Chromatin regulators, phenotypic robustness, and autism risk

Reut Suliman, Eyal Ben-David, Sagiv Shifman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Though extensively characterized clinically, the causes of autism spectrum disorder (ASD) remain a mystery. ASD is known to have a strong genetic basis, but it is genetically very heterogeneous. Recent studies have estimated that de novo disruptive mutations in hundreds of genes may contribute to ASD. However, it is unclear how it is possible for mutations in so many different genes to contribute to ASD. Recent findings suggest that many of the mutations disrupt genes involved in transcription regulation that are expressed prenatally in the developing brain. De novo disruptive mutations are also more frequent in girls with ASD, despite the fact that ASD is more prevalent in boys. In this paper, we hypothesize that loss of robustness may contribute to ASD. Loss of phenotypic robustness may be caused by mutations that disrupt capacitors that operate in the developing brain. This may lead to the release of cryptic genetic variation that contributes to ASD. Reduced robustness is consistent with the observed variability in expressivity and incomplete penetrance. It is also consistent with the hypothesis that the development of the female brain is more robust, and it may explain the higher rate and severity of disruptive de novo mutations in girls with ASD.

Original languageAmerican English
Article numberArticle 81
JournalFrontiers in Genetics
Volume5
Issue numberAPR
DOIs
StatePublished - 2014

Keywords

  • Autism spectrum disorder
  • Chromatin regulators
  • Common genetic variants
  • De novo mutation
  • Phenotypic robustness

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