Autism is diagnosed in boys four times more frequently than in girls. Recent genetic research suggests that this difference is due to the fact that girls are protected from autism risk factors rather than boys being subjected to additional risk factors. The nature of this ‘female protective effect’ remains unknown.
Stephan Sanders and his colleagues have previously shown that spontaneous, or de novo, mutations (seen only in the child and not in either parent) are important risk factors for autism and can be used to find the genes involved in causing autism. These de novo mutations are more common in affected girls than affected boys. The researchers plan to test the hypothesis that in girls, some of these de novo mutations lead to autism by disrupting the female protective effect.
To find these mutations, they plan to build a map of the differences in gene expression between males and females in multiple brain regions and across multiple stages of brain development. They hope to look for a group of genes that have mutations in girls with autism and that also show a difference in brain expression between the sexes. Such genes will be candidates for female protective effect genes. By looking for brain regions and stages of development at which these genes converge, the researchers will seek to understand when, where and how the female protective effect occurs. Finally, they aim to test the top two gene candidates in mouse models or induced pluripotent stem cells to ensure that they show the predicted expression pattern and to learn whether they exaggerate phenotypes of known autism genes in females but not males.