Spatiotemporal transcriptomic divergence across human and macaque brain development

Abstract

INTRODUCTION Improved understanding of how the developing human nervous system differs from that of closely related nonhuman primates is fundamental for teasing out human-specific aspects of behavior, cognition, and disorders. RATIONALE The shared and unique functional properties of the human nervous system are rooted in the complex transcriptional programs governing the development of distinct cell types, neural circuits, and regions. However, the precise molecular mechanisms underlying shared and unique features of the developing human nervous system have been only minimally characterized. RESULTS We generated complementary tissue-level and single-cell transcriptomic datasets from up to 16 brain regions covering prenatal and postnatal development in humans and rhesus macaques ( Macaca mulatta ), a closely related species and the most commonly studied nonhuman primate. We created and applied TranscriptomeAge and TempShift algorithms to age-match developing specimens between the species and to more rigorously identify temporal differences in gene expression within and across the species. By analyzing regional and temporal patterns of gene expression in both the developing human and macaque brain, and comparing these patterns to a complementary dataset that included transcriptomic information from the adult chimpanzee, we identified shared and divergent transcriptomic features of human brain development. Furthermore, integration with single-cell and single-nucleus transcriptomic data covering prenatal and adult periods of both species revealed that the developmental divergence between humans and macaques can be traced to distinct cell types enriched in different developmental times and brain regions, including the prefrontal cortex, a region of the brain associated with distinctly human aspects of cognition and behavior. We found two phases of prominent species differences: embryonic to late midfetal development and adolescence/young adulthood. This evolutionary cup-shaped or hourglass-like pattern, with high divergence in prenatal development and adolescence/young adulthood and lower divergence in early postnatal development, resembles the developmental cup-shaped pattern described in the accompanying study by Li et al . Even though the developmental (ontogenetic) and evolutionary (phylogenetic) patterns have similar profiles, the overlap of genes driving these two patterns is not substantial, indicating the existence of different molecular mechanisms and constraints for regional specification and species divergence. Notably, we also identified numerous genes and gene coexpression modules exhibiting human-distinct patterns in either temporal (heterochronic) or spatial (heterotopic) gene expression, as well as genes with human-distinct developmental expression, linked to autism spectrum disorder, schizophrenia, and other neurological or psychiatric diseases. This finding potentially suggests mechanistic underpinnings of these disorders. CONCLUSION Our study provides insights into the evolution of gene expression in the developing human brain and may shed some light on potentially human-specific underpinnings of certain neuropsychiatric disorders. Concerted ontogenetic and phylogenetic transcriptomic divergence in human and macaque brain. Left: Human and macaque brain regions spanning both prenatal and postnatal development were age-matched using TranscriptomeAge. Right: Phylogenetic transcriptomic divergence between humans and macaques resembles the developmental (ontogenetic) cup-shaped pattern of each species, with high divergence in prenatal development and adolescence/young adulthood and lower divergence during the early postnatal period (from perinatal to adolescence). Single-cell transcriptomics revealed shared and divergent transcriptomic features of distinct cell types.