Differentially Active and Conserved Neural Enhancers Define Two Forms of Adaptive Noncoding Evolution in Humans

Area of Science:

• Evolutionary biology
• Neuroscience
• Genomics

Background:

• Human and chimpanzee genomes show high similarity, yet exhibit significant differences in neural phenotypes.
• Changes in gene expression, potentially driven by adaptive evolution, are hypothesized to underlie these neural differences.
• The precise location and evolutionary impact of functional regulatory changes in the human genome remain unclear.

Purpose of the Study:

• To investigate the location and function of cis-regulatory elements (CREs) that have undergone accelerated evolution or are active in the human brain.
• To compare CREs showing signs of positive selection with those exhibiting differential activity between humans and chimpanzees.
• To identify CREs associated with neuropsychiatric diseases.

Main Methods:

• Experimentally combined human and chimpanzee CREs exhibiting accelerated evolution or brain activity.
• Utilized massively parallel reporter assays (MPRA) to test CRE transcriptional activity in human neural progenitor cells and neurons.
• Analyzed CREs for signs of positive selection and differential expression.

Main Results:

• Identified 179 CREs with differential activity between human and chimpanzee neural cells.
• Detected 722 CREs with evidence of positive selection in the human lineage.
• Found that selected and differentially expressed CREs vary in expression levels, size, and genomic location.
• Discovered 69 CREs in loci linked to genetic variants associated with neuropsychiatric diseases.

Conclusions:

• Regulatory element evolution plays a crucial role in human neural phenotype divergence.
• The study provides a novel framework for examining noncoding element evolution contributing to human-specific neural traits.
• Identified CREs highlight the importance of regulatory activity in neural development and disease susceptibility.