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Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • The dorsolateral prefrontal cortex (DLPFC) is crucial for cognitive functions like learning and memory.
  • Individual variability in DLPFC structure and function is influenced by genetic and environmental factors.
  • Gene expression changes, including alternative splicing, are critical during brain development but not fully understood.

Purpose of the Study:

  • To investigate changes in gene isoform preferences during human brain development.
  • To identify and characterize a phenomenon termed 'isoswitching' in the DLPFC.
  • To assess the potential of isoswitching for predicting brain age.

Main Methods:

  • Analysis of RNA sequencing data from human prenatal and postnatal DLPFC samples.
  • Identification of genes exhibiting significant shifts in isoform preference.
  • Development of a predictive model based on isoswitching patterns.

Main Results:

  • Numerous genes show dramatic shifts in isoform preference around birth.
  • Thousands of genes undergo gradual, temporally regulated isoform changes ('isoswitching') throughout life.
  • Isoswitching patterns accurately predict human brain age from prenatal stages to over 80 years.
  • Isoswitching was also observed in the rhesus macaque brain.

Conclusions:

  • Isoswitching is a fundamental mechanism driving brain development and aging.
  • This study presents the first demonstration of brain age prediction using solely RNA sequencing data.
  • Isoswitching offers a novel molecular clock for tracking brain maturation and aging across species.