A Female Protective Model for Autism

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder characterized by a wide variety of phenotypes such as a lack of social interaction and awareness, underdeveloped communication skills, and a reduced ability to experience empathy. This disorder is usually diagnosed early in childhood and has an incidence rate of approximately 3 out of every 1000 children¹. It has been known that ASD differs between genders affecting males significantly more than females¹. In Lise Eliot’s Pink Brain Blue Brain, this male ASD bias has been labeled by some researches as dependent upon pre-natal testosterone and the masculinization of the brain circuits¹. A significant caveat to these experiments is that these researchers failed to look at this relationship within a given gender instead of a pooled sample¹. In addition, Eliot argues that there has not been a study suggesting this relationship between testosterone and ASD severity¹. Thus, hormonal differences in testosterone levels between males and females cannot be the source behind sex differences underlying ASD.

            However, Eliot suggests that ASD is better explained by complex gene-gene and gene-environment interactions¹. A recent study investigating genetic factors underlying gender differences in neurodevelopmental disorders, such as Autism, showed that these differences are associated with the amount of autosomal copy number varations (CNVs) for a given gender^2,3. CNVs are changes in the normal number of genes within large segments of DNA. Researchers in this study showed that females required more CNVs compared to males in neurodevelopmental disorders including ASD^2,3. Sebastien Jacquemont et. al. from the University of Washington School of Medicine used array comparative genomic hybridization (CGH) to measure CNVs and short nucleotide variations (SNVs), or SNPs, from 15,585 individuals with neurodevelopment delays, and they also measured CNVs and SNVs from an independent sample of 762 families with ASD³. In both populations, CNVs and SNVs were significantly higher for females^2,3. The study supports what has been called the “female protective model” for ASD, which hypothesizes that females require more deleterious mutations throughout their genome compared to males in order to show similar ASD-like phenotypes^2,3. Important to note is that the increase in CNVs and SNVs were found throughout the genome for females and were not associated with X-linked variants^2,3. 

            The Jacquemont et. al. investigation has important implications for the gender gaps in ASD individuals. These researchers argue that this study is the first to show strong evidence for a molecular basis for these gender differences². Consistent with Eliot, the Jacquemont et. al study does not show that masculinization of the male brain is the molecular basis, but rather a “female protective model” could explain how gender differences in ASD could arise by structural differences in the human genome.

            If these structural differences do in fact explain the gender gaps, does this mean that these CNVs and SNVs built in our genome irreconcilable? The answer is no. As Eliot states in Pink Brain Blue Brain, single gene mutations or combinations of genic mutations do not solely cause ASD¹. Instead environmental factors can heavily influence ASD prognosis through gene-environment interactions. Eliot emphasizes that we can manipulate these environmental interactions at an early age for children with ASD. The earlier treatment intervention is for individuals diagnosed with ASD, the better their prognosis later in life because of these environment-gene effects¹. These can include social interaction strategies, which have been shown to be an effective treatment intervention to improve the severity of ASD. These interventions must be done at an early age¹, however, suggesting how important the environment can affect the plasticity of the ASD-like human brain.

1. Eliot, Lise. "Is Autism a Male Trait?" Pink Brain, Blue Brain: How Small Differences Grow into Troublesome Gaps--and What We Can Do about It. Boston: Houghton Mifflin Harcourt, 2009. 79-83. Print.

2. Cell Press. "Study uncovers why autism is more common in males." ScienceDaily. ScienceDaily, 27 February 2014. <www.sciencedaily.com/releases/2014/02/140227125236.htm>.

3. Jacquemont et al., A Higher Mutational Burden in Females Supports a ‘‘Female Protective Model’’ in Neurodevelopmental Disorders. The American Journal of Human Genetics 94 1-11 (2014). http://dx.doi.org/10.1016/j.ajhg.2014.02.001