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Environmental Factor

Environmental Factor

Your Online Source for NIEHS News

October 2018

The RNA link between genes, air pollution, and autism

In an NIEHS talk, Daniel Campbell, Ph.D., suggested that long noncoding RNA may be the gene-environment link in autism risk.

Daniel Campbell, Ph.D., from Michigan State University, studies how the interplay of genetics and the environment contributes to the risk of autism spectrum disorder (ASD).

In a talk at NIEHS Sept. 5, Campbell described how specific gene variants, in the presence of air pollution, may elevate risk of ASD. Cindy Lawler, Ph.D., who leads the NIEHS Genes, Environment, and Health Branch, hosted the talk as part of the NIEHS Keystone Science Lecture Seminar Series.

“Scientists have known for a while that air pollution is associated with risk of developing ASD,” Campbell pointed out.

“There is also a robust body of work pointing to a role for genetics in ASD, but these should not be viewed as competing hypotheses,” Lawler said. “Dan’s work highlights gene-environment interaction and shows us some of the mechanisms involved.”

young boy sitting on floor with airplane toy next to him According to the CDC, one in 59 children will be diagnosed with autism in the U.S. Researchers suspect that the both genetic and environmental factors are involved. (Photo courtesy of Shutterstock)

Evidence that genes increase risk

Campbell speaks about gene-environment interactions Campbell is interested in how gene-environment interactions contribute to brain development in disorders like ASD. (Photo courtesy of Michael Garske)

Campbell’s story illustrates one of the ways that scientists build upon one another’s work. Back in 2009, a team from the Children’s Hospital of Philadelphia conducted an autism-related genome-wide association study to identify genetic variants associated with ASD.

Their data indicated that the area of the genome involved in ASD risk fell between two genes that were surprisingly far apart. The study’s authors suggested those two genes were to blame. Something seemed off to Campbell.

“I questioned the findings,” he said. “Because they were so far apart, I thought, ‘There has to be something in between’.”

An answer emerges

After years of research, Campbell and his team narrowed down the area of the genome associated with ASD risk to a gene called MSNP1AS.

The finding was unexpected, because this gene does not code for proteins. Instead, MSNP1AS codes for something called a long noncoding RNA (lncRNA, pronounced “link RNA”). LncRNA is transcribed from DNA in the normal fashion, but it is not translated into a protein.

Heacock joins the discussion about autism, genetics, and air pollution Michelle Heacock, Ph.D., left, program officer in the Division of Extramural Research and Training, joined the active discussion about autism, genetics, and air pollution. (Photo courtesy of Michael Garske)

Clues point to neurons

“Of all RNA, 38 percent of the time, they will get translated into proteins, but the rest of the time it’s an unknown,” Campbell said. “In the human brain, the majority — 62 percent — of all lncRNAs don’t code for protein, which means they likely have other functions and could be important for things like development.”

The lncRNA made from the MSNP1AS gene appears to be involved in neuron architecture. So he and his team altered human brain cells in the laboratory to increase their expression of lncRNA. They found that axons, dendrites, and other structures — called processes — that extended from these cells were shorter than usual, meaning something went wrong during development.

What is air pollution’s role?

portrait of Cindy Lawler Lawler manages autism-related grants in the Division of Extramural Research and Training. (Photo courtesy of Michael Garske)

To learn more about how environmental factors like air pollution interact with underlying genetics, Campbell exposed human brain cells to air pollutants. He observed increased expression of the lncRNAs, along with changes in neuron lengths. In a domino effect, this increased expression of lncRNAs led to decreased expression of a gene known as CHD8. That same gene is mutated in some patients with ASD.

“As it turns out, air pollution is just as bad as having a mutation that causes loss of function of the protein,” Campbell said.

Together, Campbell’s results sketch a model for how certain genetic and environmental factors combine to increase the risk for developing ASD. “Any of these factors — increase in air pollution, increase in certain lncRNAs, or a decrease in CHD8 — will lead to an increased risk of developing ASD, but the model starts with air pollution,” he said.

Citations:
Kerin T, Ramanathan A, Rivas K, Grepo N, Coetzee GA, Campbell DB. 2012. A noncoding RNA antisense to moesin at 5p14.1 in autism. Sci Transl Med 4(128):128ra40.

Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H. 2009. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459(7246):528−533.

(Sheena Scruggs, Ph.D., is the Digital Outreach Coordinator in the NIEHS Office of Communications and Public Liaison.)


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