Learning to talk is in the genes

Researchers have found evidence that genetic factors may contribute to the development of language during infancy.

Scientists from the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol worked with colleagues around the world to discover a significant link between genetic changes near the ROBO2 gene and the number of words spoken by children in the early stages of language development.

Children produce words at about 10 to 15 months of age and our range of vocabulary expands as we grow - from around 50 words at 15 to 18 months, 200 words at 18 to 30 months, 14,000 words at six-years-old and then over 50,000 words by the time we leave secondary school.

The researchers found the genetic link during the ages of 15 to 18 months when toddlers typically communicate with single words only before their linguistic skills advance to two-word combinations and more complex grammatical structures.

The results, published in Nature Communications today [16 Sept], shed further light on a specific genetic region on chromosome 3, which has been previously implicated in dyslexia and speech-related disorders.

The ROBO2 gene contains the instructions for making the ROBO2 protein. This protein directs chemicals in brain cells and other neuronal cell formations that may help infants to develop language but also to produce sounds.

The ROBO2 protein also closely interacts with other ROBO proteins that have previously been linked to problems with reading and the storage of speech sounds.

Dr Beate St Pourcain, who jointly led the research with Professor Davey Smith at the MRC Integrative Epidemiology Unit, said: "This research helps us to better understand the genetic factors which may be involved in the early language development in healthy children, particularly at a time when children speak with single words only, and strengthens the link between ROBO proteins and a variety of linguistic skills in humans."

Dr Claire Haworth, one of the lead authors, based at the University of Warwick, commented: "In this study we found that results using DNA confirm those we get from twin studies about the importance of genetic influences for language development."

"This is good news as it means that current DNA-based investigations can be used to detect most of the genetic factors that contribute to these early language skills."

The study was carried out by an international team of scientists from the EArly Genetics and Lifecourse Epidemiology Consortium (EAGLE) and involved data from over 10,000 children.

More information: 'Common Variation Near ROBO2 is Associated with Expressive Vocabulary in Infancy' by St Pourcain et al in Nature Communications.

Chindren with Autism: EphB Link through Family Genes

Harvard Medical School researchers at McLean Hospital have found that a gene family linked to autism, EphB, is essential for proper brain wiring during development.

The findings suggest that the abnormal brain wiring that results from mutations in this gene family could contribute to autism symptoms.

"Using animal models, we were able to see that EphB is required for normal brain development. Mutations in EphB that compromise its function led to abnormal connections between key brain regions involved in processing of sensory information," said Christopher Cowan, HMS associate professor of psychiatry at McLean Hospital.

The findings were reported by McLean Hospital researchers and collaborators in the Proceedings of the National Academy of Sciences on Jan. 22, 2014.

Christopher Cowan

Recent genetic analysis had revealed an EphB gene as a new candidate risk factor for human autism, so investigators targeted the gene in animals to assess its role in the proper development of communication networks between the thalamus and the cortex, the regions of the brain responsible for processing information from the senses, such as touch and hearing.

"Some individuals with autism show abnormalities in sensory perception and processing, including touch, sound and vision," Cowan explained.

Investigators, from left: Yuhong Guo, Jesse Kumar, Laura Smith, Chris Cowan, Adam Harrington, Maria Carreira, Makoto Taniguchi and Rachel Penrod-Martin. 

Not pictured: Carly Hale and Mike Robichaux. 

Image: Patrick O'Connor.

"We found that EphB genes are essential for normal wiring of at least two key parts of the brain that process sensory information, particularly regions involved in touch and sound," Cowan said.

"Our findings suggest that defects in early brain wiring might underlie at least some of the sensory-associated symptoms found in individuals with autism spectrum disorders."

Future work, supported in part by the Simons Foundation Autism Research Initiative, seeks to extend these findings to better understand the relationship between EphB genes and the risk for developing autism.

Understanding the underlying causes of autism may help in the development of effective treatments.

More information: "EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding." Robichaux MA, Chenaux G, Ho HY, Soskis MJ, Dravis C, Kwan KY, Sestan N, Greenberg ME, Henkemeyer M, Cowan CW. Proc Natl Acad Sci U.S.A.. 2014 Jan 22. 

Research Team first to Map Autism-Risk Genes by Function

Pity the poor autism researcher. Recent studies have linked hundreds of gene mutations scattered throughout the brain to increased autism risk. Where do you start?

UCLA neuroscientists may have an answer. They are the first to map groups of autism-risk genes by function, and to identify where and when these genes normally play major roles in early brain development.

In addition, they discovered disturbances in neural circuits that define key pathways between parts of the cerebral cortex.

The research suggests that these early disruptions are created by mutations in genes during fetal brain development and are not a result of autism itself.

Published in the Nov. 21 edition of Cell, the findings will help scientists understand how genetic changes cause autism on a molecular level and prioritize targets for future studies.

"Identifying gene variants that boost risk is only the first step of unraveling a disease," explained lead author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, professor of neurology at the David Geffen School of Medicine at UCLA and professor of psychiatry at the Semel Institute for Neuroscience and Human Behaviour.

"We need to figure out where genetic changes appear in the brain, at what stages during development and which biological processes they disrupt. Only then will we understand how mutations cause autism."

Using an online atlas called BrainSpan, the authors charted gene activity in the developing brain before birth.

In particular, they examined what happens during gene expression —when genes copy data from DNA to RNA in order to create proteins.

Geschwind and his colleagues found high activity in risk genes during two processes critical to early brain development.

"We found that gene variants are expressed in the developing brain when cells define their future identities and roles in neural circuits," first author Neelroop Parikshak, a graduate student researcher in Geschwind's lab.

"Therefore, changes in the genes influence the brain's wiring by altering the synapse and shaping how neurons transmit signals to each other."

The mutated genes also interfered with how the brain's layers and halves relate to one another, a phenomenon confirmed by previous imaging studies of the autistic brain.

"We discovered gene-related disruption of circuits that connect the autistic brain's layers and hemispheres to each other," explained Geschwind, who is director of the UCLA Neurogenetics Program and the Center for Autism Research and Treatment and co-director of the Center for Neurobehavioral Genetics at UCLA.

 "Our finding suggests that the mutated genes caused the miswiring; it's not a result of having the disease itself."

The UCLA team also demonstrated that while autism and intellectual disability share similar risk genes, the genes behave uniquely, showing for the first time how the two disorders differ.

"People often lump intellectual disability together with autism, because the disorders' risk genes overlap," said Parikshak.

"We showed that these genes have unique expression patterns in different brain regions at varying times during brain development.

"Genes linked to intellectual disability influence many biological processes in the body," he added. "But genes tied to autism tend to affect specific functions, such as the connections between brain regions that are essential to many human-specific behaviours, like speech and language."

The UCLA study will reap immediate benefits in the near future, when neuroscientists sequence the genomes of several thousand people for genetic mutations linked to autism and intellectual disability.

"We've made our analysis publically available to allow other researchers to expand upon our study and explore the data in detail," said Geschwind.

"We believe this will mark an important step forward in understanding the biology behind autism and other neurodevelopmental disorders."

Autism ASD: Researchers discover a potential cause

Topoisomerase inhibitors reduce the expression of long genes in neurons, including a remarkable number of genes implicated in Autism Spectrum Disorders -- 200 kb is four times longer than the average gene. 

Credit: Concept: Mark Zylka. Illustration: Janet Iwasa.

Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research announced today in the journal Nature.

Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder's genetic causes.

"Our study shows the magnitude of what can happen if topoisomerases are impaired," said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC.

"Inhibiting these enzymes has the potential to profoundly affect neurodevelopment—perhaps even more so than having a mutation in any one of the genes that have been linked to autism."

The study could have important implications for ASD detection and prevention.

Mark Zylka

"This could point to an environmental component to autism," said Zylka.

"A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. "

This study could also explain why some people with mutations in topoisomerases develop autism and other neuro-developmental disorders.

Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.

Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells.

"If there are additional compounds like this in the environment, then it becomes important to identify them," said Zylka.

"That's really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects—so that pregnant women can avoid being exposed to these compounds."

Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy.

Investigating the drug's effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long—composed of many DNA base pairs.

The group then made the serendipitous connection that many autism-linked genes are extremely long.

"That's when we had the 'Eureka moment,'" said Zylka. "We realized that a lot of the genes that were suppressed were incredibly long autism genes."

Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board—even to a small extent—means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.

The study's findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses—the connections between brain cells.

Another 20 percent are related to gene transcription—the process of translating genetic information into biological functions.

Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person's ability to construct synapses.

"Our discovery has the potential to unite these two classes of genes—synaptic genes and transcriptional regulators," said Zylka.

"It could ultimately explain the biological mechanisms behind a large number of autism cases."

More information: Nature paper dx.doi.org/10.1038/nature12504

Autism: Researchers shed light on role of genes

Research carried out by Medical Research Council (MRC) researchers at the University of Oxford (UK) has uncovered a chain of genetic events that are common in individuals with autism, and have examined for the first time how this chain may influence how messages are sent between nerve cells in the brain.

This knowledge will help researchers better understand the role that genetics plays in autism.

Autism Spectrum Disorders (ASD) affects around 1 per cent of the population and typically cause difficulties in social interaction, communication and repetitive behaviour.

While it's known that genes can play a strong role in the development of ASD, doctors are currently only able to identify the exact genetic cause in around one in five cases.

The team, based at the MRC Functional Genomics Unit (FGU), looked at 181 autism patients who had either additional copies of some genes, or fewer copies of other genes, than people without autism.

In around half of these patients, the genes whose copy count had changed were found to work together in a large biological network that plays a key role in the way in which information is passed between cells in the brain.

By changing the number of copies of genes within this network, the study highlighted disturbances in those with autism in the way the information was carried across synapses in the brain.

Notably, the study also found that while some genes had gained more copies while other genes had lost copies, the final effect was predicted to be the same.

Notably, the study also found that while some genes had gained more copies while other genes had lost copies, the final effect was predicted to be the same.

Dr Caleb Webber, lead author on the study at the MRC FGU at the University of Oxford, says: "Think of a pipe that carries water. At some points along the pipe there are genes that act as taps to let more water into the pipe. At other points genes act as holes to let some of the water out. We found that in individuals with autism the mutations in all these different types of genes act in the same way to affect waterflow. This indicates the 'tap' genes are duplicated in some individuals with autism which increases flow into the pipe, while in other individuals with autism the 'hole' genes are deleted which decreases the amount of water leaving the pipe. Both of these events cause the same thing; too much water flowing through the pipe."

"Knowing not just which 'pipes' in the cell are affected in autism but also in what way they are affected helps us to know in which way we have to change the flow to restore the balance."

Professor Hugh Perry, chair of the MRC's Neurosciences and Mental Health Board, says: "Autism Spectrum Disorders are extremely complex in the way they can influence a person's ability to communicate or interact with their environment. Tracking down and understanding the functions of genes that regulate how information is passed around the brain is a crucial part of the story and will help to underpin the evidence with which diagnoses and treatments are given. This study is a clear example of how MRC-funding can use genetic studies to improve our understanding of the brain and its networks."

The research team's findings are published in Plos Genetics

Dyslexia Study: CYP19A1 gene and the linkage region of speech and language disorders

Paper Abstract

Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions.

The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions:

• it catalyzes the conversion of androgens into estrogens; 
• during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); 
• it is involved in sexual differentiation of the brain; 
• and in songbirds and teleost fishes, it regulates vocalization. 

Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills.

Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1.

Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1−/− mice and human dyslexic brains, respectively.

An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language.

Download the Paper PDF here: CYP19A1 Gene

Read the Full Text Preview at SpringerLink

Evidence for the Late MMN as a Neurophysiological Endophenotype for Dyslexia

Dyslexia affects 5–10% of school-aged children and is therefore one of the most common learning disorders.

Research on auditory event related potentials (AERP), particularly the mismatch negativity (MMN) component, has revealed anomalies in individuals with dyslexia to speech stimuli.

Furthermore, candidate genes for this disorder were found through molecular genetic studies.

A current challenge for dyslexia research is to understand the interaction between molecular genetics and brain function, and to promote the identification of relevant endophenotypes for dyslexia.

The present study examines MMN, a neurophysiological correlate of speech perception, and its potential as an endophenotype for dyslexia in three groups of children.

The first group of children was clinically diagnosed with dyslexia, whereas the second group of children was comprised of their siblings who had average reading and spelling skills and were therefore “unaffected” despite having a genetic risk for dyslexia.

The third group consisted of control children who were not related to the other groups and were also unaffected. In total, 225 children were included in the study.

All children showed clear MMN activity to/da/−/ba/contrasts that could be separated into three distinct MMN components.

Whilst the first two MMN components did not differentiate the groups, the late MMN component (300–700 ms) revealed significant group differences.

The mean area of the late MMN was attenuated in both the dyslexic children and their unaffected siblings in comparison to the control children.

This finding is indicative of analogous alterations of neurophysiological processes in children with dyslexia and those with a genetic risk for dyslexia, without a manifestation of the disorder.

The present results therefore further suggest that the late MMN might be a potential endophenotype for dyslexia.

Read More of this article here

A Step Closer to Resolving Birth Defects

Scientists have made a landmark discovery that could help women minimize or even avoid the risk of having a baby born with congenital birth defects. The study is published April 5 in the international journal Cell.

The scientists, from universities in Australia, Japan, Canada and the United States, including Arizona State University, show for the first time how “nature” and “nurture” interact to increase the severity and likelihood of developing birth defects, including abnormalities in the heart, kidneys, brain, limbs and cranio‐facial regions (cleft palate).

They show how hypoxia, or a period of low oxygen during pregnancy, combined with a genetic risk factor of having only one functioning copy of a gene, dramatically increases the chances of a baby being born with congenital scoliosis, a malformation of the spine that affects around 1 in 1,000.

Sally Dunwoodie, head of the Embryology Laboratory at the Victor Chang Cardiac Research Institute in Sydney, Australia, a professor at the University of New South Wales and the senior author on the study, says the findings take us a step closer to understanding why some people in families develop diseases and others don’t, and, importantly, simple strategies that mothers could adopt to help prevent such defects occurring.

“We’ve long suspected that it is genes or our environment that cause birth defects, but up until now, the majority of these have been largely unknown,” says Dunwoodie. “This is the first time anyone in the world has shown that both ‘nature’ and ‘nurture’, in combination, are molecularly responsible for causing many birth defects.”

“This research is hugely exciting and will help us to genetically diagnose a whole range of birth defects, and give advice to women on how and when to avoid certain activities when pregnant,” says Dunwoodie. “We hope it will eventually lead to the development of therapeutics to stop these defects occurring in the first place.”

Hypoxia during pregnancy can be caused by a range of circumstances including poorly controlled sugar levels in diabetics, smoking, high altitude, prescription and recreational drug‐use, anemia or a poorly functioning placenta.

“Just as genetic studies of selected families led to the discovery of genes causing breast cancer, this study of the genetics and development of congenital scoliosis will lead to breakthroughs in finding the factors that cause scoliosis, a disorder affecting up to 3 percent of the general population,” says co-author Kenro Kusumi, an associate professor in the School of Life Sciences in ASU’s College of Liberal Arts and Sciences.

One of the largest genetic studies focused on congenital scoliosis was led by Kusumi’s group. Together with clinical collaborators in Philadelphia and Toronto, the group identified the first case of a patient with congenital scoliosis due to having a single defective copy of the HES7 gene. Previous studies in mice had established that disruptions in this gene could lead to spinal defects, and loss of both copies of this gene had been found in severe cases of spinal deformities. The type of defect found in the patient in the ASU study was shown by Dunwoodie’s group to clearly affect the ability of the protein to function normally. This finding meant that having just one, instead of two functioning copies of a known gene from either mother or father, was a major risk factor for causing the abnormal formation of vertebrae in embryonic development.

Dunwoodie’s group then went on to test the genetic risk factor in a mouse model combined with an environmental insult in the form of hypoxia. Surprisingly, they found a marked increase in spinal abnormalities in the offspring, when the mothers were exposed to only 8 hours of low oxygen during an entire 21‐day pregnancy.

“We found that the combination of the genetic risk as well as exposure to low oxygen, resulted in our subjects being up to 10 times more likely to develop congenital scoliosis, than those that only had the genetic risk factor,” says Dunwoodie.

“What this brief period of low oxygen essentially did was disrupt the pathway responsible for development of the spine, and we know that the same pathway is used in the development of limbs and many organs, including the heart, kidneys, brain and cranio‐facial region,” adds Dunwoodie.

Bob Graham, a professor and executive director of the cardiac research institute, says around 25 percent of patients with congenital scoliosis also have some form of congenital heart defect, indicating that a single environmental ‘insult’ such as hypoxia, can potentially affect the development of more than one organ in the body.

“This study provides a new paradigm for the interaction between our genes and environment, and may account for a lot of diseases that we haven’t understood before, such as many different forms of congenital heart disease, and conditions like hair‐lip or cleft palate,” says Graham.

Kusumi points to a recent genetic study of over 50,000 identical twins that emphasizes that the risk of developing disease arises from the environment acting together with a person’s unique genome. “For scoliosis, our study highlights how environmental conditions, such as lack of oxygen reaching the developing embryo, could interact uniquely with each individual’s genetic differences to increase the risk of birth defects,” said Kenro.

“It may not necessarily be a lack of oxygen that allows the underlying gene defect to be revealed, it could be a lot of other environmental factors, such as anemia or lack of folate. But the message is, if you have family history of disease or you know you have a defective gene, mums need to be extra careful during pregnancy,” adds Graham.

The team of researchers has begun working on similar studies in congenital heart defects, which affect around 1 in every 100 babies born world-wide every year.

The Human body's Circadian biological clock: Scientists redraw the blueprint

The discovery of a major gear in the biological clock that tells the body when to sleep and metabolize food may lead to new drugs to treat sleep problems and metabolic disorders, including diabetes.

Scientists at the Salk Institute for Biological Studies, led by Ronald M. Evans, a professor in Salk's Gene Expression Laboratory, showed that two cellular switches found on the nucleus of mouse cells, known as REV-ERBα and REV-ERBβ, are essential for maintaining normal sleeping and eating cycles and for metabolism of nutrients from food.

The findings, reported March 29 in Nature, describe a powerful link between circadian rhythms and metabolism and suggest a new avenue for treating disorders of both systems, including jet lag, sleep disorders, obesity and diabetes.

"This fundamentally changes our knowledge about the workings of the circadian clock and how it orchestrates our sleep-wake cycles, when we eat and even the times our bodies metabolize nutrients," says Evans.

"Nuclear receptors can be targeted with drugs, which suggests we might be able to target REV-ERBα and β to treat disorders of sleep and metabolism."

Nurses, emergency personnel and others who work shifts that alter the normal 24-hour cycle of waking and sleeping are at much higher risk for a number of diseases, including metabolic disorders such as diabetes.

To address this, scientists are trying to understand precisely how the biological clock works and uncover possible targets for drugs that could adjust the circadian rhythm in people with sleep disorders and circadian-associated metabolic disorders.

In mammals, the circadian timing system is orchestrated by a central clock in the brain and subsidiary clocks in most other organs.

The master clock in the brain is set by light and determines the overall diurnal or nocturnal preference of an animal, including sleep-wake cycles and feeding behaviour.

Scientists knew that two genes, BMAL1 and CLOCK, worked together at the core of the clock's molecular machinery to activate the network of circadian genes.

In this way, BMAL1 acts like the accelerator on a car, activating genes to rev up our physiology each morning so that we are alert, hungry and physically active.

Prior to this work REV-ERBα and β were thought to play only a minor role in these cycles, possibly working together to slow CLOCK-BMAL1 activity to make minor adjustments to keep the clock running on time.

However, genetic studies of two genes with similar functions can be very difficult and thus the real importance of REV-ERBα and β remained mysterious.

The Salk scientists got around this hurdle by developing mice in which both genes could be turned off in the liver at any point by giving them an estrogen derivative called tamoxifen.

Now mice could develop normally to adulthood, at which point the scientists could turn off REV-ERBα and REV-ERBβ in their livers, an organ crucial to maintaining the correct balance of sugar and fat in blood, to see what effects it had on circadian rhythms and metabolism.

"When we turned off both receptors, the animal's biological clocks went haywire," says Han Cho, first author on the paper and a postdoctoral researcher in Evan's Salk laboratory.

"The mice started running on their exercise wheels when they should have been resting. This suggested REV-ERBα and REV-ERBβ aren't an auxiliary system that makes minor adjustments, but an integral part of the clock's core mechanism. Without them, the clock can't function properly."

Digging more deeply into the clockworks, the Salk scientists mapped out the genes that the REV-ERBs control to keep the body operating on the right schedule, finding that they overlap with hundreds of the same genes controlled by CLOCK and BMAL1.

This and other findings suggested that the REV-ERBs, act as a break on the genes BMAL1 activates.

"We thought that the core of the clock was an accelerator, and that all REV-ERBα and REV-ERBβ did was to pull the foot off that pedal," says Evans.

"What we've shown is that these receptors act directly as a break to slow clock activity. Now we've got a accelerator and a break, each equally important in creating the daily rhythm of the clock."

The scientists also found that the REV-ERBs control the activity of hundreds of genes involved metabolism, including those responsible for controlling levels of fats and bile.

The mice in which REV-ERBα and REV-ERBβ were turned off had high levels of fat and sugar in their blood, common problems in people with metabolic disorders.

"This explains how our cellular metabolism is tied to daylight cycles determined by the movements of the sun and the earth," says Satchidananda Panda, an associate professor in Salk's Regulatory Biology Laboratory and co-author on the paper.

"Now we want to find ways of leveraging this mechanism to fix a person's metabolic rhythms when they are disrupted by travel, shift work or sleep disorders."

Provided by Salk Institute

Autism: Link Found In Gene Mutations From Father

The number of Americans diagnosed with autism has skyrocketed since 2002. Now it affects every one in 88 children.

One of the biggest barriers to finding an effective treatment is that the cause of autism isn't known but biotechnology advances are shedding new light on the possible role of genetics.

"Ten years ago it was as if we were looking through binoculars, when we were looking at autism through a microscope, and now it's like looking at it in high definition," Andy Shih, vice president of scientific affairs for the advocacy group Autism Speaks, reported.

Now three separate studies, all published on Thursday in the journal Nature, have identified several gene mutations, many inherited from fathers, that may play a role.

"There's no one gene that causes autism," James Sutcliffe, co-author of one study and an associate professor of molecular physiology at Vanderbilt University stated.

"But what these studies do show is that several genetic mutations increase the risk of getting autism and different mutations may affect people in a different way."

The genes are likely inherited through the paternal line because as a man ages, his sperm cells are constantly dividing, which provides more opportunity for mutations to occur.

Women, on the other hand, are born with all of the egg cells they will have for life.

Each study found multitudes of mutated genes in autistic children but among the three, only two genes were found in more than one patient, suggesting to researchers that they may be the biggest risk factors.


"That is like throwing a dart at a dart board with 21,000 spots and hitting the same one twice," Dr. Matthew State, co-author of the second study and a professor of psychiatry at the Child Study Centre, Yale, told reporters. "The chances that this gene is related to autism risk are something like 99.9999 percent."


Some Opposition
Clearly, some researchers aren't considering this the breakthrough the study authors claim.

"This is a great beginning, and I'm impressed with the work, but we don't know the cause of these rare mutations, or even their levels in the general population," Aravinda Chakravarti, researcher at the John Hopkins Institute of Genetic Medicine, replied.

"I'm not saying it's not worth it to follow up these findings, but I am saying it's going to be a hard slog."

Approximately 15 percent of all autistic children will have some form of these genetic mutations, according to one of the studies but researchers said diagnosing autism by the gene mutations is still a long way off.

"The genes highlighted are clearly the most convincing susceptibility genes that have been identified so far, but they only explain a small picture of autism," Dr. Mark Daly, coauthor of Sutcliffe's study and chief of the Analytic and Translational Genetics Unit (ATGU) at Massachusetts General Hospital, reported.

Future research will focus on identifying other mutations that could play a role, researchers said.

Going Forward
"Now we have a real path forward," State said. "As you start to accumulate these individual genes that you know are related, that opens the door to understanding the biology. Once you know the gene, you can examine the protein it makes. Then, even in people who don't have the damaged gene, adding that protein may help because a deficit in that protein might result in their autism via a different pathway."

Autism: Researchers Continue to hunt for causes

For many families, the quest for the causes of autism has grown more urgent with the news that the estimated prevalence of autism grew by 23% from 2006 to 2008, according to a Centers for Disease Control and Prevention report out last week.

In most cases, however, scientists can't tell parents what caused their child's autism, says Thomas Insel, director of the National Institutes of Mental Health. In large part, the causes of autism — which is likely not one disease, but a group of conditions with related symptoms — remain a mystery.

For years, scientists had only a few clues about the condition, noticing that autism is about four times as common in boys as in girls, for example.

Recently, scientists have found a number of risk factors for autism, many of which point toward problems that develop very early in life, such as during pregnancy or delivery, or even during the process of creating eggs and sperm, says Craig Newschaffer, a professor at Philadelphia's Drexel University.

To better understand causes of autism, researchers at four major universities are following 1,200 mothers of autistic children through a project called the EARLI study, or the Early Autism Risk Longitudinal Investigation.

Because researchers know that these moms are at high risk of having a second autistic child, they closely follow the women's subsequent pregnancies, testing blood, urine, hair, even vacuuming dust from the women's homes, says Newschaffer, one of the study's lead researchers.

Researchers ask pregnant women to keep lists of any illnesses, since infections during pregnancy are suspected of playing a role in autism.

Doctors can confidently reassure parents that one thing doesn't cause autism — vaccines, says Paul Offit, chief of infectious diseases at Children's Hospital of Philadelphia. Nearly two dozen studies have failed to find a link between autism and vaccines, whether given alone or in combination.

Researchers have clues to other causes:

Genes. About 15% to 20% of autistic children have a genetic mutation that causes their disorder, Insel says. Certain genetic disorders, such as Fragile X syndrome and Rett syndrome, are well-known for increasing the risk of autism.

Even when genes are the main contributor to autism, however, it's possible that most children have a unique mutation or set of mutations, says David Amaral, research director of the University of California-Davis MIND Institute.

Family history. If parents have one child with autism, the risk of having a second child diagnosed with the disorder is nearly 20%, according to a landmark study from U.C.-Davis. Among those with two autistic children, the risk of having a third is 32%, study author Sally Ozonoff says.

Environmental pollution. One California study published last year found that babies whose mothers lived near a highway while pregnant were more likely to be diagnosed as autistic.

Older parents. Both older father and mothers are at higher risk of having autistic children, Newschaffer says. Research from Israel and the Harvard School of Public Health also suggests that infertility treatments, which are more often used among older patients, are linked to a higher risk of autism.

Prematurity and low birthweight. An October study in Pediatrics found that, among babies born weighing less than about 4½ pounds, 5% had been diagnosed as autistic by age 21.

Medications. Many studies now show that a seizure treatment called valproic acid can increase the risk of autism in children exposed before birth. A single study published last year found a higher risk among children exposed prenatally to antidepressants. Using prenatal vitamins is also linked to a lower risk of autism.

Closely spaced pregnancies. In a 2011 study, children who were born less than one year after an older sibling were three times as likely to be diagnosed with autism, compared with children born three years after their mom's last pregnancy.

Autism: Defective Genes May Explain Uncontrolled Brain Growth

As a baby grows inside the womb, its brain does not simply expand like a dehydrated sponge dropped in water.

Early brain development is an elaborate procession. Every minute some 250,000 neurons bloom, squirming past one another like so many schoolchildren rushing to their seats at the sound of the bell.

Each neuron grows a long root at one end and a crown of branches at the other, linking itself to fellow cells near and far.

By the end of the second trimester, neurons in the baby's brain have formed trillions of connections, many of which will not survive into adulthood—the least traveled paths will eventually wither.

Sometimes, the developing brain blunders, resulting in "neuro-developmental disorders," such as autism.

But exactly why or how early cellular mistakes cause autism has eluded medical science. Now, Eric Courchesne of the University of California, San Diego, thinks he has linked atypical gene activity to excessive growth in the autistic brain.

With the new data, he has started to trace a cascade of genetic and cellular changes that he thinks define autism.

Although intrigued by Courchesne's work, other researchers caution that explosive neural growth is not necessarily a defining feature of all autistic brains.

Since 1998 Courchesne has been searching autistic brains for unusual structural features.

His studies suggest that while in the womb, the autistic brain sprouts an excess of neurons and continues to balloon during the first five years of life, as all those extra neurons grow larger and form connections.

Sometime after age four or five, Courchesne has also found, autistic brains actually start to lose neural connections, faster than typical brains.

In a study published November 2011 in JAMA, The Journal of the American Medical Association, Courchesne reported that children with autism have 67 percent more neurons in their prefrontal cortex (PFC) than typical children.

Located in the area of the brain just behind the eyes, the PFC is responsible for what psychologists call "executive functions"—high-level thinking, such as planning ahead, inhibiting impulses and directing attention. In his 2011 study Courchesne sliced up brain tissue from six autistic children and seven typical children who had passed away and counted the number of cell bodies in the sections to estimate the total number of neurons in their PFCs.

Now, Courchesne and his colleagues have analyzed DNA and RNA in 33 cubes of brain tissue from people who passed away, 15 of whom were autistic (nine children and six adults) and 18 who had typical brains (seven children and 11 adults).

Looking at the order of DNA's building blocks reveals whether individual genes have mutations; measuring levels of RNA indicates how often those genes were translated into proteins.

Such gene expression, Courchesne and his colleagues found, varied between autistic and typical brains.

In brain tissue from both autistic children and autistic adults, genes coding for proteins that identify and repair mistakes in DNA were expressed at unusually low levels.

Additionally, all autistic brains demonstrated unusual activity levels for genes that determine when neurons grow and die and how newborn neurons migrate during early development.

Some genes involved in immune responses, cell-to-cell communication and tissue repair, however, were expressed at unusual levels in adult autistic brains, but not in autistic children's brains.

The results appear in the March 22 issue of PLoS Genetics.

You can also Read More of this article here at Scientific American: The Ballooning Brain