Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions

Area of Science:

• Genomics
• Neuroscience
• Developmental Biology

Background:

• Interindividual variation in neurodevelopmental conditions is common but poorly understood.
• Gene expression can vary even within genetically identical cells, suggesting stochastic processes are at play.

Purpose of the Study:

• To investigate if neurodevelopmental conditions increase gene expression variability, beyond differential expression.
• To explore the mechanisms and implications of this variability in brain development.

Main Methods:

• Analysis of single-cell and single-nucleus RNA sequencing datasets from human brain-relevant cell and tissue types.
• Comparison of gene expression variability in conditions like Trisomy 21 and CHD8 haploinsufficiency versus controls.

Main Results:

• Trisomy 21 and CHD8 haploinsufficiency significantly increase gene expression variability in brain cells.
• This increase in variability is global, partly stochastic, and uncoupled from average transcript abundance.
• Highly variable genes are often cell-type specific and associated with repressive histone marks, while less variable genes are constrained and linked to active marks.

Conclusions:

• Neurodevelopmental conditions can drive increased gene expression variability in brain cells, potentially contributing to diverse phenotypic outcomes.
• Understanding gene expression variability is crucial for deciphering genotype-phenotype relationships in neurodevelopmental disorders.