One gene could explain why autism appears to affect boys more than girls 

Autism’s striking sex difference has long presented researchers with a puzzle. Why are boys diagnosed around three to four times as often as girls, when the genes associated with autism aren’t confined to either group?

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A study led by researchers from the Boston Children’s Hospital in the US points to a single gene that escapes the usual silencing of an X chromosome in women, potentially giving developing brains with an X chromosome double-feature a significant buffer against many autism-related changes.The research set out to address the question of how hundreds of different genes – each a relatively rare factor on its own – seem to contribute to overlapping sets of characteristics we broadly include within autism’s spectrum.

Using lab-grown cultures of the progenitor cells that precede the development of neurons, the team dialed down the activity of a number of individual autism-associated genes.

They found that different disruptions repeatedly reduced activity across other genes associated with autism. Twenty-seven other genes implicated in autism subsequently grew quieter in at least 10 of the team’s experiments following the initial tweak. Follow-up experiments based on clumps of lab-grown tissue called brain organoids backed up this genetic “convergence.”

Mapping the regulatory relationships drew attention to a single X-linked gene called a “zinc finger transcription factor gene,” or ZFX, which encodes a protein that helps activate other genes – including many associated with autism.

In most cases, genes on one of the two X chromosomes in each cell are naturally switched off, preventing excessive doses of their products. ZFX is a notable exception, typically remaining active on both copies of the X chromosome.

This higher baseline expression in female brains could therefore help maintain activity across this network when other genes are disrupted.

The Y chromosome does happen to have a similar gene called ZFY, yet its effect as an activator of other genes is weaker, potentially explaining the sex difference.

The researchers also reanalyzed existing gene-expression data from donated brain tissue, uncovering evidence of reduced ZFX activity in excitatory neurons from autistic males.

The findings support a hypothesis known as the female protective effect. A 2014 genetic study found that while women were diagnosed with autism less often, those who were autistic carried more autism genes than autistic males, suggesting women simply may have a higher threshold for developing key characteristics.

As intriguing as the new findings are, they fall short of proving that ZFX is solely responsible for this added protection. For one thing, the experiments used a single male-derived stem-cell line. Comparing cells from men and women and testing whether the extra ZFX provides some degree of protection will be critical in building a strong case.

There is also still the possibility that the marked difference in diagnoses is largely a cultural phenomenon, with underlying changes present but masked, or misinterpreted.

A population study published in 2012 found girls with high autistic-trait scores were less likely to meet diagnostic criteria unless they also had intellectual or behavioral difficulties. Diagnostic bias, or differences in how girls present, could leave many individuals with the condition unrecognized. Camouflaging autistic characteristics could also complicate its identification.

There are competing biological explanations that are yet to be ruled out, too. A study of amniotic fluid from male fetuses who were later diagnosed with autism found relatively higher steroid hormone activity, suggesting a possible developmental influence. Other studies have uncovered environmental exposure to hormone-mimicking pollutants that could skew the odds.

The new work also warrants a funding caveat, with the research receiving a postdoctoral fellowship from Autism Speaks – an organization with a controversial history among neurodiversity advocates who have criticized its presentation of autism as a disease to be cured. Though Autism Speaks says it no longer supports research seeking a cure, a legacy of debate over autism as a disease versus a neurodiversity continues to color the practical implications of findings like these.

From a theoretical perspective alone, knowing that single genes can influence entire networks in such distinct fashions could help us simply better appreciate the amazing complexity of …[for the balance of this amazing article please visit: https://newatlas.com/mental-health/one-gene-autism-affect-boys-more-than-girls/]
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The study was published in Nature.  Source: Boston Children’s Hospital via Phys.org