Comparative Proteome and Cis-Regulatory Element Analysis Reveals Specific Molecular Pathways Conserved in Dog and Human Brains

Brain development and function are governed by precisely regulated protein expressions in different regions. To date, multiregional brain proteomes have been systematically analyzed only for adult human and mouse brains. To un-derstand the underpinnings of brain development and function, we generated proteomes from six regions of the postnatal brain at three developmental stages of domestic dogs (Canis familiaris), which are special among animals in terms of their remarkable human-like social cognitive abilities. Quantitative analysis of the spatiotemporal pro-teomes identified region-enriched synapse types at different developmental stages and differential myelina-tion progression in different brain regions. Through inte-grative analysis of inter-regional expression patterns of orthologous proteins and genome-wide cis-regulatory element frequencies, we found that proteins related with myelination and hippocampus were highly correlated be-tween dog and human but not between mouse and human, although mouse is phylogenetically closer to human. Moreover, the global expression patterns of neurodegen-erative disease and autism spectrum disorder-associated proteins in dog brain more resemble human brain than in mouse brain. The high similarity of myelination and hippocampus-related pathways in dog and human at both proteomic and genetic levels may contribute to their shared social cognitive abilities. The inter-regional expression patterns of disease-associated proteins in the brain of different species provide important information to guide mechanistic and translational study using appropriate animal models.

Automated summary

This study analyzed proteomes from six regions of the postnatal brain at three developmental stages of domestic dogs, revealing the correlation between myelination and hippocampus-related proteins in dogs and humans. The global expression patterns of disease-associated proteins in the brain of dogs resemble those in humans more than in mice. These findings provide insights into brain development and function, and can guide mechanistic and translational research using appropriate animal models.