery that may improve diagnosis and offers the promise of developing treatments for the frustratingly mysterious disorder.

Their findings, published in the journal Nature, compared the genomes of thousands of autistic people with those of thousands of people without the disorder — a massive task that new technology has only recently made possible. The genome is the complex system of DNA coding that builds and runs the human body.

Up to now, the medical community could say very little about what causes autism or how to treat it. The lack of scientific knowledge about autism has led to a proliferation of pseudoscientific explanations for the disorder, as well as unproven treatments.

Though this is not the first time geneticists have found a link between autism and DNA, past discoveries have involved extremely rare instances in which a tiny bit of DNA was missing or there were too many copies of another bit. Those differences were helpful in understanding how trouble in those regions of the genome can lead to autistic symptoms, but they accounted for only a tiny fraction of autism cases.

By contrast, the new research is “a big step,” said Thomas Lehner, chief of the Genomics Research Branch at the National Institute of Mental Health.

The first of two Nature studies released Tuesday found that 65% of autistic participants shared a variation between cadherin 10 and cadherin 9, a region of the genome that controls cell-adhesion molecules in the brain. Those molecules help brain cells connect, and autism researchers have long suspected that trouble there may be linked to the disorder. The second study suggested a link between autism and an excess of genetic material associated with ubiquitin, a protein involved with connections between cells.

The reports also do not explain the rising numbers of diagnosed cases of autism. That increase may be occurring because of heightened awareness, because the definition of autism has expanded, because of some environmental factor, some combination of these factors or something else entirely.

Source:  http://www.latimes.com/features/health/la-na-autism29-2009apr29,0,4441598.story

From CBS

Scientists found what is being considered a breakthrough in understanding autism, a possible genetic link among thousands of autistic children around the country. Manuel Gallegus reports.

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