Evan Dennis ’20 and Julia Rosander ’20
Imagine if your memory was so good, you could learn to speak a whole language fluently in a week. This is the case for Daniel Tammet, an extraordinary individual who can speak 11 languages, including Icelandic which he was challenged to learn in just seven days. Daniel is considered an autistic savant, and in addition to being exceptionally gifted with language and numbers, he suffers from Asperger Syndrome, a milder form of autism. In contrast to Daniel, some individuals who live with autism spectrum disorder (ASD) never develop any linguistic ability at all and must navigate the world unable to communicate verbally with those around them. How can two people with such drastically different abilities possibly be diagnosed with the same condition? Autism is a spectrum disorder, meaning the types and severity of symptoms experienced vary widely. While some people on the autism spectrum lead largely normal lives with only slight social deficits, others have severe social and behavioral disabilities and require constant supervision. In instances of the later, ASD presents significant challenges in the lives of those affected as well as their families. But such diversity of symptoms is just one aspect of autism that makes it so mysterious. The genetic and environmental factors that lead to autism remain elusive and hundreds of genes have been linked to the disorder, though the exact genes affected vary widely from case to case1.
Autism Spectrum Disorder is categorized as a neurodevelopmental disorder characterized by repetitive behaviors and social deficits such as reduced eye contact, restricted interests or hobbies, and the inability to control emotions. ASD affects people from a variety of backgrounds and does not discriminate. In that autism is a spectrum disorder, children and patients can have a variety of deficits with differing severities. The prevalence rate in males is two to three times higher than in females2. Most children are diagnosed with Autism Spectrum Disorder around the age of three when social interaction can be identified. Diagnosis usually occurs through consultation with professionals and specific screening tools that assess language and cognitive abilities.
A single underlying cause of Autism Spectrum Disorder has yet to be identified. However, deficits in multiple physiological pathways have been correlated with diagnoses. In the past two decades, the diagnosis of ASD has increased dramatically with little understanding as to why. A popular misconception is that vaccinations may cause ASD, but this is a completely untrue claim originating from a single faulty research article that was discredited later on3. Genetic risk factors for autism are a common area of research due to the ease of hypothesis testing regarding the abnormal expression of specific genes.. Of particular interest is the influence of the environment on gene expression and how these changes can affect genetic pathways related to autism. However, to understand the nuances of this interaction, we must briefly discuss DNA structure and the relatively new field of epigenetics.
Think of your DNA as an old-fashioned road map, giving each cell in your body directions on how to do its job. A gene is like a route on your map that tells molecules in your cells how to make a specific protein. Just like a road map, your DNA can be neatly compacted to save space. Often, it is not necessary to look at every section of a road map at once. In fact, if you were to completely unfold it, your map would be far too large and unwieldy to be of much use (Figure 1A). Instead, it is much easier to keep most of the map folded while you look only at the area you need to get you where you are going (Figure 1B). The same goes for your DNA: not every cell needs to read every part of your DNA and many parts of your DNA remain neatly folded to make things more orderly.
Sometimes, however, the environment may prompt the cell to change the way it folds its molecular road map. Epigenetics is the study of how these alterations lead to changes in the way a cell does its job. While the directions on the map itself remain the same, the regions that the cell can read are altered due to epigenetic marks. For example, to save space in a cell, your DNA is tightly wrapped around proteins called histones. You can think of histones as paper clips that keep the folded regions of your map bound tight so that they don’t expand and get in the way.
Perhaps you want to mark certain areas of the map that you are particularly interested in or that you want to avoid. For example, if a road is under construction, you might stick a pin in your map to tell you that the road is closed. In fact, when you see the pin you may decide to fold up that section of the map and add a paper clip (histone) if there are no other roads in that area you are interested in taking. Alternatively, you might also stick a pin in the map near a route that you want to take because it is especially scenic. The same goes for DNA! Instead of pins, there are molecular marks called methyl groups on DNA and histones that inform the cell what areas it should access and what to avoid. For a more detailed explanation of methyl groups, histones, and other molecular marks, feel free to check out the first episode of Neuroepic entitled “Introduction to Neuropigenetics: An Interview with David Sweatt”.
So how does the field of epigenetics relate to autism? Epigenetic mechanisms are crucial for providing cells with an accurate road map that gives them direction to mature into their specific cell type. Specifically, research has suggested that epigenetic regulation of the genetic pathways involved in neurodevelopment and inflammation plays a role in the development of ASD.
The wide variation in severity and symptoms of autism may not be surprising given that proper neurodevelopment is a complex task that is influenced by many different cellular processes. These processes determine how neurons communicate with one another and decide how to arrange or pattern themselves within the growing brain. If environmental factors cause the addition of pins in the molecular road map of these processes, abnormal protein levels and deficits in brain function may result. Autism is correlated with several of these epigenetic modifications that change the expression levels of genes that guide the cell down the road for correct neurodevelopment. It should be noted that correlation simply means that there is a relationship between two variables and does not necessarily suggest that change in one variable is causing the change in the other. Still, observation of these relationships have led scientists to identify many genes potentially linked to ASD and investigation of epigenetic modifications in autism is an active area of research.
For example, prenatal exposure to the anti-epileptic medication valproic acid (VPA) is an environmental factor that is known to increase the risk of autism. When a pregnant woman takes VPA, it can throw up roadblocks in the directions for brain development in the fetus. Scientists can study autism by injecting pregnant rats with VPA to create an animal model of ASD in the offspring. One study using this model to investigate sleep disturbances in autism reported that prenatal exposure to VPA led to decreased levels of a protein called GAD1 used to make the neurotransmitter GABA4. Neurotransmitters are the chemical messengers cells use to communicate with each other. GABA is particularly important because it prevents the brain from being overactive, prompting cells to quiet down and not talk to each other so often. It is well documented that autistic individuals can have decreased GAD1 levels in certain parts of their brain, but you may be wondering how exactly this decrease occurs.
When a cell reads your genetic roadmap, there are molecules that act as navigators that recognize methyl groups and tell the cell not to take a certain route. One of these navigators, known as MeCP2, is essential for proper neural development. At the beginning of a gene in your DNA, there is an area called the promoter region that is like a loading ramp that lets you get on the highway of that gene. When methyl groups (or pins) are added at these areas, navigators like MeCP2 bind to the promoter and block protein from being made from that gene. One experimental study showed that in autistic individuals, there are more of a specific type of methyl group at the promoter region of the GAD1 gene5. This causes MeCP2 to bind to the promoter region and block the loading ramp more often, potentially leading to the decreased GAD1 protein levels seen in the brains of autistic individuals. Mutations in the MeCP2 gene are actually the cause of another related neurodevelopmental disorder called Rett’s syndrome. For more details on the epigenetics of Rett syndrome, listen to episode 20 of Neuroepic: “Navigating Rett Syndrome”.
Another possible cause of Autism Spectrum Disorder is dysfunction of the immune system leading to excessive inflammation. The immune system is composed of complex structures and processes that defend against harmful pathogens and bacteria. Usually, our immune system serves to protect us, but dysfunction of the immune system can be detrimental to the body and is the cause of a variety of disorders. Just like in neurodevelopment, environmental factors can alter the genetic roadmap and affect the levels of proteins involved in correct immune response, increasing the risk for dangerous levels of inflammation.
One protein that plays an important role in immune response is known as ROR-ɑ. One interesting report by Nguyen et al. studied differences in methylation levels between autistic individuals and their non-autistic, identical twins6. Twin studies are valuable to epigenetic research because identical, or monozygotic, twins have the same genetic road map with the same directions. However, despite having the same underlying map, the pins and folds in these maps can differ, leading to distinct characteristics of two otherwise identical individuals. This study found that the route of the ROR-ɑ gene in individuals with ASD had more pins, or methyl groups than that of their identical, non-autistic siblings6. Additionally, ROR-ɑ protein levels were found to be decreased in the cerebellum and cortex of autism patients, making it potential candidate gene for causation6. This epigenetic regulation of a major contributing gene to immune response and inflammation demonstrates how immune dysfunction may be involved in ASD.
So these studies show how ROR-ɑ is epigenetically affected on a cellular level, but you may be wondering what role the environment plays in ROR-ɑ expression. ROR-a levels are naturally impacted by the male and female sex hormones testosterone and estrogen. Testosterone acts to decrease the levels of ROR-ɑ while estrogen does the opposite and increases ROR-ɑ7. This has led to speculation that environmental pollutants called Endocrine Disruptor Chemicals (EDCs) can interfere with normal hormone levels and be a potential risk factor for ASD through their effects on RORA, though more research needs to be done on this topic7. You may have heard of an EDC called BPA that can be found in plastic water bottles. For more information on the epigenetics of BPA, tune in to Neuroepic episode 14 entitled “BPA: Not A-gouti Thing for You”.
While these studies begin to scratch at the surface of just how the environment may impact autism, Autism Spectrum Disorder remains somewhat shrouded in mystery. Through epigenetic modifications, the environment can shape our genome and with so many potential pathways of causation, it is important to consider the role epigenetics plays in the development of ASD. Notably, neurodevelopmental and immune system/inflammation pathways are epigenetically regulated in autistic individuals, affecting expression levels of critical proteins needed for proper brain function. However, more and more is being learned about epigenetics each day, revealing new insights into how the environment makes us who we are. Therefore, it is critical to continue to explore this environment/DNA interaction in autism and related neurodevelopmental disorders in order to reach a more complete understanding and better our treatment of individuals living with these conditions.
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- Baio J, Wiggins L, Christensen DL, et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ 2018;67(No. SS-6):1–23. DOI: http://dx.doi.org/10.15585/mmwr.ss6706a1
- Gerber, Jeffrey S., and Paul A. Offit. “Vaccines and Autism: A Tale of Shifting Hypotheses.” Clinical Infectious Diseases, vol. 48, no. 4, 2009, pp. 456–461., doi:10.1086/596476.
- Cusmano, Danielle M., and Jessica A. Mong. “In UteroExposure to Valproic Acid Changes Sleep in Juvenile Rats: A Model for Sleep Disturbances in Autism.” Sleep, vol. 37, no. 9, 2014, pp. 1489–1499., doi:10.5665/sleep.3998.
- Zhubi, A, et al. “Increased Binding of MeCP2 to the GAD1 and RELN Promoters May Be Mediated by an Enrichment of 5-HmC in Autism Spectrum Disorder (ASD) Cerebellum.” Translational Psychiatry, vol. 4, no. 1, 2014, doi:10.1038/tp.2013.123.
- Nguyen, Anhthu, et al. “Global Methylation Profiling of Lymphoblastoid Cell Lines Reveals Epigenetic Contributions to Autism Spectrum Disorders and a Novel Autism Candidate Gene, RORA , Whose Protein Product Is Reduced in Autistic Brain.” The FASEB Journal, vol. 24, no. 8, 2010, pp. 3036–3051., doi:10.1096/fj.10-154484.
- Hu, Valerie W. “Is Retinoic Acid-Related Orphan Receptor-Alpha (RORA) a Target for Gene–Environment Interactions Contributing to Autism?” NeuroToxicology, vol. 33, no. 6, 2012, pp. 1434–1435., doi:10.1016/j.neuro.2012.07.009.
- Nagarajan, Raman, et al. “Reduced MeCP2 Expression Is Frequent in Autism Frontal Cortex and Correlates with Aberrant MECP2 Promoter Methylation.” Epigenetics, vol. 1, no. 4, 2006, pp. 172–182., doi:10.4161/epi.1.4.3514.
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