Functional and Evolutionary Insights into Human Brain Development through Global Transcriptome Analysis
Open accessAbstract
Our understanding of the evolution, formation, and pathological disruption of human brain circuits is impeded by a lack of comprehensive data on the developing brain transcriptome. A whole-genome, exon-level expression analysis of 13 regions from left and right sides of the mid-fetal human brain revealed that 76% of genes are expressed, and 44% of these are differentially regulated. These data reveal a large number of specific gene expression and alternative splicing patterns, as well as coexpression networks, associated with distinct regions and neurodevelopmental processes. Of particular relevance to cognitive specializations, we have characterized the transcriptional landscapes of prefrontal cortex and perisylvian speech and language areas, which exhibit a population-level global expression symmetry. We show that differentially expressed genes are more frequently associated with human-specific evolution of putative cis-regulatory elements. These data provide a wealth of biological insights into the complex transcriptional and molecular underpinnings of human brain development and evolution.
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Different brain regions are associated with complex patterns of alternative splicing.
“and different brain regions are associated with complex patterns of alternative splicing (Johnson et al., 2009).”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Johnson et al., 2009
The PFC, Broca area, and Wernicke area in humans display a temporarily enriched gene expression pattern distinct from mouse or macaque cerebrum at comparable prenatal stages.
“Thus, the PFC as well as the Broca and Wernicke association areas in humans, which are formed in the frontal and temporal lobes, display a temporarily enriched gene expression pattern that is distinct from the mice or macaque cerebrum at the comparable prenatal stages (e.g., [21, 22]).”
From Development of prefrontal cortex (2022) · cites this paper as [21]
Analysis of DE from a dataset of gene expression in developing fetal human brain showed a highly significant (p = 5.8E-9) overlap of DE genes with those found in controls in this study.
“Analysis of DE from a data set 10 of gene expression in developing fetal human brain showed a highly significant (p = 5.8E-9) overlap of DE genes with those found in controls in this study, independently confirming that these genes differentiate normal temporal and frontal lobes.”
From Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology (2011) · cites this paper as [10]
All of the genes shown (top 20) are also differentially expressed between frontal and temporal cortex in fetal midgestation brain.
“All of the genes shown are also differentially expressed between frontal and temporal cortex in fetal midgestation brain 10”
From Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology (2011) · cites this paper as [10]
Genes associated with psychiatric disorders are highly expressed during development.
“Transcriptomic analyses suggest that genes associated with psychiatric disorders are highly expressed during development 5,6 ,”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [5]
This percentage is consistent with the percentage of genes expressed in mouse brain by ISH (80%) and fetal human brain by microarrays (76%).
“consistent with the percentage of genes expressed in mouse brain by ISH (80%; ref. 1) and fetal human brain by microarrays (76%; ref. 11).”
From An anatomically comprehensive atlas of the adult human brain transcriptome (2012) · cites this paper as [11]
This absence of hemispheric differences is consistent with a recent study of developing human neocortex that failed to identify hemispheric differences.
“this finding is consistent with a recent study of developing human neocortex that failed to identify hemispheric differences despite extensive efforts using microarrays and quantitative PCR11.”
From An anatomically comprehensive atlas of the adult human brain transcriptome (2012) · cites this paper as [11]
Rostral and caudal genes identified in grossly dissected cortex largely represent gradients in postmitotic cells, as they overlap with gradient genes in MZ, CP, and IZ.
“Interestingly, rostral and caudal genes that can be identified in grossly dissected cortex3 largely represent gradients in postmitotic cells, as they show significant overlap with gradient genes in MZ, CP, and IZ (Extended Data Fig. 9).”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [3]
Profiling of mid-gestational human brain identified many genes differentially expressed between major regions, including genes associated with human-accelerated conserved noncoding sequences.
“Profiling of mid-gestational human brain3,5 identified many genes differentially expressed between major regions, including genes associated with human-accelerated conserved noncoding sequences (haCNSs)15.”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [3]
Genes near haCNSs are particularly likely to show differential expression between regions of developing human neocortex, suggesting transcriptional regulation by haCNSs may be important in human-specific neurodevelopment.
“Genes near CNSs with significantly accelerated rates of substitution in the human lineage (haCNSs)15 are particularly likely to show differential expression between regions of developing human neocortex3,5, suggesting transcriptional regulation by haCNSs may be important in human-specific neurodevelopment.”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [3]
Prior studies have examined only a restricted subset of prenatal human brain regions and cortical layers.
“Several recent studies have assayed a limited set of brain structures1,3–5 and layers2 from prenatal human brain.”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [3]
Expression trajectories of modules exhibit dynamic patterns across development, consistent with roles in distinct biological processes.
“The expression trajectories of the modules, which can be summarized using the module eigengene or an intramodular hub gene, often exhibit dynamic expression patterns across development, consistent with their roles in distinct biological processes (Johnson et al., 2009; Kang et al., 2011; Miller et al., 2014; Parikshak et al., 2013; Willsey et al., 2013).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Johnson et al., 2009
Recent transcriptome studies have identified substantial regional/areal differences in the developing human neocortex.
“Recent transcriptome studies have identified substantial regional/areal differences in the developing human neocortex (Johnson et al., 2009; Kang et al., 2011; Lambert et al., 2011; Miller et al., 2014; Pletikos et al., 2014).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Johnson et al., 2009
Robust inter-areal transcriptional differences were particularly prominent during early and mid-fetal development and included specific transcriptional signatures associated with prospective prefrontal and perisylvian areas.
“Robust inter-areal transcriptional differences were particularly prominent during early and mid-fetal development and included specific transcriptional signatures associated with prospective prefrontal and perisylvian areas (Johnson et al., 2009; Kang et al., 2011; Miller et al., 2014; Pletikos et al., 2014), which are involved in some of the most distinctly human aspects of cognition and behavior”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Johnson et al., 2009
Regional/areal transcriptional profiles were largely bilaterally symmetrical across the two hemispheres at population-level during fetal, early postnatal development and adulthood.
“Interestingly, these regional/areal transcriptional profiles were largely bilaterally symmetrical across the two hemispheres at the population-level during fetal, early postnatal development and in adulthood (Johnson et al., 2009; Kang et al., 2011; Lambert et al., 2011; Miller et al., 2014; Pletikos et al., 2014).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Johnson et al., 2009
Comparative genomic methods have identified putative conserved cis-regulatory elements or regulatory RNAs, a disproportionate number of which are proposed to regulate human brain-expressed genes.
“Comparative genomic methods have been applied by several groups (Lindblad-Toh et al., 2011; Margulies et al., 2007; Pennacchio et al., 2006; Pollard et al., 2006; Prabhakar et al., 2006; Siepel et al., 2005) to identify putative conserved CREs or regulatory RNAs, a disproportionate number of which are proposed to regulate human brain-expressed genes (Johnson et al., 2009; Pennacchio et al., 2006;”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Johnson et al., 2009
Many genomic regions with accelerated sequence divergence in humans are predicted to be enhancers active during development, with a disproportionate number predicted to regulate human brain-expressed genes.
“In addition to conserved sequences, many genomic regions that display accelerated sequence divergence in humans are predicted to be enhancers active during development, with a disproportionate number predicted to regulate human brain-expressed genes (Capra et al., 2013; Franchini and Pollard, 2015; Johnson et al., 2009; Lambert et al., 2011; Miller et al., 2014; Prabhakar et al., 2006).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Johnson et al., 2009
Differentially expressed genes are more frequently associated with human-specific evolution of putative cis-regulatory elements.
“Differentially expressed genes are more frequently associated with human-specific evolution of putative cis-regulatory elements (Johnson et al., 2009).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Johnson et al., 2009
The transcriptome of the developing prenatal human neocortex is quite heterogeneous across different cortical areas.
“The transcriptome of the developing, prenatal human neocortex, however, is quite heterogeneous across different cortical areas (Johnson et al., 2009; Kang et al., 2011; Miller et al., 2014).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Johnson et al., 2009
RNA expression studies across the mammalian brain have shown significant differences in the transcriptome between neuronal cell types, brain regions, developmental stages, and species.
“Each have reinforced findings of significant differences in the transcriptome between neuronal cell-types, brain regions, developmental stages, and species.”
From Decoding neuroproteomics: integrating the genome, translatome and functional anatomy (2014) · cites this paper as [11]
Splicing in the brain has been extensively profiled using transcriptomics, and specific alternative transcript usage has been implicated in neuropsychiatric disorders.
“Splicing in the brain has been extensively profiled using transcriptomics and specific instances of alternative transcript usage have been implicated in neuropsychiatric disorders11.”
From Decoding neuroproteomics: integrating the genome, translatome and functional anatomy (2014) · cites this paper as [11]
Microarray studies have revealed distinct gene expression profiles and coexpression networks associated with different human brain regions, major cell types, and cellular processes.
“Microarray studies have also revealed distinct gene expression profiles and coexpression networks associated with different human brain regions, major cell types, and cellular processes (Johnson et al., 2009; Miller et al., 2010; Oldham et al., 2006; Oldham et al., 2008).”
From Large-Scale Cellular-Resolution Gene Profiling in Human Neocortex Reveals Species-Specific Molecular Signatures (2012) · cites this paper as Johnson et al., 2009
This finding is consistent with previous microarray gene expression profiling studies, extending the conclusion further by providing cellular level details.
“This finding is consistent with previous microarray gene expression profiling studies (Caceres et al., 2003; Gu and Gu, 2003; Johnson et al., 2009; Miller et al., 2010; Oldham et al., 2008), extending the conclusion further by providing cellular level details.”
From Large-Scale Cellular-Resolution Gene Profiling in Human Neocortex Reveals Species-Specific Molecular Signatures (2012) · cites this paper as Johnson et al., 2009
ROBO1 was differentially expressed in fetal human speech brain regions and in the RA analog of avian vocal learners.
“ROBO1 itself was also found to be differentially expressed in fetal human speech brain regions (77) and in the RA analog of avian vocal learners (70).”
From Convergent transcriptional specializations in the brains of humans and song-learning birds (2014) · cites this paper as [77]
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- Authors
- Johnson, M. B., Kawasawa, Y. I., Mason, C. E., Krsnik, Ž., Coppola, G., Bogdanović, D., Geschwind, D. H., Mane, S. M., State, M. W., & Šestan, N.
- Affiliations
- Yale University (US)
- University of California, Los Angeles (US)
- Corresponding author
- Šestan, Nenad
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 62
- Issue
- 4
- Pages
- 494-509
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2739738
- OpenAlex
- W2126527896
- Cited by
- 603
- References
- 8
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 18 · 2023: 22 · 2022: 21 · 2021: 35 · 2020: 44 · 2019: 27 · 2018: 43 · 2017: 42 · 2016: 26 · 2015: 58 · 2014: 56 · 2013: 43 · 2012: 47
- FWCI
- 17.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1538 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (MH060233, MH081896, NS051869, NS054273, NS056276)
- James S. McDonnell Foundation
- Kavli Foundation
- National Alliance for Research on Schizophrenia and Depression
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- human brain development, gene expression, alternative splicing, co-expression network, prefrontal cortex, hemispheric symmetry, human brain evolution, cis-regulatory elements, brain development
- MeSH terms
- Brain, Fetus, Humans, Functional Laterality, Models, Biological, Neural Pathways, Postmortem Changes, Transcription Factors, Alternative Splicing, Gene Expression Regulation, Developmental, Evolution, Molecular, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Embryonic Development
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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