Girls, genes and autism

Tychele Turner is a member of the 2012 class of Autism Speaks Weatherstone Predoctoral Fellows. Today, Dr. Turner is expanding on the groundbreaking findings of her Weatherstone project as a senior research fellow in the genomics lab of Evan Eichler, at the University of Washington, in Seattle.

I want to start by saying "thank you" to the Autism Speaks community for its support of my research. My Weatherstone Fellowship launched my scientific career by helping fund my first big study – into the genetics of autism in females.

My fellowship gave me opportunities to meet, network and collaborate with other autism researchers. It continues to inspire my current studies analyzing the whole genomes of a large number of families affected by autism – an ambitious investigation made possible, in part, by the Autism Speaks MSSNG project.

Learn more about MSSNG (pronounced “missing”) and the importance of whole genome autism research.

I greatly appreciate this opportunity to tell you a little more about my research and what inspired it.

The inspiration begins with my mother, an occupational therapist who works with special-needs kids. Growing up, I had the privilege to become friends with many of these children.

During my undergraduate years at Michigan State University, I fell in love with genetics and laboratory research. At a genetics conference, I learned about some of the first whole genome research on autism. I saw then that I could combine my love of genetics with my devotion to children who have autism.

I proceeded full-force, pursuing a doctorate in human genetics and molecular biology at the Johns Hopkins University School of Medicine. It was there, while working in the lab of Aravinda Chakravarti, that I received my Autism Speaks Weatherstone Predoctoral Fellowship.

The missing girls in autism research

At the time, few scientists were studying one of the most striking aspects of autism: the fact that autism is four times more common in males than in females. In fact, it’s been common for autism researchers to exclude females from their studies to avoid complicating recruitment and findings.

There are many possible reasons for so few girls receiving a diagnosis of autism. They may include under-diagnosis as girls may have different symptoms or “hide” their autism more successfully.

However, there is ample research suggesting that it somehow takes more to tip brain development in the direction of autism in a girl than in a boy. In terms of genetics, this means that autism in females tends to involve more genetic “hits,” or severe mutations, than it does in boys.

That’s where my Weatherstone project comes in. My colleagues and I wanted to use a relatively new gene-sequencing technique – called exome sequencing – to sequence all the genes in a group of girls and women on the autism spectrum. [Editor’s note: Standard genetic testing involves the sequencing of only a sampling of genes, and whole genome sequencing involves a person’s entire DNA sequence – both genes and the little understood “noncoding” DNA between those genes. Exome sequencing falls between the two.]

Our study participants came from families where two or more females had autism.

Genetic discoveries deepen understanding of autism’s early development

Our analysis led to the discovery of unusually high rates of mutations in 18 genes, which previously had not been associated with autism. Of these 18 autism-associated genes, we delved deeper into the role played by a gene called delta 2 catenin (CTNND2) in brain development. We analyzed the gene’s activity in the brain development of various laboratory animals. We studied its presence and activation in human post-mortem brain tissue.

We found that CTNND2 produced a protein called delta-catenin, which occurred at high levels in the brain before birth. This strongly suggested that it played an important role in early brain development.

We also found that mutations in the CTNND2 gene disrupted the normal formation of synapses – the vital connections that link brain cells with each other. This finding supported earlier evidence that problems with brain connectivity are a root cause of autism. In addition, we found many interactions between CTNND2 and other genes involved in brain development and autism. The results of our study appeared last March in the prestigious scientific journal Nature.

The female factor proves powerful

Like many – perhaps most – gene changes implicated in autism, changes in the CTNND2 gene turn up in only a small subgroup of people with autism – probably less than 1 percent.

However, in addition to showing the important role that CTNND2 can play in autism, our research broke ground in other directions as well.

It clearly demonstrated the power of studying autism genetics in girls and women. Because females need those more powerful “genetic hits” to develop autism, their genomes are particularly valuable for finding autism-linked genes. We proved the usefulness of this approach by discovering 18 genes whose link to autism was previously unknown!

Also by characterizing one of these genes so thoroughly – how it functioned, what controlled its expression and how its activity interconnected with that of other autism risk genes – we set a new and higher standard for the depth of understanding that a gene study can produce.

Already, our discovery of CTNND2 is making a difference in the genetic tests medical centers use to diagnose autism. In the future, we hope that our findings will guide research into potential treatments that address this cause of autism.

Meanwhile, I continue to study the genetic architecture of autism in collaboration with my colleagues here at the University of Washington. We are currently analyzing the whole-genome sequencing data from thousands of people with autism and their family members – many of them being participants in the Autism Speaks MSSNG project.

Learn how you can participate in MSSNG

Our goal is to find additional genetic risk factors for autism that can guide diagnostics and advance the development of future treatments.

Working together with families, organizations such as Autism Speaks and our fellow scientists, we know we can deepen our understanding of autism in ways that can improve the lives of people across the autism spectrum.

Thanks again to the Autism Speaks community for supporting this work.