Dear Students!
Our next speaker on the 28th of February will be Donna Werling who will talk about: "Genetics of Autism"
You will need to read the paper "Advancing the understanding of autism disease mechanisms through genetics" by Torre-Ubieta et al!
Please post your comments not later than Tuesday afternoon!
Torre-Ubieta et al. review progress made in identifying genetic pathways and neurobiological mechanism implicated in ASD. They argue that autism spectrum disorders are heterogenous but related disorders that are united by similarities in their behavioral phenotypes. The genetic precursors to autistic phenotypes are diverse and extremely complex. Much of the success in these efforts has come from identifying de novo mutations associated with autistic phenotypes. However, the phenotypes associated with ASD are also highly heritable. Family and twin studies have shown that ASD phenotypes are significantly more likely to be shared by closer genetic relatives (e.g. identical twins) than fraternal twins. Furthermore, heritable gender differences have been found to affect how de novo mutations are expressed. The authors note that while the most successful efforts to understand genetic pathways have come from the identification of de novo mutations, efforts to understand the heritable genetic pathways should not be ignored.
ReplyDeleteThe authors review a range of neurobiological studies in humans and non-human animals that have identified common patterns between autistic phenotypes and altered cortical development in utero, patterns of synaptic dysfunction, RNA expression in certain brain areas, as well as altered neural circuitry. These studies have been relatively successful in accounting for some of the biological mechanisms that contribute to the expression of autistic-like phenotypes in both animals and humans. However, finding a way to link the complex pathways of genes that regulate some of these mechanisms to the phenotypes they are associated with has been more challenging. Continued research in this area will no doubt answer many of these questions.
An evidenced-based theoretical framework is needed to better understand autism spectrum disorder (ASD). Autism is explained diagnostically by behavior in social cognition, communication, and repetitive behaviors. As such, the primary treatment options are behavior-based, with only secondary behaviors treated pharmaceutically due to a limited knowledge with genetic components of ASD. It is known that ASD is highly heritable and influenced by susceptibility for de novo mutations with significant convergence of their pathways. Mouse models and stem-cell research have been used to study the pathogenesis of ASD and have contributed to the identification of variants and evidence on activity-dependent transcription and translation, synaptic dysfunction, dysregulation and neuroinflammation of neuron-glia, altered neural activity, and altered fetal cortical development. Pharmacotherapy in mouse models has been shown to be inconclusive, which highlights our current reduced understanding of social cognition. Model systems can continue to aid our understanding of neurobiological markers for ASD.
ReplyDeleteQuestion: There seems to be little mention of efficacy in mixing behavioral and pharmaceutical treatments for ASD. Is this because of the paper’s focus on genetics of ASD, or because of a reduced emphasis for behavioral treatments by geneticists?
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ReplyDeleteJessica Yoo
ReplyDeleteAdvancing the understanding of autism disease mechanisms through genetics (Torre-Ubieta, 2016)
The article aims to understand the complex genetic role in ASD and the need to employ the knowledge to build a better model for therapies. Current therapies include mainly behavioral treatment, while medicinal treatment seems to be limited. There have been studies that found possible genetic variants in the affected ASD patients. Few genetic models are presented with supports, which differ by their assumption of genetic risk factors by the number (amount) of variants. The current data shows that genetic risk holds an important contribution from de novo variation, from which we can create a treatment plan accordingly of the research direction. Further research for genetic pathways to ASD is much needed. With mouse models continuously being used for genetic research in ASD, latest research in human stem cell has been progressive to study the neurons in association with the development of ASD. However, the research field struggles to find clear merging pathways for phenotypes. Although there have been some successful treatments (such as oxytocin) in mice that lessen social dysfunction, discrepancy remains, and cannot yet expect analogous outcome for humans. It may be important to combine different models to perform more consistent experiments in depth to ultimately find appropriate therapy plan for ASD
Article
ReplyDeleteThis article provides a comprehensive study in trying to better diagnose ASD by better understanding its genetic etiology. It does so by defining ASD according to DSM-5 standards which involves social cognition and repetitive behaviors. ASD is more prevalent in males than females and usually carries other disorders such as epilepsy, various motor disorders etc with it. These disorders being a common symptom in other neuropsychiatric disorder as well creates an overlap and increases the difficulty of accurately diagnosing ASD. Treatment of ASD has been very successful through early behavioral intervention and use of pharmaceutical drugs have only been for very specific cases. The study of genetic variants using microarrays such as whole-exome sequencing (WES) and whole-genome sequencing (WGS) have revealed that de novo mutation is entirely possible in case of healthy parents and affected child. Mouse models have also proven to be quite successful and show similar behavioral patterns such as motor dysfunction, anxiety etc as exhibited in a human being.
This paper provides a broad overview of the genetic findings that are associated with autism spectrum disorder (ASD), characterized by social interaction and communication deficits as well as repetitive, restrictive behaviors (DSM-5). Although some de novo mutations have been linked to ASD, mounting evidence, including familial risk and heritability studies, supports a polygenic model, whereby many inherited variants in combination with environmental factors may contribute to ASD. Identification of these genetic variants is crucial to develop better therapies, and mouse models have been particularly useful for studying the molecular, cellular, circuit, and behavioral links to ASD. The complexity and causal diversity of this disorder are made apparent by this review article. Combining evidence from various fields—genetics, functional genomics, animal modeling, human treatments—into a unified, cohesive picture of ASD will be an incredible challenge, but one that seems necessary in order to improve targeted molecular therapies.
ReplyDeleteThis article reviews previous works describing the genetic and neurobiological mechanisms associated with autism spectrum disorder (ASD). The heterogeneity within both the clinical classification of ASD as well as associated genetic components contribute to the ambiguity in identifying specific underlying causal neuropathologies or genetic variants. Significant advances have been made in identifying de novo mutations, and genetic models such as polygenic and major gene models may provide a framework to further explain heritability and variation in expression of ASD characteristics. Additionally, studies using mouse and in vitro human models have revealed particular abnormalities that may contribute to the development of ASD. These abnormalities have led to altered cortical development, synaptic dysfunction, disruptions in activity-dependent transcription and translation, altered neural circuitry, and dysregulated neuron-glia signaling and neuroinflammation. Further interdisciplinary investigations may provide greater insight related to the underlying neurobiological mechanisms contributing to ASD and in turn lead to the development of novel and more efficient therapeutic interventions.
ReplyDeleteThe understanding of ASD will continue to be a complex issue. However, innovations are being made in the fields of genetics, genomics, animal studies, as well as humans to better understand causal relationships. The paper for this week provided a nice overview of the genetics behind ASD. The authors looked at several studies that tackle this issue by trying to gain a better understanding of the underlying neurobiological mechanisms. While reading, I began to think about our focus this semester. How does this apply to Neurodiversity? One of the biggest issues with the Neurodiversity arugment regarding ASD is how to treat the low functioning people within the group. This article shed light on the diversity of the etiologies in ASD. This group contains many genetic variants. As genetic studies continue to grow momentum for understanding neurodevelopment disorders, can the identification of genetic risk factors be used to create a distinction between what is actually disordered and what is purely diversity?
ReplyDeleteAdvancing the understanding of autism disease mechanisms through genetics
ReplyDeleteThe article showed an effort in progress of understanding the genetic etiology of autism spectrum disorders (ASD). With recent advanced technologies in genetics and genomics, the identification of mutations regarding to rare Mendelian conditions and in the etiology of more common, complex diseases. As genetic findings provide a flatform for , many genes contributing to ASD are identified. Based on studies of family and twins together with analyzing genetic variants using microarrays, whole exome/genome-sequencing showed that ASD is highly heritable. These genetic findings also confirm the relationship of molecular pathways with cellular and circuit dysfunction, and ultimately with behavior via the brain tests from subjects with ASD. Gender mechanism currently favors in male, as well as genetic models provide a route for identifying and testing the role of potential female protective factors, this leads to new therapeutic opportunities. Studies in animal models, in human cell, post mortem human brains, and genetic therapy for identifying deno vo and inherited variants help drive therapeutic innovations.
Questions: When we have many lens for looking at a thing (ASD), which lens are the most significant for a deep understanding and from it to find a good treatment?