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Autism research news and opinion 20 January 2015 – 27 January 2015 For the latest news, visit SFARI.org on the Web Tweak to molecular scissors cuts path to turn on genes Jessica Wright 26 January 2015 A new technique allows scientists to turn on the expression of any gene, giving them the unprecedented ability to explore the function of every gene in the human genome. “You can now look at every gene in the genome and turn it on or turn it off and see whether or not it plays a role in a given disease or biological process,” says lead researcher Feng Zhang, assistant professor of brain and cognitive sciences at the Massachusetts Institute of Technology. Julia Yellow Gene editor: A revolutionary technique, CRISPR, allows researchers to mutate or delete genes; the new method allows them to activate genes. The technique, described 10 December in Nature, is a modified version of a method called CRISPR. Two years ago, CRISPR wowed researchers by allowing them to ‘edit’ — delete or insert mutations into — any gene they wanted. Like CRISPR, the new method gives researchers an invaluable tool to study autism-linked genes. For example, researchers could activate genes, one at a time or simultaneously, in large duplications and deletions of DNA linked to autism, says Michael Talkowski, assistant professor of neurology at Harvard Medical School. “For a long time we have been continuously coming up with methods to knock down gene expression, but there have not been really good, reliable methods to activate gene expression,” he says. “The uses of this technology are just innumerable.” The technique is restricted to cultured cells, including neurons made from stem cells of people with autism, but researchers are trying to adapt it for use in animal models and, potentially, people. Autism-linked mutations typically affect only one of two gene copies, and the new method may allow researchers to boost activity of the ‘healthy’ gene to normal levels, says Guoping Feng, professor of brain and cognitive sciences at the Massachusetts Institute of Technology, who was not involved in the new study. “It will be potentially therapeutic.” Scissor switch: CRISPR works by allowing researchers to place an enzyme called CRISPR-CAS9, which has a scissorlike domain, anywhere in the genome they choose. The new technique replaces the scissors with ‘activators’ that act as landing strips for the cellular machinery that triggers gene expression. The study is not the first to harness this approach, but earlier efforts to link activators to CRISPR-CAS9 worked only some of the time. In a study published last year, Zhang and his team analyzed the structure of CRISPR-CAS9 when bound to DNA and found that the bulky complex may sit between the activators and DNA2. In the new study, they instead placed the activators on the small, synthetic RNA molecules that guide CRISPR-CAS9 to specific points in the DNA. They also used multiple activators instead of a single one. The new method works every time, and the researchers were able to use it to boost the expression of 12 genes that could not efficiently be activated by previous methods. The researchers created an open-access library of guide RNAs that turn on every gene in the human genome. As a proof of concept, they used the library to activate each of the 20,000 human genes in skin cancer cells. This revealed genes that confer resistance to certain forms of chemotherapy. The same process could reveal genes that have compensatory effects in autism, Zhang says. “The new method provides a way to discover genes that, if they are turned on, provide an advantage.” Tricky tether: Studying the structure of the gene-editing complex when bound to DNA allowed the researchers to boost the technique’s efficiency. In another study, posted 20 December on the biology preprint server bioRxiv, researchers used multiple activators bound to CRISPR to turn on two developmental genes in induced pluripotent stem cells. This allowed them to consistently transform the cells into neurons in just four days, besting the efficiency of the standard technique. Both techniques lead to higher levels of gene expression than can be achieved with standard methods, says George Church, professor of genetics at Harvard Medical School and lead researcher on the stem cell study. This is crucial for screening large numbers of genes and finding their links to conditions such as autism, he says. “In practice, you’re going to want to get as high activation as possible.” Before the technique can be applied to animals, researchers need to control the expression levels of the activated genes and target specific organs, such as the brain. “That’s the ultimate goal,” says Zhang. “We’re working on it, because I really would like to be able to use this system to study the brain. Hopefully, other people will help out, too, to make it quicker.” News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation. References: 1: Konermann S. et al. Nature Epub ahead of print (2014) PubMed 2: Nishimasu H. et al. Cell 156, 935-949 (2014) PubMed Small snippets of genes may have big effects in autism Kate Yandell 22 January 2015 Small pieces of DNA within genes, dubbed ‘microexons,’ are abnormally regulated in people with autism, suggests a study of postmortem brains published 18 December in Cell1. These sequences, some as short as three nucleotides, moderate interactions between key proteins during development. “The fact that we see frequent misregulation in autism is telling us that these microexons likely play an important role in the development of the disorder,” says lead researcher Benjamin Blencowe, professor of molecular genetics at the University of Toronto. Network analysis: Many genes containing abnormally regulated microexons are linked to autism (red). Genes are made up of DNA sequences called exons, separated by swaths of noncoding DNA. These exons are mixed and matched to form different versions of a protein. This process, called alternative splicing, is thought to be abnormal in autism. Many sequencing studies tend to skip over microexons because they are not recorded in reference sequences. Although researchers have known about microexons for decades, they were unsure whether the small segments had any widespread purpose. The new study confirms microexons’ importance, suggesting that these tiny sequences can have big effects on brain development. “It’s really a new landscape of regulation that’s associated with a disorder,” says Blencowe. “We have a big challenge ahead of us to start dissecting the function of these microexons in more detail.” Blencowe and his team developed a tool that flags short segments of RNA flanked by sequences that signal splice sites. They used the tool to identify microexons in RNA sequences from various cell types and species throughout development. In the brain, microexons are highly conserved across people, mice, frogs, zebrafish and other vertebrates. Alternatively spliced microexons are more likely to be present in neurons than in other cell types, suggesting that they have an important, evolutionarily conserved role in neurons. Irregular splicing: The researchers analyzed patterns of microexon splicing in the postmortem brains of 12 people with autism and 12 controls between 15 and 60 years of age. Nearly one-third of alternatively spliced microexons are present at abnormal levels in autism brains compared with control brains, they found. By contrast, only 5 percent of exons longer than 27 nucleotides are differentially spliced in autism brains. Genes with microexons that are misregulated in autism tend to be involved in the formation of neurons and the function of synapses — the junctions between neurons. Both of these processes are implicated in autism. Microexons are particularly likely to be misregulated in autism-linked genes, such as SHANK2 and ANK2. What’s more, the expression of a gene called nSR100, which regulates splicing of microexons, is lower in the brains of people with autism than in those of controls. One future goal is to determine the biology underlying these differences, says Daniel Geschwind, director of the University of California, Los Angeles Center for Autism Research and Treatment. nSR100 belongs to a module of genes that includes transcription factors — which regulate the expression of other genes — and those that modify chromatin, which helps package DNA into the nucleus. Many of these genes have known links to autism. Related content: Method predicts impact of DNA variants on gene expression Genetics: Splicing gene alters expression of autism genes Online tool can predict effects of genetic variants New resource catalogs RNA-binding sites of many proteins To look at microexon splicing throughout development, Blencowe and his team sequenced RNA from mouse embryonic stem cells as they differentiated into neurons. Microexon levels tend to spike after the cells finish dividing, hinting at a role in the late stages of neuronal maturation. Studying microexon regulation at various stages of normal development in people is another logical next step, says Lilia Iakoucheva, assistant professor of psychiatry at the University of California, San Diego, who was not involved in the study. “Then, of course, we can study gene expression in autism brains and then talk about what’s regulated correctly and what’s misregulated.” As a complement to the postmortem data, the researchers could also look at how microexons are regulated in developing neurons derived from people with autism, says Chaolin Zhang, assistant professor of systems biology at Columbia University in New York, who was not involved in the study. “We should not underestimate the potential of more detailed characterization of these splicing variants,” he says. “They really expand the genome and [its] complexity in an exponential way.” Yang Li, a postdoctoral fellow at Stanford University in California also applauds the attention to the microexons. “There’s still not enough recognition that different [forms of proteins] can have very different functions,” he says. “This is especially true in the brain.” In an independent study published in December in Genome Research, Li and his colleagues reported that microexons in the brain tend to encode amino acids in locations that are likely to affect protein- protein interactions2. They also found that the autism-linked RBFOX gene family regulates microexon splicing in the brain. “I definitely think that microexons are important because of how conserved they are in terms of brain function,” says Li. “But I don’t know if they cause autism.” News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation. References: 1. Irimia M. et al. Cell 159, 1511-1523 (2014) PubMed 2. Li Y.I. et al. Genome Res. 25, 1-13 (2015) PubMed Method charts lifetime expression of DNA in brain Kate Yandell 21 January 2015 A new database that maps changes in gene expression in the prefrontal cortex shows that autism-linked genes are expressed differently than other genes through six stages of life. The results were published 15 December in Nature Neuroscience1. Most studies that measure gene expression rely on lists of genes and their protein-coding subunits, called exons. As a result, they miss sequences not on those lists. The new study takes advantage of a method called ‘derfinder’ that identifies clusters of adjacent DNA base pairs, called differentially expressed regions (DERs), that change in concert2. This captures changes in gene expression in regions of the genome that are not yet fully understood. Christos Georghiou/Shutterstock.com Cortex clock: Gene expression in the prefrontal cortex, a brain region implicated in autism, shifts dramatically from fetal development to old age. The researchers tested the method in the prefrontal cortex — a brain region implicated in several developmental and degenerative disorders, including autism. They studied a total of 72 samples from the postmortem brains of fetuses, infants, children, teenagers, adults and older adults. The method identified 50,650 DERs in the prefrontal cortex that are associated with progression through the six life stages. Roughly 41 percent of these DERs reside in introns — DNA segments that are edited out before genes are translated into proteins. Another 8 percent lie in the genetic material between genes. The researchers hypothesize that some of these DERs code for subunits of proteins that were never noted in gene and exon maps, whereas others may code for regulatory RNAs. The researchers investigated whether changes in gene expression over different life stages correlate with shifts in the brain, such as an increase in the proportion of support cells called glia. Instead, they found that the changes reflect developmental changes within neurons as they mature. The researchers used the method to analyze preexisting gene expression data and found that DERs are conserved across multiple brain regions. Humans and mice also express similar DERs in fetal versus adult brain tissue. Genes linked to neurodegenerative diseases tend to include DERs expressed late in life, whereas those implicated in neurodevelopmental disorders contain more DERs in the fetal prefrontal cortex. DERs are overrepresented in autism-linked genes, suggesting that the expression of these genes changes at key times in early development. The database is freely available on the University of California, Santa Cruz Genome Browser, and derfinder is available for download on Bioconductor. Researchers can surf the dataset for genetic regions of interest or apply the tool to their own samples. News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation. References: 1. Jaffe A.E. et al. Nat. Neurosci. 18, 154-161 (2014) PubMed 2. Frazee A.C. et al. Biostatistics 15, 413-426 (2014) PubMed Researchers urge caution in studies of mice and microbes Sarah DeWeerdt 20 January 2015 Over the past several years, researchers have begun to investigate links between the trillions of bacteria that inhabit our digestive tract and autism. These studies reflect the undeniable presence of gastrointestinal symptoms in autism, as well as a growing appreciation for the so-called microbiome and its role in overall health. HerPhotographer/flickr A new review raises caution, however, about using mice to model the human microbiome. Published in this month’s issue of Disease Models & Mechanisms, it serves as an important reminder for autism researchers to interpret such studies with skepticism. One reason for this caution comes down to anatomy. Compared with people, mice have a proportionally larger large intestine and cecum — the pouch at the beginning of the large intestine where bacteria ferment undigestible plant material. These differences reflect different diets: Although mice, like humans, are omnivores, they eat a greater proportion of plants. The two organisms also have different distributions of goblet cells and Paneth cells in the gut wall. These cells help to coordinate immune responses in the gut and so are likely to influence the composition of the microbial community. The types of resident bacteria also vary between people and mice. Both microbiomes are dominated by two major bacterial groups: bacteroidetes and firmicutes. But their precise composition is difficult to compare because researchers have usually used different methods to study them. There are at least 79 subgroups, or genera, of bacteria that exist in both mice and people. However, the relative abundance of genera may differ between the two. For example, Prevotella appears to be abundant in the human gut but rare in the mouse; the opposite is true of Lactobacillus. Despite these differences, mouse models have helped to uncover the interrelationships between diet, the microbiome and obesity in people. Dietary manipulations in mice produce microbiome changes similar to those seen in people, for example. On the other hand, researchers have struggled to create mouse models of inflammatory bowel disease that accurately reflect the human condition. Some microbiome changes are similar between the two organisms but others are puzzlingly inconsistent. For example, a bacterium called Akkermansia is scarce in people with inflammatory bowel disease but more abundant than normal in one mouse model of the disease. No research tool is perfect, and the idea that mice do not always accurately model a human condition is hardly news to autism researchers. After all, the field continues to debate which mouse behaviors best correspond to the social and communication deficits seen in autism. Some researchers go so far as to question whether it’s even possible to model autism in an animal that strays so significantly from people in terms of social behavior and cognition. Still, I think there’s great potential for mouse microbiome studies of autism because there are so many mouse models of the disorder. Researchers could compare the microbiomes of different mouse models to look for subsets that have similar changes. They could also manipulate the mouse microbiome to tease out the relationships between gut bacteria, gastrointestinal symptoms and autism traits — even if this practice only provides clues about those relationships in people. Related content: Clinical research: Gut bacteria prevalent in autism Studies implicate gut bacteria in autism Cognition and behavior: Epilepsy drug alters rodent gut Study finds no link between autism and gut microbes Finally, researchers could test whether drugs being developed for specific forms of autism affect the microbiome and whether such changes are key to a drug’s effectiveness. An imperfect model can nevertheless be a perfect opportunity. News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation. Toddlers with autism show few symptoms during brief exams Nicholette Zeliadt 23 January 2015 Many children with autism show early signs of the disorder, such as lack of eye contact and repetitive behaviors. A pediatrician’s ability to spot these subtle signs during a routine exam opens the door to early intervention. But many toddlers with autism display so few abnormal behaviors during brief exams that they evade the diagnostic eye of even expert clinicians, according to a study published 12 January in Pediatrics. This suggests that behavioral observation alone is not enough for doctors to detect the disorder in young children. The researchers recorded two 10-minute videos for each of 42 children as they underwent thorough diagnostic exams for autism. The study included 14 children with autism, 14 children with language delay and 14 controls, all between 15 and 33 months of age. Monkey Business Images/Shutterstock.com Two autism experts, both of whom were unaware of the children’s diagnoses, reviewed the videos. They measured the number of times each child performed certain behaviors, such as playing with toys, making sounds or responding to their name being called, and rated each behavior as ‘typical’ or ‘atypical.’ They then decided whether each child’s overall behavior warranted a referral for an autism evaluation. Based on these observations, the autism experts incorrectly flagged 39 percent of the children with autism as not needing further evaluation. That may be because they thought these children showed typical behavior 89 percent of the time. In other words, the atypical behaviors occur so seldom that they are overshadowed by typical ones, the researchers suggest. This doesn’t necessarily mean that pediatricians and family physicians are missing children with autism, as mainstream news reports suggested last week. Beyond making behavioral observations, doctors typically consider a child’s family history, the results of autism screening tests and parental reports of symptoms displayed outside the doctor’s office. The findings highlight just how difficult it can be to diagnose autism based on behavior. When rating typical behaviors, the experts in the study agreed 97 percent of the time, but this fell to 35 percent for atypical behaviors. If anything, the study underscores the need for more objective measures of autism symptoms. News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation. Webinar: The female autism conundrum Greg Boustead 20 January 2015 Due to the winter weather emergency affecting the northeastern U.S. this week and its potential effect on operational resources at the Simons Foundation, we are unfortunately forced to reschedule the webinar on 28 January featuring David Skuse and William Mandy. We apologize for the inconvenience. We will announce a new date for the webinar soon. If you've already registered for the session, you will be sent new log-in details automatically once the new date is confirmed. David Skuse; William Mandy. The webinar will feature David Skuse, professor of behavioral and brain sciences at University College London, and his colleague William Mandy, senior lecturer of clinical psychology. Skuse and Mandy are interested in exploring and refining the current conventional definitions of autism — specifically how it manifests itself in girls. They argue that the apparent gender gap often reported in autism is overblown due to fundamental flaws in the way autism is diagnosed. During this webinar, they will present evidence to support the notion that the tools available for diagnosing girls with autism show an inherent gender bias. They will also share interviews with a former patient to provide specific examples of the ideas they discuss. Here’s how the presenters describe the session: For many years, our conceptualization of autism was based on a male stereotype. There was a widespread consensus that the sex ratio was at least 4-to-1, males predominating, and epidemiological evidence appeared to support that assumption. An influential theory of autism susceptibility — that it represents an ‘extreme male brain’ — has subsequently been promulgated with great success. This 4-to-1 ratio is not consistent across the full range of intelligence quotients (IQ), however, which makes the observation hard to understand in terms of genetic susceptibility. No evidence for X-linked susceptibility has been proven. Females with autism and high IQ are rarely clinically identified, yet in those with the lowest intellectual functioning, the sex ratio is no more than 2-to-1. One possible explanation is that our current ascertainment methods for autism are biased toward males. A corollary of this biased ascertainment hypothesis is that so-called ‘high-functioning’ females with autism are harder to diagnose. In this webinar, we will discuss the reasons for this bias. There are three significant factors. First, our standardized measures of autism are derived from historical conventions based on the stereotypical symptom profile of boys. Second, boys with autism tend to have co-occurring symptoms and conditions that prompt clinical attention (including attention deficit hyperactivity disorder and disruptive behavior). Girls with autism, on the other hand, tend to have more subtle related symptoms (such as social withdrawal, depression and anxiety), so their underlying social communication problems are often overlooked. Third, there is increasing evidence that females with autism show a greater capacity to ‘mask’ or compensate for their difficulties, and this leads to the development of compensatory behaviors in those who are intellectually able. During the session, we will present empirical evidence to support these hypotheses and describe the female phenotype. Press policy: The SFARI Webinar Series aims to facilitate the free exchange of ideas among autism researchers, including discussion of published and unpublished research, hypotheses and results. Members of the press may report information presented during a SFARI webinar only if that material has already been published elsewhere or they have first obtained express written consent from the presenter. Like us on Facebook » | Follow us on Twitter @SFARIorg » | Join our newsletter » News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation. Lecture: One brain, many genomes Due to the winter weather emergency affecting the northeastern U.S. this week and its potential effect on operational resources at the Simons Foundation, we are unfortunately forced to reschedule the lecture on 28 January featuring Christopher Walsh. We apologize for the inconvenience. We will announce a new date for the lecture soon. About the lecture: Christopher Walsh and his team are interested in genetic mechanisms underlying the development of the cerebral cortex and abnormalities in this development resulting in intellectual disability, autism and epilepsy. The lab pioneered the analysis of recessive causes of autism by studying children with autism whose parents share ancestry. Walsh will review recent work on ‘somatic mutations’ — de novo mutations that are present in only some brain cells but not in all cells of the body — in several neurological conditions associated with intellectual disability and seizures. His talk will cover the extent to which somatic mutations are an inevitable part of normal brain development, such that the neurons in the human brain are a tapestry of cells with distinct genomes. He will briefly discuss the possible relevance of somatic mutations to autism. About the speaker: Christopher A. Walsh is chief of the genetics and genomics division at Boston Children's Hospital, Bullard Professor of Pediatrics and Neurology at Harvard Medical School, and an investigator at the Howard Hughes Medical Institute. He completed his M.D. and Ph.D. at the University of Chicago, trained in neurology at Massachusetts General Hospital and has worked at Boston Children’s Hospital since 2006.