Adaptive functions of structural variants in human brain development

Area of Science:

• Genomics
• Evolutionary Biology
• Primate Genetics

Background:

• Structural variants (SVs) in nonhuman primates are crucial for understanding human-specific traits but are underrepresented in research.
• Accurate SV maps are needed to investigate genetic variations and their functional impacts.

Purpose of the Study:

• To create a comprehensive SV map in rhesus macaques.
• To identify and prioritize functional human-specific inversions.
• To explore the role of these inversions in human brain development and cognitive evolution.

Main Methods:

• Generated an accurate SV map using long-read sequencing data from 562 rhesus macaques.
• Validated SV calls using in-house benchmarks of multiple macaque genomes.
• Identified and prioritized 75 human-specific inversions based on functional constraints.

Main Results:

• The macaque SV map revealed stronger selective constraints on inversions within regulatory regions.
• Prioritized human-specific inversions significantly altered the human transcriptome.
• These inversions reconfigured ancestral genomic architecture and introduced mutation hotspots.
• Linked theAPCDD1 gene, located on a human-specific inversion, to neuronal maturation and cognitive ability.

Conclusions:

• Structural variants, particularly inversions, play a significant role in shaping human uniqueness.
• Inversions contribute to human brain development and cognitive evolution by altering gene regulation and genomic architecture.
• This study provides a valuable resource for understanding primate genomics and human evolution.