Research Article

Spatiotemporal transcriptomic divergence across human and macaque brain development

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Science  14 Dec 2018:
Vol. 362, Issue 6420, eaat8077
DOI: 10.1126/science.aat8077
  • 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.

  • Fig. 1 Conserved and divergent transcriptomic features of human and macaque neurodevelopmental processes.

    (A) Plot depicting the real age (x axis) and the age predicted by TranscriptomeAge (y axis) of human, chimpanzee, and macaque. Macaque (164 PCD) and human (266 PCD) births are shown as green and red dashed lines, respectively. (B) Schematic showing human developmental periods as described in Kang et al. (29) and the matched macaque developmental and chimpanzee adult datasets. Each line corresponds to one macaque or one chimpanzee specimen and the corresponding predicted age when compared to human neurodevelopment. PCD, post-conception day; PY, postnatal year. The asterisk indicates the extension of the early fetal period, in which early fetal macaques (60 PCD) cluster with midfetal humans. (C) The weight (W) of five transcriptomic signatures in the developing human (solid line) and macaque (dashed line) NCX and the respective association with neurodevelopmental processes. In signature 1 (neurogenesis), the arrow indicates the point at which the signature reaches the minimum in humans (red) and macaques (green). The asterisk indicates the same as in (B). In transcriptomic signatures 2, 3, 4, and 5, arrows indicate the point at which the signatures reach the maximum in humans (red) and macaques (green). Note that for transcriptomic signatures 2 and 3 (neuronal differentiation and astrogliogenesis), there is a synchrony between humans and macaques, whereas for transcriptomic signatures 4 and 5 (synaptogenesis and myelination), there is heterochrony between the species, with acceleration in human synaptogenesis and delay in human myelination. Prefrontal cortical areas are plotted in red, primary motor cortex in orange, parietal areas in green, temporal areas in blue, and primary visual cortex in gray. MFC, medial prefrontal cortex; OFC, orbital prefrontal cortex; DFC, dorsolateral prefrontal cortex; VFC, ventrolateral prefrontal cortex; M1C, primary motor cortex; S1C, primary somatosensory cortex; IPC, inferior posterior parietal cortex; A1C, primary auditory cortex; STC, superior temporal cortex; ITC, inferior temporal cortex; V1C, primary visual cortex. (D) Cell type enrichment is shown for each signature. P values adjusted by Benjamini-Hochberg procedure are plotted (with ranges indicated by size of dots); significance is labeled by color (red, true; gray, false). H, human; M, macaque; eNEP/RGC, embryonic neuroepithelial progenitor/radial glial cell; eIPC, embryonic intermediate progenitor cell; eNasN, embryonic nascent neuron; ExN, excitatory neuron; InN, interneuron; Astro, astrocyte; OPC, oligodendrocyte progenitor cell; Oligo, oligodendrocyte; Endo, endothelial cell; VSMC, vascular smooth muscle cell.

  • Fig. 2 Ontogenetic interregional transcriptomic differences display a cup-shaped pattern in humans and macaques.

    (A and B) The interregional difference was measured as the average distance of each neocortical area to all other areas in the human (A) and macaque (B) neocortices across development. The upper-quartile interregional difference among all genes is plotted; the color scale indicates magnitude. The gray planes represent the transition from prenatal to early postnatal development (late fetal transition) and from adolescence to adulthood. (C) The number of coexpression modules that display gradient-like expression (anterior to posterior, posterior to anterior, medial to lateral, temporal lobe–enriched) and enrichment in primary areas or enrichment in association areas in each developmental phase. Left, human modules; right, macaque modules. (D) Donut plots depicting the modules from (C) that exhibited species-distinct interregional differences. The expression pattern of each species-distinct module is shown for humans (top) and macaques (bottom). Color scales indicate expression level of the genes in each module. Prenatal modules show a human-distinct anterior-to-posterior expression gradient (left); macaque-distinct early postnatal modules show enrichment in primary or association areas (center); and a macaque-distinct adult module is enriched in association areas, especially in MFC (right). HS, human (Homo sapiens) module; MM, macaque (Macaca mulatta) module.

  • Fig. 3 Transcriptomic divergence between humans and macaques throughout neurodevelopment reveals a phylogenetic cup-shaped pattern.

    (A) Interspecies divergence, measured as absolute difference in gene expression, between humans and macaques in each brain region throughout development (coded as in Fig. 2A). The upper-quartile divergence among all genes is plotted. The gray planes represent the transition from prenatal to early postnatal development (late fetal transition, left) and from adolescence to adulthood (right). (B) Venn diagrams displaying the number of differentially expressed genes (DEX, top) or genes with differential exon usage (DEU, bottom) between humans and macaques in at least one brain region during prenatal development, early postnatal development, and adulthood. (C) Bubble matrix with examples of genes showing global or regional interspecies differential expression. Brain regions displaying significant differential expression between humans and macaques are shown with black circumference. Red circles show up-regulation in humans; blue, up-regulation in macaques. Circle size indicates absolute log2 fold change. (D) Percentage of overlap between genes showing the highest interspecies divergence in each region (driving the evolutionary cup-shaped pattern) and genes with the largest pairwise distance between brain regions in prenatal, early postnatal, and adult human and macaque brains (driving the developmental cup-shaped pattern). The result is plotted using a variable number of the highest-ranked genes based on interregional difference and interspecies divergence. Data are means ± SD across regions.

  • Fig. 4 Cell type specificity of species differences.

    (A) Cell type enrichment for differentially expressed genes up- or down-regulated in human neocortical areas. Enrichment of genes up-regulated in humans or macaques was tested using single cells from prenatal human NCX (33) or macaque DFC, respectively. The plot shows –log10 P values adjusted by Benjamini-Hochberg procedure averaged across all neocortical areas (NCX), prefrontal areas (PFC), and non-prefrontal areas (nonPFC). Significance (average −log10 P > 2) is labeled by color (red, true; gray, false). (B) Same as (A) for early postnatal and adult periods. (C) Cell type enrichment of selected genes showing human-distinct up- or down-regulation in adult brain regions or neocortical areas (34). Preferential expression measure is plotted to show the cell type specificity.

  • Fig. 5 Shared and divergent transcriptomic features of homologous cell types between humans and macaques.

    (A) Dendrogram and heat map showing diversity and correlation of prenatal cell types within and between the two species. The human single cells were from (33). (B) Dendrogram and heat map showing diversity and correlation of adult cell types within and between the two species. (C) Cell type specificity of interspecies differentially expressed genes based on the single cell/nucleus information. Blue, human down-regulated genes; red, human up-regulated genes.

  • Fig. 6 Heterochronic expression of regional and interspecies gene clusters.

    (A) Clusters of genes exhibiting species-distinct regional heterochronic expression patterns in human and macaque brains at various prenatal periods and adulthood. The timing of expression of genes in the cluster is represented by a color scale (blue, earlier expression; red, later expression). Prenatal heterochronic regional clusters RC21 and RC34 show earlier expression in human prenatal frontoparietal perisylvian neocortical areas (M1C, S1C, and IPC) and enrichment in neural progenitors. RC10 is composed of genes with earlier expression in the human prenatal prefrontal cortex and enrichment in astrocytes. These observed regional expression patterns are not present in the macaque prenatal NCX. Adult heterochronic cluster RC25 shows earlier expression in primary areas of the macaque cortex and enrichment for genes associated with oligodendrocytes. (B) A network of 139 interspecies heterochronic genes (blue) is enriched for targets of putative upstream transcriptional regulators that include those encoded by eight genes of the same network (red) and TWIST1 (green), a transcription factor with interspecies heterotopic expression (fig. S34). Arrows indicate direction of regulation. (C) Top five canonical pathways enriched among interspecies heterochronic genes in at least one neocortical area. The dashed red line corresponds to P = 0.01. (D) Cluster EC14 shows interspecies heterochronic expression, exhibits a delayed expression specifically in the human prenatal prefrontal cortex, and is enriched for genes selectively expressed by intermediate progenitor cells (IPC).

  • Fig. 7 Heterotopic and/or heterochronic expression of disease-associated genes between humans and macaques.

    (A) Bar plot depicting the number of genes associated with autism spectrum disorder (ASD; hc, high confidence), neurodevelopmental disorders (NDD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD), Alzheimer’s disease (AD), and Parkinson’s disease (PD) that display heterochronic divergence between humans and macaques. (B) Bubble matrix showing the heterochronic expression of ASD- and SCZ-associated genes. Blue represents earlier expression in humans; red represents earlier expression in macaques. (C) Bar plot depicting the number of genes associated with neuropsychiatric disorders that exhibit heterotopic divergence between humans and macaques. The 14 SCZ-associated genes that displayed heterotopy are grouped into five clusters on the basis of their spatiotemporal expression profiles (fig. S41). (D) Donut plots exhibiting the centered expression of the five SCZ-associated heterotopic clusters in prenatal development, early postnatal development, and adulthood. Clusters that are not significantly divergent between species in each period are gray and do not have a black border. Red indicates high expression; blue indicates low expression.

Supplementary Materials

  • Spatiotemporal transcriptomic divergence across human and macaque brain development

    Ying Zhu, André M. M. Sousa, Tianliuyun Gao, Mario Skarica, Mingfeng Li, Gabriel Santpere, Paula Esteller-Cucala, David Juan, Luis Ferrández-Peral, Forrest O. Gulden, Mo Yang, Daniel J. Miller, Tomas Marques-Bonet, Yuka Imamura Kawasawa, Hongyu Zhao, Nenad Sestan

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Figs. S1 to S47
    • Captions for tables S1 to S27
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    Tables S1 to S3
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    Tables S7 to S23
    Tables S24 to S27

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