November 8, 2016

Cornell Researchers Confirm Genetic Link to Autism

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The Centers for Disease Control and Prevention estimates that one in 68 children have Autism Spectrum Disorder (ASD). Yet, despite extensive research, the reason for the disorder’s development remains unclear. But that could soon change, thanks to research conducted by Yiqin Wang grad and Prof. Zhenglong Gu, nutritional sciences.

The duo studied the link between certain states of mitochondrial DNA (mtDNA) and ASD. mtDNA, unlike nuclear DNA, is inherited from the mother and while there are over three billion base pairs of nuclear DNA, there are about 16,500 base pairs of mtDNA. The difference has meant that research in genetics and pathology has primarily been focused on nuclear DNA.

“The research of mtDNA is falling behind that of nuclear DNA in many diseases,” Gu said. “One of the major reasons is that we lack the tool for accurately manipulating mtDNA in cells, which largely limits our understanding of the downstream consequences of mtDNA mutations.”

Published in PLOS Genetics’ october edition, the study, ‘Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder,’ analyzed DNA in 903 families. The DNA of a child diagnosed with ASD, their mother and an unaffected sibling was compared, with researchers focusing on identifying heteroplasmies: a state in which different copies of mtDNA coexist in a cell.

“Heteroplasmy is a unique feature of mtDNA. Different from nuclear DNA, which only has two copies in human cells, a cell can have hundreds, even thousands of copies of mtDNA. Both mutant mtDNA molecules and wild-type mtDNA molecules can coexist in a single cell. That state is called a heteroplasmy,” Wang said.

The group was then able to identify pathogenic, or disease-related, heteroplasmies. Specifically, they uncovered that children affected by ASD had twice as many harmful mtDNA mutations. According to Gu and Wang, this crucial connection between mtDNA and ASD may help guide future diagnostic and treatment procedures.

“The current testing of mitochondrial function usually includes blood tests and biopsies, which can be laborious and is an unpleasant process for patients,” Wang said. “If mtDNA mutations underlie the mitochondrial defects observed in autism, then you do mtDNA sequencing in the affected children, his or her mom and also siblings to see if they have pathogenic mtDNA mutations, which can then be used to infer the disease risk.”

It is unclear whether the increased prevalence of ASD is due to better diagnostic tools or changes in environmental conditions, but Gu explains another potential reason, which is linked with mtDNA.

“A fascinating process occurs during mother lineage for egg production. It can limit the number of mother’s mtDNA copies transmitted to the egg, so bad mutations cannot survive, but some of the bad mutations can still leak to the next generation,” Gu said. “This cleanup process may be affected by the mother’s physiology, like obesity, diabetes, etc. So one of our future research goals is to figure out what factors can make this cleanup process less efficient.”

The relationship between mtDNA and disease may not just be limited to ASD but may exist for age-related diseases as well.

“Our lab has been focusing on age-related disease, but because of this particular finding, we have started to look at childhood diseases,” Gu said. “Now, we are also trying to develop tools to manipulate mtDNA to have a mechanistic understanding of the impact of mtDNA mutations.”