Developmental origins of the female protective effect in autism

  • Awarded: 2018
  • Award Type: Explorer
  • Award #: 600568

Autism spectrum disorders (ASD) have a strong male bias, as documented extensively in both epidemiological and genetic studies. Four times as many boys present with ASD traits and receive a diagnosis of ASD compared to girls. However, genetic analysis demonstrates that girls with ASD possess more de novo damaging copy-number variations (CNVs) and point mutations than boys with ASD. To explain these phenomena, researchers have proposed a ‘female protective effect’ (FPE) theory, which suggests that females with loss-of-function mutations in ASD-associated genes are resistant to developing ASD symptoms. Despite much interest, it has been difficult to identify causal mechanisms for the FPE.

Jessica Tollkuhn and colleagues propose to reveal developmental trajectories that contribute to male vulnerability or female resilience to ASD by focusing on the most sexually differentiated brain regions and cell types. They recently performed a targeted screen for sex differences in gene expression in two sexually dimorphic brain regions from mouse pups and, using data from the Simons Simplex Collection (SSC), found that their female-biased gene set is strikingly enriched for genes that have de novo likely gene disrupting (LGD) ASD mutations. Furthermore, ASD-associated genes are not enriched in male-biased gene expression data sets, and genes with de novo mutations linked to intellectual disability or schizophrenia do not display a sex-bias in expression. These unpublished findings are the first report of sex differences in the expression of autosomal, high-confidence ASD candidate genes and support the hypothesis that increased expression of select genes in females could buffer the deleterious effects of heterozygous LGD mutations in those genes, thus providing an FPE. Tollkuhn’s laboratory now proposes to determine if this female bias in expression of ASD-linked genes extends to cortical brain regions and is restricted to specific cell types. Their long-term goal is to

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