Female Protective Effect in Autism

The "female protective effect" hypothesis in autism suggests that females have a biological or genetic protection against developing autism. This hypothesis is supported by the observation that autism is more commonly diagnosed in males than in females, with a widely reported ratio of approximately 4 males for every 1 female diagnosed with autism. While exact mechanisms behind this protective effect are still being studied, there are several theories, including genetic, hormonal, and neuroanatomical differences between males and females.

One significant area of research focuses on the role of genetic differences, particularly those related to the X chromosome. Because females have two X chromosomes (XX) while males have one X and one Y chromosome (XY), it's theorized that the presence of an additional X chromosome in females may offer some protection against the development of autism. Here's how the mechanism is thought to work:

• X-Chromosome Inactivation: In females, one of the X chromosomes in each cell is randomly inactivated, which means that it does not express its genes. This process could potentially mitigate the impact of harmful mutations on the X chromosome, as there is a chance the mutated gene is on the inactivated X chromosome.
• Genetic Buffering: The presence of two X chromosomes in females provides a "genetic buffer" against mutations. If a gene related to autism is mutated on one X chromosome, the other X chromosome may carry a normal copy of the gene that can compensate for the mutation. In contrast, males, with only one X chromosome, do not have this potential buffering, making them more susceptible to the effects of mutations on the X chromosome.
• Single-Nucleotide Polymorphisms (SNPs): Research has identified certain SNPs that are associated with an increased risk of autism. Some of these SNPs are located on the X chromosome. The female protective effect could be related to how these SNPs are expressed or compensated for in females compared to males.

It's important to note that while the X chromosome and the mechanisms mentioned above play a role, autism is a complex disorder influenced by multiple genes across various chromosomes, as well as environmental factors. The female protective effect is just one possible explanation in understanding the gender disparity in autism diagnoses.

References

"Sex differences in autism spectrum disorder: evidence from a large sample of children and adolescents" by Loomes R, Hull L, Mandy WPL. (Journal of Autism and Developmental Disorders, 2017) 
"The female protective effect in autism spectrum disorder is not mediated by a single genetic locus" by Werling DM, Geschwind DH. (Molecular Autism, 2015)