Genetic Changes Shaping the Human Brain
Open accessAbstract
The development and function of our brain are governed by a genetic blueprint, which reflects dynamic changes over the history of evolution. Recent progress in genetics and genomics, facilitated by next-generation sequencing and single-cell sorting, has identified numerous genomic loci that are associated with a neuroanatomical or neurobehavioral phenotype. Here, we review some of the genetic changes in both protein-coding and noncoding regions that affect brain development and evolution, as well as recent progress in brain transcriptomics. Understanding these genetic changes may provide novel insights into neurological and neuropsychiatric disorders, such as autism and schizophrenia.
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Written from the paper’s full text.
TL;DR
This review synthesizes genetic, genomic, and transcriptomic evidence on human brain development and evolution, focusing on protein-coding changes, noncoding regulatory elements, and somatic mosaicism. It argues that human neocortical evolution reflects both human-specific coding changes and extensive regulatory/transcriptomic divergence, with implications for neurodevelopmental and psychiatric disorders.
Key findings
- Comparative genomics identified ∼2,700 human accelerated regions (HARs), most noncoding, with at least ∼250 functioning as brain developmental enhancers; HAR1 encodes a lncRNA expressed in Cajal-Retzius neurons. Human-specific SRGAP2 paralogs arose 2–3 million years ago; SRGAP2C inhibits SRGAP2A dominantly, and its overexpression in mouse brain sustains radial migration and increases spine density/neoteny.
- FOXP2 differs by only 3 amino acids from mouse and 2 from chimpanzee/gorilla/macaque; humanized FoxP2 mice show accelerated learning, altered ultrasonic vocalizations, and increased dendrite length/synaptic plasticity in striatal medium spiny neurons. Neanderthals, Denisovans, and modern humans share an identical FOXP2 protein.
- Noncoding and transcriptomic analyses show extensive regulatory complexity: human GPR56 has at least 17 alternative promoters versus a handful in mouse; ∼45% of the human genome is transposable elements; >100 primate-specific and 20 human-specific microRNAs are expressed in developing brain; ∼80–95% of protein-coding genes are expressed in at least one brain region.
- Somatic mutations in hemimegalencephaly implicate PI3K–AKT3–mTOR; mosaicism as low as 8% can disrupt neocortical architecture/function. In 158 persons with brain malformations, deep sequencing found somatic mutations represented more than a quarter of all identified mutations, and mutations in as few as 10% of brain cells could cause epilepsy and intellectual disability.
Methods
- Design: narrative review of genetic changes shaping human brain development and evolution, covering comparative genomics, human genetics, noncoding DNA, transcriptomics, and somatic mutation studies.
- Data: published human, primate, archaic human, mouse, and other model-organism studies, including genome sequences, RNA-seq datasets, single-cell sequencing, and clinical mutation cohorts.
- Analysis: synthesis of cited literature; no new primary data, systematic search strategy, or meta-analysis is reported.
Limitations
- The paper states that genome comparisons alone are insufficient because there are nearly 20 million human–chimpanzee differences, functional consequences are mostly unknown, and apparent differences may reflect low sequencing coverage or improper annotation of primate genomes.
- It notes unresolved debates: whether neocortical progenitors are multipotent or fate-restricted, and whether outer radial glia alone explain gyrification; it also cautions that these debates were mainly explored in mice and that results from ferrets, inbred mice, or cell culture should not be quickly extrapolated to humans.
- It states that single-cell sequencing can identify somatic mutations only in surgically resected or postmortem brain tissue, making noninvasive identification of brain-limited mosaicism impossible; evident from the text, this is a review rather than a systematic synthesis, so its conclusions depend on selected cited studies.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
0 of 127 cited sources checked · 0 supported · 0 flagged
- Premisecitation
Many known genetic mutations causing human primary microcephaly target the centrosome.
“Many of the known genetic mutations causing human primary microcephaly target one subcellular organelle – the centrosome (Gilmore and Walsh, 2013).”
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- Interpretationreasoning
The cortico-striatal circuitry mediates speech and language in humans.
“These findings suggest that the cortico-striatal circuitry mediates speech and language in humans (Enard et al., 2009; Fujita et al., 2008; Schreiweis et al., 2014; Shu et al., 2005).”
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AHI1 has undergone evolutionary changes along the human lineage.
“Another crucial neurodevelopmental gene, AHI1, has undergone evolutionary changes along the human lineage (Ferland et al., 2004).”
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SRGAP2C dimerizes with full-length SRGAP2A and inhibits SRGAP2A function in a dominant negative manner.
“With its truncated F-BAR domain, SRGAP2C dimerizes with full-length SRGAP2A and inhibits SRGAP2A function in a dominant negative manner.”
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Neanderthals, Denisovans and modern humans share an identical FOXP2 protein.
“Perhaps surprisingly, Neanderthals, Denisovans and modern humans share an identical FOXP2 protein (Meyer et al., 2012; Noonan et al., 2006).”
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Somatic genetic changes during development and lifetime can affect the brain.
“Most recently, we have been discovering the extent to which genetic changes that occur somatically, during the development and lifetime of an individual, can affect the brain (Jamuar et al., 2014; Poduri et al., 2013).”
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Genetic changes that occurred as Homo sapiens diverged from the common ancestor of primates are identifiable as human-specific regions of the genome.
“Genetic changes that occurred as Homo sapiens diverged from the common ancestor of primates are identifiable as human-specific regions of the genome (Pollard et al., 2006).”
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Human and chimpanzee FOXP2 have strikingly different transcriptional targets, many of which are involved in central nervous system development.
“These amino acid changes are functionally critical as the human and chimpanzee FOXP2 have strikingly different transcriptional targets, many of which are involved in central nervous system development (Konopka et al., 2009).”
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Microcephaly is largely caused by mutations disrupting genes encoding centrosomal proteins: MCPH1, ASPM, CDK5RAP2, CENPJ, STIL, WDR62, CEP152, and CEP63.
“Microcephaly is largely caused by mutations that disrupt genes encoding centrosomal proteins: MCPH1, ASPM, CDK5RAP2, CENPJ, STIL, WDR62, CEP152, and CEP63 (Bilguvar et al., 2010; Bond et al., 2002; Bond et al., 2005; Guernsey et al., 2010; Jackson et al., 2002; Kumar et al., 2009; Nicholas et al., 2010; Sir et al., 2011; Yu et al., 2010).”
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A systematic search identified 510 human-specific deletions compared with other primate genomes, almost exclusively in noncoding regions.
“Conversely, a systematic search for human-specific deletions compared with other primate genomes identified 510 such deletions in humans that fall almost exclusively in noncoding regions (McLean et al., 2011).”
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ASPM and CDK5RAP2 show evidence for positive selection not only in primates but also across placental mammals.
“Intriguingly, a few microcephaly-associated genes, notably ASPM and CDK5RAP2, show evidence for positive selection not only in primates but also across placental mammals.”
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Mutations in AHI1 cause Joubert syndrome, a congenital brain malformation of the cerebellar vermis and brainstem.
“Mutations in AHI1 cause Joubert syndrome, a congenital brain malformation of the cerebellar vermis and brainstem.”
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- Interpretationreasoning
At least some neurobiological and physiological aspects of speech and language probably emerged after divergence from chimpanzees.
“Thus, at least some neurobiological and physiological aspects of speech and language probably emerged after divergence from chimpanzees.”
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The human-specific SRGAP2 paralogs emerged when the genus Homo diverged from Australopithecus 2-3 million years ago.
“Thus, the human-specific SRGAP2 paralogs emerged when the genus Homo diverged from Australopithecus 2–3 million years ago (Dennis et al., 2012).”
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Some apparent differences between humans and non-humans may reflect technical effects such as low sequencing coverage and improper annotation of primate genomes.
“One important caveat here is that some of the apparent differences between humans and non-humans may simply reflect technical effects such as low sequencing coverage and improper annotation of primate genomes compared to the human genome.”
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A BLASTP-based search revealed a few de novo genes that are unique to the human genome.
“A search based on BLASTP (Protein Basic Local Alignment Search Tool) revealed a few de novo genes that are unique to the human genome (Knowles and McLysaght, 2009; Wu et al., 2011).”
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- cites Wu et al., 2011
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There are many qualitative and quantitative differences in cerebral cortex development between humans and mice.
“However, there are many qualitative and quantitative differences in the development of the cerebral cortex (neocortex) between humans and mice (Geschwind and Rakic, 2013; Hill and Walsh, 2005)”
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Alternative splicing can produce multiple different functional mRNAs and proteins with diverse expression patterns from the same gene.
“Although the actual number of protein-coding genes in humans is much smaller than initial estimates of approximately 100,000 genes, alternative splicing has been recognized as an important source of variation, potentially producing multiple different functional mRNAs and proteins with diverse expression patterns from the same gene (Keren et al., 2010; Nilsen and Graveley, 2010).”
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- cites Nilsen and Graveley, 2010
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- Interpretationreasoning
The centrosome-associated cell division machinery may be critical to neocortical evolution.
“These data suggest that the centrosome-associated cell division machinery may be critical to neocortical evolution.”
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In the absence of a microcephaly protein, human neural progenitors may fail to asymmetrically inherit the ciliary membrane or grandmother centriole, thereby losing stem cell character prematurely.
“Thus, in the absence of a microcephaly protein, human neural progenitors may fail to asymmetrically inherit the ciliary membrane or grandmother centriole, thereby losing stem cell character prematurely.”
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One human-specific deletion removes a forebrain germinal zone enhancer near GADD45G, suggesting a possible role in the expansion of specific brain regions in humans.
“One such deletion removes a forebrain germinal zone enhancer near the tumor suppressor gene growth arrest and DNA-damage-inducible, gamma (GADD45G), suggesting a possible role in the expansion of specific brain regions in humans.”
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Mere comparison of genomes from different species is not sufficient to identify functionally relevant genetic changes.
“However, mere comparison of the genomes from different species is not sufficient to identify functionally relevant genetic changes, as there are countless differences between the human genome and the genomes of other species.”
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Duplicated genes diverge functionally over time by accumulating changes in coding sequence and associated noncoding regulatory elements, altering protein expression patterns.
“Duplicated genes diverge functionally over time by accumulating changes in the coding sequence as well as in associated noncoding regulatory elements, which alter protein expression patterns (Carroll et al., 2005; Conant and Wolfe, 2008).”
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- cites Conant and Wolfe, 2008
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The developing prefrontal cortex has a distinct gene network that contains a number of schizophrenia genes.
“Regionally enriched transcriptomes form a co-expression network; for example, the developing prefrontal cortex has a distinct gene network that contains a number of schizophrenia genes (Gulsuner et al., 2013).”
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Primate-specific microRNAs target cell-cycle and neurogenesis regulators, thereby increasing proliferation of neocortical progenitors.
“The primate-specific microRNAs target cell-cycle and neurogenesis regulators, thereby increasing proliferation of neocortical progenitors.”
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Mutations in GPR56 coding sequences cause polymicrogyria in most of the neocortex.
“Mutations in the coding sequences cause polymicrogyria (‘too many small gyri’) in most of the neocortex (Piao et al., 2004).”
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More than 100 primate-specific and 20 human-specific microRNAs are expressed in the developing brain.
“For example, there are more than 100 primate-specific, and 20 human-specific microRNAs that are expressed in the developing brain (Berezikov, 2011).”
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Excitatory neurons, which constitute the majority of neocortical neurons, are derived from radial glial cells in the ventricular zone.
“Excitatory neurons, which constitute the majority of neocortical neurons, are derived from neocortical progenitors called radial glial (RG) cells in a germinal zone called the ventricular zone (VZ) (Ayoub et al., 2011; Fietz et al., 2012).”
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Almost half of the known protein-coding genes in humans utilize alternative promoters.
“In addition to alternative splicing, almost half of the known protein-coding genes in humans utilize alternative promoters.”
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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).”
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Somatic mutations identified in human hemimegalencephaly (HMG) reveal the dysregulated PI3K-AKT3-mTOR pathway as the causative mechanism.
“Somatic mutations that were identified in human hemimegalencephaly (HMG) revealed the dysregulated phosphoinositide 3-kinase (PI3K)–AKT3-mTOR pathway as the causative mechanism (Lee et al., 2012; Poduri et al., 2012; Riviere et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Diversification of noncoding elements and promoters results in region-specific gene expression in the cortex, allowing independent development and functional specialization of distinct neocortical regions.
“These data suggest that diversification of noncoding elements and promoters results in region-specific gene expression in the cortex, thus allowing independent development and functional specialization of distinct neocortical regions.”
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Many complex alternative promoters and exons of human GPR56 were derived from LINEs and SINEs.
“For example, many of the complex alternative promoters and exons of human GPR56 were derived from LINEs and SINEs (Bae et al., 2014).”
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- Interpretationcitation
Primate-specific co-evolution of microRNAs and their targets in the germinal zones may have contributed to neocortical expansion in primates.
“Primate-specific co-evolution of microRNAs and their targets in the germinal zones may have contributed to neocortical expansion in primates (Arcila et al., 2014).”
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RBFOX targets are frequently dysregulated in autism.
“RBFOX targets are also frequently dysregulated in autism, highlighting the critical role of alternative splicing in brain development and function (De Rubeis et al., 2014; Voineagu et al., 2011; Weyn-Vanhentenryck et al., 2014).”
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The mouse neocortex transcriptome is markedly different from the primate transcriptome.
“In contrast, the mouse neocortex transcriptome is markedly different from the primate transcriptome.”
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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).”
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The outer subventricular zone shows minimal transcriptional differences from the inner subventricular zone.
“However, the OSVZ shows minimal transcriptional differences from the inner subventricular zone (Miller et al., 2014)”
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The precise introduction of mutations that cause severe human neocortical phenotypes into the mouse genome often leads to negligible phenotypes in the mouse.
“Hence, the precise introduction of mutations that cause severe human neocortical phenotypes into the mouse genome often leads to negligible phenotypes in the mouse.”
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Humans, non-human primates, and placental mammals with an enlarged brain have an additional expanded germinal zone called the outer subventricular zone, where outer or basal RG cells are abundant.
“Remarkably, humans, non-human primates, and placental mammals with an enlarged brain have an additional, expanded germinal zone called the outer subventricular zone (OSVZ), where a unique population of neocortical progenitors called outer or basal RG cells are abundant (Betizeau et al., 2013; Fietz et al., 2010; Hansen et al 2010; Lui et al., 2011; Reillo et al., 2011; Smart et al., 2002).”
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A recurrent AKT3 mutation (Glu17Lys) was identified in HMG by direct study of resected tissue.
“Direct study of resected tissue led to the identification of a recurrent AKT3 mutation (Glu17Lys) in HMG.”
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Somatic mutations were often missed by Sanger sequencing and by some whole exome sequencing with typical calling algorithms.
“This study revealed that such somatic mutations represented more than a quarter of all identified mutations, and were often missed both by Sanger sequencing and by some whole exome sequencing with typical calling algorithms.”
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- Premisecitation
Single-cell sequencing has been used to evaluate the rate of somatic LINE1 retrotransposition in the human brain.
“In the human brain, single-cell sequencing has been successfully used to detect somatic mosaicism in HMG and to evaluate the rate of somatic long interspersed nuclear element-1 (LINE1) retrotransposition (Evrony et al., 2012).”
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Levels of mosaicism as low as 8% are sufficient to disrupt the normal architecture and function of the neocortex in HMG.
“Surprisingly, levels of mosaicism as low as 8% are sufficient to disrupt the normal architecture and function of the neocortex in HMG (Evrony et al., 2012; Lee et al., 2012; Poduri et al., 2012; Riviere et al., 2012).”
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LINE1 retrotransposition is not a major generator of neuronal diversity in the brain.
“Fewer than one unique insertion was detected per neuron, suggesting that LINE1 retrotransposition is not a major generator of neuronal diversity in the brain.”
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- Interpretationcitation
Functional studies of human neurogenetic mutations are challenging because the human brain has evolved novel circuits, cell types, and signaling pathways that are rare or absent in animal models.
“Functional studies of human neurogenetic mutations are obviously challenging, due to the fact that the human brain has evolved dramatically in the last 2–3 million years, gaining novel circuits, cell types, and signaling pathways that are rare or absent in animal models (Geschwind and Rakic, 2013; Molnar et al., 2014; Paabo, 2014).”
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In the human brain, single-cell sequencing has been successfully used to detect somatic mosaicism in HMG.
“In the human brain, single-cell sequencing has been successfully used to detect somatic mosaicism in HMG and to evaluate the rate of somatic long interspersed nuclear element-1 (LINE1) retrotransposition (Evrony et al., 2012).”
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- Interpretationcitation
High-coverage sequencing panels provide an important complement to whole exome and genome sequencing in the evaluation of somatic mutations in the human brain.
“This report suggests that high-coverage sequencing panels provide an important complement to whole exome and genome sequencing in the evaluation of somatic mutations in the human brain (Jamuar et al., 2014).”
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- Interpretationnone given
At 50-60 times coverage, it is possible to dismiss low levels of true somatic mosaicism as errors (false negative results).
“Typical whole genome sequencing or Sanger sequencing of pooled DNA from many cells covers each base in the genome 50–60 times; at this level of coverage, it is possible to dismiss low levels of true somatic mosaicism as errors (false negative results).”
Quote in the paperSubstantial claim- Rests on an assumption: Typical whole genome sequencing or Sanger sequencing of pooled DNA from many cells covers each base in the genome 50–60 times.
- Interpretationreasoning
Noninvasive identification of somatic mosaicism limited to the brain is impossible.
“Noninvasive identification of somatic mosaicism limited to the brain is impossible.”
Quote in the paperSubstantial claim - Premisecitation
The human brain has evolved dramatically in the last 2-3 million years, gaining novel circuits, cell types, and signaling pathways that are rare or absent in animal models.
“Functional studies of human neurogenetic mutations are obviously challenging, due to the fact that the human brain has evolved dramatically in the last 2–3 million years, gaining novel circuits, cell types, and signaling pathways that are rare or absent in animal models (Geschwind and Rakic, 2013; Molnar et al., 2014; Paabo, 2014).”
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Additional somatic mutations causing HMG implicate key upstream and downstream components of the PI3K-AKT3-mTOR pathway, namely PI3K and mTOR.
“Additional somatic mutations causing HMG have been identified that implicate key upstream and downstream components of this pathway, namely PI3K and mTOR (Lee et al., 2012; Riviere et al., 2012).”
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Fewer than one unique insertion was detected per neuron.
“Fewer than one unique insertion was detected per neuron, suggesting that LINE1 retrotransposition is not a major generator of neuronal diversity in the brain.”
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Low levels of somatic mosaicism are difficult to detect.
“While low levels of somatic mosaicism are clinically important, they are also difficult to detect.”
Quote in the paperSubstantial claim - Interpretationnone given
Somatic mutations that occurred during or after neurogenesis can be identified only in surgically resected or postmortem brain tissues.
“One caveat of single-cell sequencing is that somatic mutations that occurred during or after neurogenesis can be identified only in surgically resected or postmortem brain tissues.”
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Substantial disability in the form of epilepsy and intellectual disability could be caused by mutations present in as few as 10% of brain cells.
“Substantial disability in the form of epilepsy and intellectual disability could be caused by mutations present in as few as 10% of brain cells.”
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- Premisecitation
In the study of brain malformations, somatic mutations represented more than a quarter of all identified mutations.
“This study revealed that such somatic mutations represented more than a quarter of all identified mutations, and were often missed both by Sanger sequencing and by some whole exome sequencing with typical calling algorithms.”
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- Premisecitation
Analysis of leukocyte-derived DNA samples from 158 persons with brain malformations identified somatic mosaicism that had been difficult to detect previously.
“Analysis of leukocyte-derived DNA samples from 158 persons with brain malformations identified somatic mosaicism that had been difficult to detect previously.”
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Single-cell sequencing has been used to measure the prevalence of large copy number variants in the brain.
“Single-cell sequencing has also been used to measure the prevalence of large copy number variants in the brain (McConnell, 2013; Cai, 2014).”
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Single-cell sequencing can re-purpose LINE1 retrotransposition events for cell lineage analysis in the developing human brain.
“Interestingly, single-cell sequencing can re-purpose the LINE1 retrotransposition events for cell lineage analysis in the developing human brain (Evrony et al., 2015).”
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- Premisecitation
The AKT3 Glu17Lys mutation renders AKT3 constitutively active.
“AKT3 is a RAC-gamma serine/threonine protein kinase that is highly expressed in the developing neocortex, and the Glu17Lys mutation renders AKT3 constitutively active (Lee et al., 2012; Poduri et al., 2012).”
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PremisecitationNearly 99% of the human genome does not encode proteins and the approximately 21,000 human protein-coding genes are generally surprisingly similar across placental mammals.
“Indeed, the human genome project has made it clear that nearly 99% of the human genome does not encode proteins and that the approximately 21,000 human protein-coding genes are in general surprisingly similar across placental mammals (Lander, 2011; Lander et al., 2001; Venter et al., 2001).”
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PremisecitationMice carrying humanized FoxP2 show accelerated learning, qualitatively different ultrasonic vocalizations, and increased dendrite length and synaptic plasticity in medium spiny neurons of the striatum.
“Mice carrying humanized FoxP2 show accelerated learning, qualitatively different ultrasonic vocalizations, and increased dendrite length and synaptic plasticity in the medium spiny neurons of the striatum.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Enard et al., 2009
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- cites Fujita et al., 2008
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- cites Schreiweis et al., 2014
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PremisecitationCASC5, KIF18A, and SPAG5 carry modern human-specific amino-acid substitutions and localize to the mitotic spindle or kinetochore.
“The centrosome-associated cell division machinery contains at least three more proteins that carry modern human-specific amino-acid substitutions. CASC5 (cancer susceptibility candidate 5), KIF18A (kinesin family member 18A), and SPAG5 (sperm-associated antigen 5) localize to the mitotic spindle, which is organized by the centrosome, or to the kinetochore, which attaches chromosomes to the spindle”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Paabo, 2014
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- cites Prufer et al., 2014 source
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PremisecitationHuman FOXP2 protein differs at only 3 amino acid residues from the mouse ortholog and at 2 residues from the chimpanzee, gorilla, and rhesus macaque orthologs.
“Comparison of the FOXP2 cDNAs from multiple species indicates that the human FOXP2 protein differs at only 3 amino acid residues from the mouse ortholog, and at 2 residues from the chimpanzee, gorilla, and rhesus macaque orthologs (Enard et al., 2002).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Enard et al., 2002 source
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PremisecitationThe majority of human genes have been generated by gene duplication.
“Indeed, the majority of human genes have been generated by gene duplication (Ohno, 1970; Zhang, 2003).”
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PremisecitationOverexpression of SRGAP2C in the mouse brain results in sustained radial migration of neurons, increased spine density, and neoteny during spine maturation, which are human-specific features of neuronal development.
“Overexpression of SRGAP2C in the mouse brain results in sustained radial migration of neurons as well as increased spine density and neoteny during spine maturation, which are human-specific features of neuronal development.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationApproximately 2700 human accelerated regions (HARs) have been identified, most in noncoding regions, and at least about 250 of these HARs seem to function as developmental enhancers in the brain.
“So far, ∼2700 HARs have been identified, again most of them in noncoding regions: at least ∼250 of these HARs seem to function as developmental enhancers in the brain (Capra et al., 2013).”
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InterpretationcitationThe human and non-human primate amino acid sequences of the N-terminal coiled-coil domain of AHI1 are highly divergent and this domain is totally missing in mice and rats, suggesting AHI1 may play a crucial human-specific role during neurodevelopment.
“In particular, the human and non-human primate amino acid sequences of the N-terminal coiled-coil domain of AHI1 are highly divergent – and this domain is totally missing in mice and rats – suggesting that AHI1 may play a crucial, human-specific role during neurodevelopment.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThe evolution of ASPM and CDK5RAP2 is strongly correlated with brain size, suggesting their roles in brain evolution.
“The evolution of ASPM and CDK5RAP2 is strongly correlated with brain size, suggesting their roles in brain evolution (Montgomery and Mundy, 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Montgomery and Mundy, 2014
Not checked in the free run.
May combine two claims.
PremisecitationHumans have four forms of SRGAP2: one ancestral form (SRGAP2A) orthologous to mouse Srgap2 and three human-specific paralogs (SRGAP2B, SRGAP2C, SRGAP2D) produced by incomplete segmental duplication.
“Mice have only one form of the Srgap2 gene, but humans have four forms: one ancestral form (SRGAP2A), which is orthologous to mouse Srgap2, and three human-specific paralogs (SRGAP2B, SRGAP2C, and SRGAP2D) that were produced by incomplete segmental duplication.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationPrimates share common, closely matched gene expression patterns in the neocortex, while the human frontal lobe is transcriptionally more complex.
“Comparison of the adult human and non-human primate brain transcriptomes shows that primates share common, closely matched gene expression patterns in the neocortex, while the human frontal lobe is transcriptionally more complex (Bernard et al., 2012; Konopka et al., 2012; Pletikos et al., 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Bernard et al., 2012
Not checked in the free run.
- cites Konopka et al., 2012
Not checked in the free run.
- cites Pletikos et al., 2014 source
Not checked in the free run.
May combine two claims.
PremisecitationLINE1 is still active and has been implicated in dozens of diseases.
“Most transposable elements are inactive due to mutations, but LINE1 is still active and has been implicated in dozens of diseases (Hancks and Kazazian, 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hancks and Kazazian, 2012
Not checked in the free run.
May combine two claims.
PremisecitationThe PDYN gene is expressed in layers 4 and 5 in primary visual cortex in primates, but only in scattered GABAergic interneurons in mice.
“The prodynorphin (PDYN) gene, which encodes dynorphin and other kappa opioid receptor peptide agonists, is expressed in layers 4 and 5 in primary visual cortex in primates, but is expressed only in scattered GABAergic interneurons in mice (Bernard et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bernard et al., 2012
Not checked in the free run.
May combine two claims.
PremisecitationnSR100 controls alternative splicing of 3-15 nucleotide microexons during neurogenesis, and reduced nSR100 and dysregulated neuronal microexons are implicated in some cases of autism.
“nSR100 controls alternative splicing of 3–15 nucleotide “microexons,” which in turn alters protein-protein interactions, during neurogenesis. Reduced levels of nSR100 and dysregulated neuronal microexons are implicated in some cases of autism (Irimia et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Irimia et al., 2014 source
Not checked in the free run.
May combine two claims.
PremisecitationMany conserved noncoding elements were derived from transposable elements, and the number of conserved noncoding elements is sharply increased in the genome of placental mammals.
“Many conserved noncoding elements were derived from transposable elements. Comparison of placental and marsupial genomes demonstrates that the number of conserved noncoding elements is sharply increased in the genome of placental mammals (Lindblad-Toh et al., 2011; Mikkelsen et al., 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationTranscriptional differences are found between different neocortical areas, and each area expresses specific gene expression and alternative splicing patterns often with a rostrocaudal, mediolateral, or frontotemporal gradient.
“First, transcriptional differences are found between different neocortical areas (e.g., orbital/dorsolateral/ventrolateral/medial prefrontal, motor-somatosensory, parietal association, temporal auditory, temporal association, and occipital visual neocortex). Each area expresses a large number of specific gene expression and alternative splicing patterns, often with a rostrocaudal, mediolateral, or”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationClustered protocadherins are alternatively spliced and there are approximately 350,000 possible combinatorial protocadherin proteins from about 60 Pcdh loci.
“Clustered protocadherins are perhaps the most complex synapse-specificity and circuit-assembly molecules that are alternatively spliced (Zipursky and Sanes, 2010). With numerous alternative exons for multiple protein domains, there are approximately 350,000 possible, combinatorial protocadherin proteins from about 60 Pcdh loci.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zipursky and Sanes, 2010
Not checked in the free run.
May combine two claims.
PremisecitationThe SV2C gene is expressed preferentially in layer 3 pyramidal neurons in primates, but in layer 5 pyramidal neurons in mice.
“For example, the synaptic vesicle protein 2c (SV2C) gene is expressed preferentially in layer 3 pyramidal neurons in primates, but is expressed in layer 5 pyramidal neurons in mice.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bernard et al., 2012
Not checked in the free run.
May combine two claims.
PremisecitationTransposable elements provide novel binding sites for the host transcriptional machinery and help create novel regulatory networks.
“Over the course of evolution, transposable elements provide novel binding sites for the host transcriptional machinery, and thus help create novel regulatory networks (Davidson, 2010; Wray, 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationTranscription profiles in the adult neocortex are relatively homogeneous throughout the cortex, although some heterogeneity exists.
“Surprisingly, it turned out that transcription profiles in the adult neocortex are relatively homogeneous throughout the cortex, although a certain level of heterogeneity still does exist (Hawrylycz et al., 2012; Kang et al., 2011; Pletikos et al., 2014)”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationRG cells and the ventricular zone are common to all mammals and express cell proliferation genes, with human RG cells showing species-specific signaling pathways such as PDGFD signaling.
“RG cells and the VZ are common to all mammals, and express cell proliferation genes (e.g., SOX2, PAX6, ASPM), with human RG cells showing a number of species-specific signaling pathways such as platelet derive growth factor D (PDGFD) signaling (Lui et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lui et al., 2014
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe human BDNF gene has nine promoters that are used in specific tissues and brain regions.
“For example, the human brain-derived neurotrophic factor (BDNF) gene has nine promoters that are used in specific tissues and brain-regions (Pruunsild et al., 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pruunsild et al., 2007 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA polymorphism in the promoter region of the human serotonin transporter gene SLC6A4 is associated with several dimensions of neurosis and psychopathology.
“A polymorphism in the promoter region of the human serotonin transporter gene SLC6A4 has also been associated with several dimensions of neurosis and psychopathology (Hariri et al., 2002).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hariri et al., 2002 source
Not checked in the free run.
May combine two claims.
PremisecitationThe human noncoding element directs gene expression in a highly restricted pattern, whereas the mouse element directs more diffuse expression.
“Intriguingly, the human noncoding element directs gene expression in a highly restricted pattern, whereas the mouse element directs more diffuse expression.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bae et al., 2014 source
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May combine two claims.
PremisecitationPolymicrogyria restricted to neocortical areas surrounding the Sylvian fissure including Broca's area was identified, and the causative mutation in the GPR56 locus disrupts a noncoding element that is a strong neural promoter in the 5'-upstream regulatory region.
“Recently, polymicrogyria restricted to the neocortical areas surrounding the Sylvian fissure including Broca’s area, the primary language area, was identified (Bae et al., 2014). The causative mutation is found in the GPR56 locus, but disrupts a noncoding element, which constitutes a strong neural promoter during development, in the 5’-upstream regulatory region of GPR56.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bae et al., 2014 source
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May combine two claims.
InterpretationcitationAt least one-third of human brain candidate enhancers are unique to humans and not functionally conserved in mice, suggesting that a significant portion of human brain enhancers emerged after the divergence of primates and rodents.
“At least one-third of human brain candidate enhancers are unique to humans and not functionally conserved in mice, suggesting that a significant portion of human brain enhancers emerged after the divergence of primates and rodents (Visel et al., 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Visel et al., 2013
Not checked in the free run.
May combine two claims.
PremisecitationHuman GPR56 has at least 17 alternative promoters, whereas mouse Gpr56 has only a handful.
“It turned out that the human GPR56 has at least 17 alternative promoters, whereas mouse Gpr56 has only a handful.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bae et al., 2014 source
Not checked in the free run.
Classified as probably not a substantial claim.
InterpretationreasoningResults from ferrets, inbred mice, or cell culture systems cannot be quickly extrapolated to human neocortical development per se.
“Regardless, caution must be taken against quick extrapolation of results from ferrets, inbred mice, or cell culture systems to human neocortical development per se.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAKT3 is a RAC-gamma serine/threonine protein kinase that is highly expressed in the developing neocortex.
“AKT3 is a RAC-gamma serine/threonine protein kinase that is highly expressed in the developing neocortex, and the Glu17Lys mutation renders AKT3 constitutively active (Lee et al., 2012; Poduri et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Lee et al., 2012
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- cites Poduri et al., 2012
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSingle-cell sequencing has been used to evaluate the clonal evolution of tumors.
“Single-cell sequencing has already been used to evaluate the clonal evolution of tumors (Hou et al., 2012; Navin et al., 2011; Xu et al., 2012) and the spontaneous mutation of sperm cells (Lu et al., 2012; Wang et al., 2012).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSingle-cell sequencing has been used to evaluate the spontaneous mutation of sperm cells.
“Single-cell sequencing has already been used to evaluate the clonal evolution of tumors (Hou et al., 2012; Navin et al., 2011; Xu et al., 2012) and the spontaneous mutation of sperm cells (Lu et al., 2012; Wang et al., 2012).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Lu et al., 2012
Not checked in the free run.
- cites Wang et al., 2012
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHMG is occasionally associated with TSC.
“although there had been rare cases of HMG associated with the overgrowth syndromes tuberous sclerosis complex (TSC) (Cartwright et al., 2005)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cartwright et al., 2005
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenLow levels of somatic mosaicism are clinically important.
“While low levels of somatic mosaicism are clinically important, they are also difficult to detect.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningIt is not known how common a cause of complex neurogenetic disease somatic mosaic mutations are, because standard methods such as Sanger sequencing or whole exome sequencing have difficulty detecting them.
“Given the difficulty of detecting somatic mosaic mutations by standard methods such as Sanger sequencing or even whole exome sequencing, it is not known how common a cause of complex neurogenetic disease they are.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
Where there is a phenotype, there is likely to be an associated genetic or epigenetic change.
“The basic premise of human genetics is simple: where there is a phenotype, there is likely to be an associated genetic (or epigenetic) change.”
The paper relies on this without support.
Humans have a remarkably similar number of protein-coding genes to model organisms such as mice and worms, and most essential evolutionary changes did not happen by simple gene addition or subtraction.
“However, a general consensus is that humans have a remarkably similar number of protein-coding genes to model organisms such as mice and worms, and that most of the essential evolutionary changes did not happen by simple gene addition or subtraction.”
The paper relies on this without support.
Somatic mutations arise during the cell divisions that generate the embryo.
“Somatic mutations, which arise during the cell divisions that generate the embryo, have recently been implicated in several important neurological diseases.”
The paper relies on this without support.
TSC is caused by mutations in TSC1 and TSC2, which encode members of the mTOR pathway.
“TSC is caused by mutations in TSC1 and TSC2, which encode members of the mTOR pathway.”
The paper relies on this without support.
Typical whole genome sequencing or Sanger sequencing of pooled DNA from many cells covers each base in the genome 50–60 times.
“Typical whole genome sequencing or Sanger sequencing of pooled DNA from many cells covers each base in the genome 50–60 times; at this level of coverage, it is possible to dismiss low levels of true somatic mosaicism as errors (false negative results).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Many genes localized to the centrosome and mitotic spindle are involved in maintaining the polarity of dividing neuroblasts, and some mutations affecting these genes are thought to be critical for the development of the human neocortex.
“Many genes localized to the centrosome and mitotic spindle are involved in maintaining the polarity of dividing neuroblasts, and some mutations affecting these genes are thought to be critical for the development of the human neocortex (44).”
From An ancestral recombination graph of human, Neanderthal, and Denisovan genomes (2021) · cites this paper as [44]
In “Identification of Evolutionarily Important Genomic Regions Using Human Genetics” (page unavailable), the review links centrosomal proteins to asymmetric inheritance in dividing neural progenitors and identifies mutations in centrosomal genes that cause microcephaly. It also identifies spindle-localized proteins as possible contributors to neocortical evolution. It does not establish that many centrosome- and spindle-localized genes maintain neuroblast polarity, or that mutations in those spindle genes are critical to human neocortical development. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe mechanisms underlying the assembly of human neurons into complex neural circuits remain poorly understood.
“those underlying the assembly of human neurons into complex neural circuits remain poorly understood”
From Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits (2019) · cites this paper as Bae et al., 2015
The Abstract says that understanding of brain development remains incomplete, and “Neurogenetics is Just the Beginning” describes the challenges of studying human-specific circuits. The paper also discusses circuit-assembly molecules in “Noncoding DNA and Human Brain Evolution,” but it does not specifically say that the mechanisms by which human neurons assemble into complex circuits remain poorly understood. No page numbers are available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe developing human CNS has derived features including expanded proliferative zones and diverse neural stem/progenitor cell subtypes with enhanced proliferative capacity that facilitate brain expansion, especially neocortical expansion.
“the developing human CNS possesses certain divergent and highly derived features, such as expanded proliferative zones and diverse subtypes of neural stem and progenitor cells with enhanced proliferative capacities that facilitate brain expansion, especially of the neocortex (Bae et al., 2015; Bystron et al., 2006; Dehay et al., 2015; Gulden and Sestan, 2014; Howard et al., 2008; Lui et al., 2011;”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Bae et al., 2015
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Evolution of genetic and genomic features unique to the human lineage
O'Bleness, M., Searles, V. B., Varki, A., Gagneux, P., & Sikela, J. M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3336 · Cited by 168 · see citing works
Radial glia require PDGFD-PDGFRβ signalling in human but not mouse neocortex
Lui, J. H., Nowakowski, T. J., Pollen, A. A., Javaherian, A., Kriegstein, A. R., & Oldham, M. C. (2014) · Nature · doi:10.1038/nature13973 · Cited by 166 · see citing works
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Hiller, M., Schaar, B. T., Indjeian, V. B., Kingsley, D. M., Hagey, L. R., & Bejerano, G. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.08.032 · Cited by 144 · see citing works
Renewed focus on the developing human neocortex
Clowry, G. J., Molnár, Z., & RAKIC, P. T. (2010) · Journal of Anatomy · doi:10.1111/j.1469-7580.2010.01281.x · Cited by 141 · see citing works
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A genome-wide screen for noncoding elements important in primate evolution
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Evolution and development of the mammalian cerebral cortex
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NOBEL LECTURE: Nature's Gift to Science
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The Genetic Geography of the Brain
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Flagged first, then by citations
Research works printed but not linked: 1
- Bae, 2013, Neuroscience. What are mini-brains?, Science, 342, 200, 10.1126/science.1245812 · DOI
Cited by
Sorted by citations
The genetic architecture of the human cerebral cortex
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Integrative functional genomic analysis of human brain development and neuropsychiatric risks
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Evolution of the Human Nervous System Function, Structure, and Development
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The Dynamic Landscape of Open Chromatin during Human Cortical Neurogenesis
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Molecular and cellular reorganization of neural circuits in the human lineage
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“This is an open access article under the CC BY-NC-ND license (http:// progress in understanding the mechanisms of human cortical expansion, those underlying the assembly of human neurons into complex neural circuits remain poorly understood (Bae et al., 2015; Defelipe, 2011; Geschwind and Rakic, 2013; Lui et al., 2011…”
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Sestan, N., & State, M. W. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.015 · Cited by 127 · see citing works
An ancestral recombination graph of human, Neanderthal, and Denisovan genomes
Schaefer, N. K., Shapiro, B., & Green, R. E. (2021) · Science Advances · doi:10.1126/sciadv.abc0776 · Cited by 106 · see citing works
“Many genes localized to the centrosome and mitotic spindle are involved in maintaining the polarity of dividing neuroblasts, and some mutations affecting these genes are thought to be critical for the development of the human neocortex (44).”
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From Human Pluripotent Stem Cells to Cortical Circuits
Astick, M., & Vanderhaeghen, P. (2018) · Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2018.02.011 · Cited by 34 · see citing works
- Authors
- Bae, B.-I., Jayaraman, D., & Walsh, C. A.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Walsh, Christopher A.
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 32
- Issue
- 4
- Pages
- 423-434
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC4429600
- OpenAlex
- W1995877138
- Cited by
- 135
- References
- 147
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 7 · 2023: 13 · 2022: 9 · 2021: 20 · 2020: 16 · 2019: 12 · 2018: 25 · 2017: 11 · 2016: 6 · 2015: 5
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc)
- PubMed Central (acceptedVersion, cc-by-nc)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (T32HL087735)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Neurological Disorders and Stroke (T32NS007473)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- human brain evolution, brain development, genetic loci, neuroanatomical phenotypes, neurobehavioral phenotype, non-coding regions, protein-coding genes, brain transcriptomics, autism spectrum disorder, schizophrenia, neuropsychiatric disorders
- MeSH terms
- Animals, Brain, Biological Evolution, Gene Expression Regulation, Humans, Phenotype, Genomics, Databases, Genetic
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
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