NRC genomics researchers play key role in ground-breaking autism study

- Ottawa, Ontario

Next-generation sequencing technologies can sequence an entire genome in a matter of hours, generating billions of bits of genetic data for analysis. (NRC photo)

A Canadian-led study is attracting international attention after delivering new evidence of a connection between defects in endothelial cells—the lining of blood vessels—and autism spectrum disorder (ASD).

Led by Ottawa Hospital scientist Dr. Baptiste Lacoste, the 4-year study also involved researchers at the University of Ottawa, McGill and Laval universities, as well as the National Research Council of Canada (NRC), where a team led by senior research officer Dr. Qing Yan Liu provided the crucial genomics and bioinformatics expertise that established the genetic foundation for the study's findings.

Could blood flow play a role?

While ASD studies have tended to focus on neurons in the brain, which control behaviour, this study was the first in-depth examination of whether impaired blood supply to the brain could affect the function of parts of the brain responsible for social behaviours.

Using MRIs and other imaging techniques, the researchers looked at blood flow in the brains of mice with the so-called "16p deletion," in which a number of genes on chromosome 16 are missing. This deletion, repeated in every cell in the body, is one of the most common genetic mutations found in people diagnosed with ASD.

The researchers found that, when neurons in different regions of the brains of the mice were stimulated, the blood flow response to those regions was slower and weaker than in mice without the 16p deletion. They also found significant differences between the 2 groups in the development of brain vasculature, the network of blood vessels supplying the brain.

Endothelial cells

As NRC's Dr. Liu points out, these findings were a strong indication of the involvement of endothelial cells.

"Among other functions, endothelial cells that line blood vessels manage blood flow by controlling how and when vessels contract," says Dr. Liu. "They are also crucial to angiogenesis, the growth of new blood vessels."

To investigate whether a genetic basis for this dysfunction in development and performance of brain vasculature existed, Dr. Lacoste turned to Dr. Liu and her team at NRC's Human Health Therapeutics Research Centre and her collaborators, Youlian Pan and Ziying Liu, at NRC's Digital Technologies Research Centre where ongoing investment through the Genomics Research and Development Initiative (GRDI) has supported the development of advanced knowledge of the genes and proteins in brain cells, including endothelial cells.

Demonstrating the connection

Taking advantage of next-generation sequencing technologies, Dr. Liu and her team compiled and analyzed transcriptomic profiles of mice with and without the 16p deletion at 14 days and 50 days of age.

"The transcriptomic profiles contained the sum of all the RNA representing each of the 25,000 or so genes in each genome, literally billions of bits of data," says Dr. Liu.

"Through bioinformatics analysis, we identified a number of genes associated with blood circulation as well as genes associated with blood vessel development that were being expressed differently in the mice with and without the 16p deletion.

Using imaging and observation, Dr. Lacoste examined a third group of mice, developed especially for the study to have the 16p deletion only in their endothelial cells, which displayed similar blood flow and functional deficits.

Essential partner

The study, already being cited by researchers around the world, produced several lines of new evidence linking defects in endothelial cells to some forms of autism, including the NRC findings which provide the first evidence of a molecular basis for the dysfunction in the development and performance of brain vasculature.

Dr. Lacoste says Dr. Liu and her team were fundamental to the success of the study.

"As soon as the collaboration commenced, our study took a new turn," says Dr. Lacoste. "The genomics and bioinformatics capacity at NRC is a tremendous resource, truly state-of-the-art infrastructure and expertise. Dr. Liu and her team were instrumental for the publication of our work on the vascular underpinnings of autism and the part endothelial dysfunction may play in ASD, knowledge that could set the foundations for new ASD diagnostics and, potentially, therapies targeting blood supply to affected regions of the brain."