Evolutionarily informed gene sets reveal conserved and lineage-modified transcriptional programs during vertebrate...

Area of Science:

• Neuroscience
• Evolutionary Biology
• Genomics

Background:

• Vertebrate forebrain displays anatomical diversity despite conserved gene regulatory programs.
• Understanding evolution of conserved cell types requires cross-species comparisons.
• Gene evolutionary histories complicate joint analyses of orthologs.

Purpose of the Study:

• To construct a unified cross-vertebrate cell atlas of the forebrain.
• To investigate how conserved cellular programs are maintained and modified during vertebrate evolution.
• To map human neuropsychiatric genetic signals onto conserved neural substrates.

Main Methods:

• Derived evolutionarily informed gene sets from a global homology graph.
• Represented cells in a shared, interpretable gene-set feature space.
• Applied framework to forebrain single-cell profiles from eleven vertebrate species.

Main Results:

• Identified conserved transcriptional programs defining stable cell-type identities across vertebrates.
• Found evolutionary divergence primarily within cell types, not between them.
• Observed conserved radial glia fate bifurcation with lineage-dependent modulation.
• Mapped human neuropsychiatric GWAS signals to conserved neural substrates.

Conclusions:

• Vertebrate forebrain evolution involves lineage-specific tuning of conserved transcriptional programs.
• Stable cellular architectures underpin conserved neural functions and behaviors.
• Gene-set conservation correlates with evolutionary age; lineage programs show clade-level remodeling.