X Chromosome Inactivation Timing is Not eXACT: Implications for Autism Spectrum Disorders

Area of Science:

• Genetics
• Developmental Biology
• Neuroscience

Background:

• Autism spectrum disorder (ASD) etiology is complex, involving genetic and environmental interactions.
• DNA methylation is a key epigenetic modification reflecting molecular pathogenesis in ASD.
• Previous studies identified DNA methylation differences in X-linked genes in newborns later diagnosed with ASD.

Purpose of the Study:

• To review recent advancements in X chromosome inactivation (XCI) in humans and primates.
• To investigate the role of XCI in the context of ASD etiology and sex biases.
• To explore the challenges in studying human peri- and post-implantation development.

Main Methods:

• Comparative analysis of XCI mechanisms across mammalian species.
• Review of findings on the noncoding transcript XACT in human pluripotent stem cells.
• Examination of recent data from non-human primate post-implantation embryos.

Main Results:

• X-linked genes show enrichment in DNA methylation differences associated with later ASD diagnosis.
• XCI mechanisms vary across species, with unique features in humans.
• The transcript XACT is linked to X chromosome erosion in human pluripotent stem cells.

Conclusions:

• Human XCI is prolonged and imprecise during early development, posing research challenges.
• Understanding XCI in early human development may shed light on biased sex ratios at birth.
• Further research into XCI and DNA methylation is crucial for understanding the male bias in ASD incidence.