Massively parallel discovery of human-specific substitutions that alter enhancer activity

Area of Science:

• Evolutionary biology
• Genetics
• Neuroscience

Background:

• Genetic changes in gene regulatory elements are crucial for human trait evolution, like cerebral cortex expansion.
• Identifying specific genetic alterations impacting regulatory activity during human evolution is challenging.

Purpose of the Study:

• To quantify the functional impact of human-specific genetic substitutions on regulatory elements.
• To identify genetic changes driving regulatory evolution in the human lineage.

Main Methods:

• Utilized massively parallel enhancer assays in neural stem cells.
• Assessed over 32,000 human-specific substitutions in human accelerated regions (HARs) and human gain enhancers (HGEs).
• Differentiated effects of substitutions from background genetic variation.

Main Results:

• Over 30% of active HARs and HGEs displayed differential activity between humans and chimpanzees.
• Substitutions influenced enhancer function through additive and nonadditive interactions.
• Substitutions in HARs had smaller effects compared to HGEs, indicating buffering in constrained regions.

Conclusions:

• Human-specific genetic changes significantly altered enhancer function, contributing to human evolution.
• Findings provide candidate regulatory elements for further studies on human evolutionary divergence.
• The study offers insights into the mechanisms of regulatory evolution in the human lineage.