DNA and the Environment: What Determines How Our Genes Work?
One of the hottest areas of research is the study of how the outside world – the air we breathe, the food and medications we consume, the experiences we have – affects the way our genes work.
Unfortunately, it's also an area of science that is easily misunderstood. Take the recent reports suggesting that astronaut Scott Kelly's genes were changed by space travel, so much so that he and his identical twin were no longer identical. The authors of those articles confused genetics – our DNA – with epigenetics – the chemicals and proteins that surround our DNA and influence their work, as The Washington Post noted. Kelly's DNA was not changed. But the experience of living in space for almost a year had altered his epigenetics.1
Of course, you do not need to leave Earth to experience changes to your epigenome. The epigenome describes the "chemical compounds and proteins that can attach to DNA"2 and, like a bossy sibling, tell it how to do its work. Understanding epigenetics is crucial to understanding autism. "Given that neurodevelopment is influenced by genetic and epigenetic factors, it is important to study both processes to fully understand the basis of autism and related disorders," said Silvia De Rubeis, PhD, assistant professor of psychiatry at the Seaver Autism Center for Research and Treatment in New York.
DNA is a major force in the development of autism in a child, but it is certainly not the only one. Consider research on identical twins, who have identical genes. Usually, if one identical twin has autism, the other twin does too.3-5 But not always. "Identical twins, who share the exact same DNA, don’t always both have autism, or have the same severity of autism. Two identical twins are known to be different in a number of illnesses and disorders," said psychologist Alycia Halladay, PhD, chief science officer at the Autism Science Foundation.
Epigenetic changes or environmental factors – such as twins' competing for nutrition in the womb or having different environmental exposures after birth – could help explain those differences. Scientists are only beginning to understand the complex interaction of our DNA, the environment, and epigenetics.
DNA and its Surroundings
An example of the power of epigenetics is the diversity of cell types in the human body.
What does epigenetics describe? First, let's start with DNA, the molecule that contains the entire instruction manual for making us who we are. DNA is made up of thousands of genes that contain the codes for making proteins, which in turn control cells. Your DNA lies along 23 pairs of chromosomes inherited from your biological parents.
The epigenome is like a conductor, directing when and where DNA instructions are read and messages are sent to cells throughout the body. Cells, in turn, follow these directions so that organs function properly. These chemicals can turn genes on when they are needed, and off when they are not.
One example of an epigenetic process is methylation. A group of atoms – one carbon and three hydrogen – function as a genetic light switch. These so-called methyl groups can attach to sections of DNA and turn off genes.
"Genes shouldn’t be turned on all the time, in every situation," explained Dr. Halladay. "The amazing human body already knows that. Some genes need to be kept off either temporarily or permanently. Some genes should be tightly regulated so that certain triggers turn them on and off."
"At crucial times in human development, including when the sperm and egg is formed, and also before the embryo attaches to develop into a fetus, these cells undergo massive changes in DNA methylation," she said. "This makes these times critical periods for methylation to turn on or turn off different genetic processes, and when the environment can have a major influence on cell development."
"An example of the power of epigenetics is the diversity of cell types in the human body," explained geneticist Jeremy Willsey, PhD, an assistant professor at the University of California San Francisco Weill Institute for Neurosciences. "All of these cells – heart cells, liver cells, skin cells – have the exact same DNA sequences, with a few exceptions, yet they are vastly different." These differences between cell types arise when certain genes are switched on or off at certain times.2
This system of controlling our genes is affected by both outside influences – the environment – as well as internal ones, our genes themselves.
The Prenatal Environment
For a fetus, the environment largely means its mother: what she eats and drinks, the quality of the air she breathes, her stress level, the drugs she takes, and the illnesses she experiences. Those environmental influences can affect the epigenetic machinery around genes.6
More than a decade ago, scientists showed how changes in the womb can dramatically affect a gene in mice. They experimented with mice that had a mutation of the Agouti gene; this genetic change turned their fur yellow and led to obesity and poor health. They fed methyl-rich food to these pregnant mice. The food changed the chemical environment (methylation) around their offspring's Agouti gene. As a result, most of their babies had brown fur and a normal weight.7, 8 The experiment did not change their DNA, just how the Agouti gene was expressed in their bodies.
It's easy to understand how environmental changes during pregnancy affect a fetus, but could those changes actually affect future generations, the way genes do? In other words, could something a grandmother experienced while pregnant with her child actually affect her grandbaby? Yes, according to other studies, involving mice.9-11 Usually these epigenetic changes are erased for the next generation but not always. Some changes to a mouse's epigenome could be passed to a future generation, along with the DNA to which it is attached.
Mice are Nice, but What about People?
The same can be true for people, at least "under some circumstances," according to the U.S. National Human Genome Research Institute.2 However, research into this is in the relatively early stages, especially as it relates to autism.
"We know that factors like diet – for example, starvation – influence epigenetic state. What is not clear is the relationship of these changes to autism risk," said Dr. Willsey, whose lab is involved in mapping gene pathways in autism and other conditions, as part of the Psychiatric Cell Map Initiative.
Controls from Within: Genes Directing Other Genes
While the environment can affect the epigenetic machinery, so can genes themselves. Our DNA contains instructions that control the way its code is read and processed by cells. Scientists have discovered mutations, or changes, in a large number of genes that regulate epigenetic processes in people with autism. They made these discoveries by examining the DNA of people in the Simons Simplex Collection (SSC) and other autism studies.12, 13
A key player in this process appears to be chromatin – the complex of DNA and proteins that makes up our chromosomes.14 "Many of the genes that have been implicated in autism are involved in the regulation of chromatin," Dr. Willsey said. "What this means is that they add or remove the chemical tags that influence the expression of nearby genes."
Given this information, he said, "it follows that epigenetic processes influence autism risk in some way." A mutation that affects chromatin could affect the expression of thousands of genes, which in turn could increase the risk of autism. "What is not clear is whether this risk is related to specific pathways being perturbed or just general 'unhappiness' of the cells," he said.
Looking Outside and Within
Could genetic mutations, along with environmental influences, work together to affect the way autism develops in a child?
Yes, suggested researchers involved in one autism study.15 Children with a genetic mutation linked to autism may have been more susceptible to infections their mothers experienced while pregnant with them, according to that study. Those children had more severe social communication problems and repetitive behaviors than other children with autism, who did not have those risk factors. However, this apparent interaction between genes and prenatal infections did not affect the children's learning and everyday living skills. That study involved children in the SSC project, who were the only members of their families with autism.
Although not familiar with that study, Dr. Willsey noted that, in general, many different prenatal conditions and events could be involved. It is difficult to sort out what factor is causing which effect, he said.
Genetic mutations and environmental influences involve different processes, he said, but either one could affect autism risk by changing a person's epigenome while his or her brain is developing.
Looking for Evidence of Epigenetic Changes in Autism
Researchers have found signs of epigenetic changes in autism. For example, when examining blood and brain tissue, scientists found areas with "different methyl tags" in people with autism, Dr. Halladay said. "That can explain why genes are turned on or turned off differently, leading to differences in gene expression and ultimately protein function, which affects brain development."
Dr. Halladay works with Autism BrainNet, which seeks postmortem brain donations for autism research. "Research has shown that what is seen in blood doesn’t always match what is in the brain, and that different brain cells have different epigenetic profiles. That’s why it’s so important to study the brain directly, and looking directly at epigenetic changes in brain tissue from autism patients is crucial," she said. By studying brain tissue, scientists discovered that those genes with different methyl tags in the brain's cortex affect the way cells talk to each other, among other things.16
Some scientists have begun using new ways of researching similar questions. They have the technology to generate nerve cells in a lab, using skin cells from a living person, for example, Dr. Willsey said.
Learning how the environment, epigenetics and genes interact to influence autism could answer many questions about how autism develops and why it looks different in each person, sometimes including identical twins.
- To learn more about Autism BrainNet, please visit TakesBrains.org.
- The U.S. National Human Genome Research Institute's fact sheet on epigenetics.
- For information on the Psychiatric Cell Map Initiative, please see its website and the University of California San Francisco (UCSF) release, Cell Mapping Initiatives Aim to Uncover Hidden Pathways of Disease.
- Learn more about genetics in IAN's article, Unraveling DNA: What Does This Mean for Autism?
- IAN's article on environmental factors in ASD: Researchers Look for Clues to Autism in the Environment
- For more details on methylation, see Genes, Environment, and the Causes of Autism: Why solving the methylation mystery is important by Christine Ladd Acosta, PhD, and Alycia Halladay, PhD.
Photo of Dr. Willsey reprinted with permission of UCSF. Other photos by iStock.
- Kaplan S. The truth about astronaut Scott Kelly's viral 'space genes'. The Washington Post. March 16 2018. Available from: https://www.washingtonpost.com/news/speaking-of-science/wp/2018/03/16/the-truth-about-astronaut-scott-kellys-viral-space-genes/?utm_term=.29818aa26bab. Accessed March 27, 2018.
- National Human Genome Research Institute. Epigenomics. https://www.genome.gov/27532724/epigenomics-fact-sheet/. Updated 2016. Accessed April 5, 2018.
- Rosenberg RE, Law JK, Yenokyan G, McGready J, Kaufmann WE, Law PA. Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch Pediatr Adolesc Med. 2009;163(10):907-914.
- Frazier TW, Thompson L, Youngstrom EA, et al. A twin study of heritable and shared environmental contributions to autism. J Autism Dev Disord. 2014;44(8):2013-2025.
- Hallmayer J, Cleveland S, Torres A, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68(11):1095-1102.
- Kanherkar RR, Bhatia-Dey N, Csoka AB. Epigenetics across the human lifespan. Frontiers in Cell and Developmental Biology. 2014;2:49.
- Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect. 2006;114(4):567-572.
- Waterland RA, Jirtle RL. Transposable elements: Targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23(15):5293-5300.
- Blewitt M, Whitelaw E. The use of mouse models to study epigenetics. Cold Spring Harb Perspect Biol. 2013;5(11):a017939.
- Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci. 2013;17:89.
- Ziv-Gal A, Wang W, Zhou C, Flaws JA. The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice. Toxicol Appl Pharmacol. 2015;284(3):354-362.
- Sanders SJ, He X, Willsey AJ, et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron. 2015;87(6):1215-1233.
- O'Roak BJ, Deriziotis P, Lee C, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43(6):585-589.
- Reece JB, Urry, L.A.,Cain, M.L., Wasserman SA, Minorsky PV, Jackson RB. Campbell biology. Vol 10th Edition. 10th ed. Boston: Pearson; 2014.
- Mazina V, Gerdts J, Trinh S, et al. Epigenetics of autism-related impairment: Copy number variation and maternal infection. J Dev Behav Pediatr. 2015;36(2):61-67.
- Nardone S, Sams DS, Zito A, Reuveni E, Elliott E. Dysregulation of cortical neuron DNA methylation profile in autism spectrum disorder. Cereb Cortex. 2017;27(12):5739-5754.