DLX5/6 GABAergic Expression Affects Social Vocalization: Implications for Human Evolution.

Area of Science:

• Neuroscience
• Evolutionary Biology
• Genetics

Background:

• DLX5 and DLX6 are transcription factors crucial for brain development and GABAergic neuron differentiation.
• The DLX5/6 locus is regulated by FoxP2, a gene implicated in language evolution and neurodevelopmental disorders.
• Targeted inactivation of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre) leads to increased lifespan and altered phenotypes.

Purpose of the Study:

• To investigate the behavioral and vocalization phenotypes of Dlx5/6VgatCre mice.
• To explore the role of DLX5/6 in human evolution, self-domestication, and longevity.
• To analyze the evolutionary history of the DLX5/6 locus in humans and Neanderthals.

Main Methods:

• Generation and behavioral analysis of Dlx5/6VgatCre mice, including vocalization recording and social interaction tests.
• Comparative genomic analysis of DLX5/6 regions in modern humans, Neanderthals, and Denisovans.
• Genotyping of human populations to identify Neanderthal introgression and association studies with longevity.

Main Results:

• Dlx5/6VgatCre mice exhibit significantly increased vocalizations (higher quantity and complexity) and hyper-socialization.
• A Neanderthal-introgressed haplotype (DLX5/6-N-Haplotype) in modern humans contains regulatory elements and is associated with neurodevelopmental disorders.
• The DLX5/6-N-Haplotype is underrepresented in semi-supercentenarians, suggesting a link to aging and longevity.

Conclusions:

• DLX5/6 plays a significant role in regulating vocalization and social behavior, with implications for neurodevelopment.
• The DLX5/6-N-Haplotype represents a Neanderthal contribution to human evolution potentially influencing sociability, speech, and longevity.
• These findings suggest a coevolutionary link between DLX5/6, human social behavior, language, and lifespan.