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Combining and investing functions of the nervous system

combining and investing functions of the nervous system

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Compared to their wild-type littermates, juvenile mice carrying the two human-specific mutations also showed differences in ultrasonic vocalizations Enard et al. Each row presents a study that investigated a different type of human-specific change in a mouse model, with the right column highlighting a specific finding of the study. In order, the studies are Enard et al. Pt, Pan troglodytes , common chimpanzee; Hs, Homo sapiens , human. Note that the findings displayed, particularly for the Enard et al.

Beyond single nucleotide substitutions, studies have begun to explore the contribution of larger structural changes, such as duplications, to phenotypic differences between human and NHP brains. Human-specific duplications of genes with neurodevelopmental functions are of particular interest, as these duplications may have resulted in novel gene function that is restricted to humans.

Investigating these events generally involves accurate sequencing of large-insert bacterial artificial chromosome BAC libraries to fully resolve the structure and evolution of these highly complex regions. There are more than 30 gene families expanded specifically in humans Sudmant et al. After the divergence of human and chimpanzee lineages, SRGAP2 underwent a series of duplications in humans, with one duplication fixed across all human populations studied Dennis et al.

Interestingly, experiments in mouse suggest that this human-specific paralog interferes with the function of the ancestral copy of SRGAP2 , antagonizing its role in synapse regulation, maturation, and density, resulting in protracted synapse maturation, increased synaptic density in neocortical pyramidal neurons, and prolonged spine maturation Fossati et al.

Recently, Florio and collaborators discovered that this gene is highly expressed in isolated radial glial cells, while its expression was undetectable in cortical neurons and cortical plate. It appears to do so by promoting apical radial glia cells to undergo symmetric-differentiative divisions producing two basal progenitors in each mitosis Florio et al.

Due to their human-specific evolution at the genomic level along with their phenotypic characterization in mouse, SRGAP2 and ARHGAP11B are strong candidates for playing an important role in producing differences in human brain development that occurred after the split of human and chimpanzees. Among other promising candidate genes under study in the context of evolutionary neuroscience are BOLA2 and DUF repeats, which are both linked to autism spectrum disorder Davis et al.

These domains are mostly present in the NBPF gene family and mainly found in chromosome 1 1q Almost all DUF regions accumulated in humans since the split with chimpanzee are located within a human-specific pericentromeric inversion. Deletions and duplications in this DUF -rich locus have been implicated in microcephaly and macrocephaly, respectively Brunetti-Pierri et al. There appears to be a positive correlation between brain size and DUF content in the genome within the human population and between species Keeney et al.

All of the protein-coding changes discussed above stem from modifications of existing genes. Human-specific protein-coding genes created de novo from noncoding sequence are rare. Estimates on the number of de novo protein-coding genes present only in humans vary widely, with up to 60 genes proposed Knowles and McLysaght, ; McLysaght and Guerzoni, ; Guerzoni and McLysaght. These genes are largely functionally uncharacterized but show a tendency for increased expression in the brain and testes Wu et al.

Many phenotypic differences between humans and NHPs, including those involving the nervous system, may be rooted in regulatory variation. A meta-analysis of positive selection in coding and noncoding regions of the genome has provided support for this idea, as neural genes are enriched for regulatory evolution Haygood et al.

In addition, comparative genomics has facilitated the identification of putative regulatory regions marked by exceptional change in the human lineage. Collectively, genome-wide scans have revealed more than 2, non-coding regions that, while highly conserved in other species, have accumulated a remarkable number of substitutions in humans Bird et al. These studies provide a set of putative regulatory elements that, due to their pattern of sequence evolution, are candidates for producing human-specific gene regulation, which may ultimately lead to human-specific phenotypes, including unique features of human neurodevelopment.

Because these human-specific regions are identified from genomic comparisons, additional information is needed to infer the spatiotemporal context in which any given sequence operates. For example, several studies have reported that differentially expressed genes across brain regions disproportionately neighbor conserved noncoding sequences that display human-specific acceleration Lambert et al.

However, a recent study suggests that this association is confounded by the number of conserved noncoding sequences that a gene neighbors Meyer et al. Using enhancer assays in transgenic mice, several studies have identified cases where a human-accelerated region, compared to the orthologous region from other species, drives a distinct pattern of expression of a reporter gene in the developing mouse brain Boyd et al.

Another recent study found that some rare human mutations occurring in specific human-accelerated regions were associated with autism spectrum disorder Doan et al. Of the 14 accelerated regions, all of which reside in introns of NPAS3 , transgenic assays in zebrafish provided evidence that 11 were capable of driving reproducible expression of a reporter gene in the CNS.

Focusing on one of these regions, Kamm et al. The human-accelerated sequence, by contrast, drove LacZ expression in an extended region that included the developing anterior telencephalon Figure 5 ; Kamm et al. This example is among the currently small catalog of human-specific changes in regulatory regions that likely generate human-specific expression patterns of genes that are important in brain development. In a search for conserved sequences with human-specific deletions instead of an accelerated rate of base-pair substitutions, McLean et al.

As with accelerated sequences, transgenic enhancer assays have provided evidence for the relevance of a human-specific deletion in brain development. The chimpanzee and mouse versions of a sequence that was deleted near GADD45G are able to drive expression of a reporter gene in the subventricular zone of developing mice Figure 5. This finding raises the possibility that a human-specific deletion of this enhancer contributes to the expansion of the human neocortex.

While expression assays are a useful step in linking genomic variants to phenotypic change, only recently has a study carried out more extensive functional characterization of a human-specific regulatory region. Boyd et al. First, they showed that the human enhancer drives the expression of a LacZ reporter more robustly and in an earlier developmental time than the homologous chimpanzee sequence Figure 5.

Then, they determined that the enhancer regulates its nearest gene, FZD8 , a member of the frizzled gene family, which produces receptors for the WNT proteins. The authors generated transgenic mice with FZD8 under the control of either the human or chimpanzee enhancer. Mice with the human enhancer had neural progenitors with a faster cell cycle and displayed an increase in brain size.

To date, many genome-wide scans have been performed using a wide range of methods and species to catalog human-specific sequence changes, and there are still changes that remain to be described. For example, a recent analysis of tandem repeats between humans and NHPs found that genes containing repeats show higher expression divergence between species, including in brain samples Bilgin Sonay et al.

Repeats that are conserved in NHPs but different in human either fixed across humans or polymorphic show enrichment for neural-development-related categories. However, while there are still sequence-level differences to explore, particularly as technological advances allow for investigation of complex regions of the genome, more extended experimental work is needed to gain a more comprehensive understanding of the role of human-specific sequences in human brain specializations.

Transcriptome profiling of tissues provides an additional level of information that can be used to prioritize genes for functional studies of human-specific gene regulation during neurodevelopment. Recent comprehensive analyses of gene expression across multiple human brain regions and time points have revealed that gene expression is dynamically regulated across brain regions and time Colantuoni et al. Within the midfetal neocortex, robust inter-regional and areal transcriptional differences were observed at the level of individual genes, as well as groups of highly co-expressed genes modules , and included specific patterns of expression demarcating prospective prefrontal and perisylvian areas, which are involved in some of the most distinctly human aspects of cognition and behavior Figure 4A Johnson et al.

Moreover, these studies have also revealed differences among humans, NHPs, and rodents in the expression of certain genes and proteins previously implicated in neurodevelopment Figure 4B. Together, these results suggest that early and mid fetal periods are key to exploring the development of human brain specializations and that human-specific, and likely transient, changes in the spatiotemporal expression of certain genes during these periods may play a role in the unique features of human neural circuit development.

Most studies comparing gene expression between humans and NHPs have analyzed transcriptional differences in adult samples. This is largely due to the lack of high-quality prenatal and early postnatal tissues, especially from great apes.

Given the difficulty of interpreting adult studies in the context of brain development, we will only briefly summarize these adult studies. However, these findings were not corroborated by other studies, which have reported that gene expression in the human brain is not more divergent Hsieh et al.

Other works reported several interesting findings on human-specific differences in the expression of genes involved in aerobic metabolism Babbitt et al. Although it is nearly impossible to comprehensively study gene expression variation among developing primates, especially the great apes, several studies have made progress in identifying human-specific differences. These studies highlighted groups of genes with developmental time-shifts and focused on neotenic features Somel et al.

Inter-species expression differences were found to be more pronounced in the human prefrontal cortex than in the cerebellum. Though intriguing, this finding is difficult to interpret because no other neocortical areas were examined and because the analyses were limited to postnatal development except Liu et al.

According to Kang et al. Extending transcriptional evolution studies to prenatal stages, when neocortical regions are most distinct from each other in terms of gene expression, will likely be essential for capturing the transcriptional differences that are important for unique features of human neurodevelopment. Beyond a global characterization of spatiotemporal gene expression differences across species, these studies are useful for selecting promising genes for future functional studies.

Alone, it is difficult to interpret gene-expression differences between species for a given gene because these differences may be due to variation in environment or tissue quality, among other confounding variables. Furthermore, even if the difference in expression is biological, it may not have an effect on a phenotypic outcome.

However, despite these limitations, genome-wide expression profiling provides a valuable snapshot that can be used to generate hypotheses and steer functional studies. One such candidate is the gene coding the transcription factor MEF2A, which appears to regulate a module of co-expressed genes involved in synaptogenesis Liu et al. These expression changes match the delay of synaptogenesis observed in humans Petanjek et al.

Interestingly, the comparison of the human, Neanderthal, chimpanzee, and macaque MEF2A locus has shown that there is an excess of SNPs in the human lineage in an upstream region to the gene, indicating that this region is under positive selection in the human lineage Liu et al. Given these findings, MEF2A is an interesting candidate for functional characterization that leverages mouse genetics. In addition to transcriptome data, several contemporary techniques provide valuable information for comparing gene regulation across species.

Chromatin immunoprecipitation sequencing ChIP-seq enables a genome-wide survey of genetic marks that signal regulatory activity of putative promoter and enhancers Reilly and Noonan, These inter-species comparisons of active regulatory elements in different tissues have so far demonstrated that promoters and enhancers are largely conserved between humans and primates with respect to position in spite of sequence divergence Cotney et al.

Conserved epigenetic marks can also be cell type specific, as neuronal epigenomes in prefrontal cortex are more similar across human and NHP chimpanzee and macaque species than they are to non-neuronal epigenomes within the same species Shulha et al. These studies emphasize the need to include a closely related species to identify human-specific gain or loss of enhancer and promoter activity.

This classification cannot be performed in the embryonic enhancer catalog because data from chimpanzees are absent, and thus, prenatal human-specific enhancer activity is yet to be uncovered. Nevertheless, those embryonic enhancers and promoters either specifically active or absent in the human samples involve genes in co-expression modules associated with neuronal proliferation and differentiation Reilly et al.

In these studies, human-accelerated sequence overlapped with some human-specific enhancers, but an overall enrichment was not observed. These new catalogs of putative human-specific enhancers active at specific stages of development and in different brain regions open a novel research space for testing hypotheses linking genes to human-acquired brain differences.

This methylation, driven by the differential expression of DNA methyltransferases, can result in species-, tissue-, and cell-type-specific patterns of gene expression Hernando-Herraez et al. For example, methylation in the brain is particularly pronounced in adult neurons as compared to non-neuronal populations Kozlenkov et al.

A comparison of methylation at putative regulatory regions of 36 genes found that CpG sites appear to be more methylated in the human brain than in the chimpanzee brain Enard et al. On the other hand, promoter regions of several genes were shown to be significantly less methylated in the human brain than in the chimpanzee brain Zeng et al.

Although no obvious global differences were found, it was reported that humans and NHPs have different methylation states at both DNA Farcas et al. There are a number of methods available for investigating these findings in experimental systems, many of which have been discussed above.

The most time-efficient method is in vitro characterization, but the separation of the cellular system from a realistic biological context, especially when it comes to the modeling of specific neural circuits, makes the results difficult to interpret for example, see Heissig et al.

Genome editing and transgenesis in mice, on the other hand, allow for evolutionary hypotheses to be tested in the context of the whole organism using a wide range of genetic tools. Species- and lineage-specific gene variants or regulatory regions can be added or replace endogenous sequences in a model organism so far mainly mice , allowing for in vivo characterization of the feature for example, see Boyd et al.

Developments in iPSC research provide another method for evolutionary and functional analyses Gallego Romero et al. Methods for generating iPSCs and directing their differentiation into specific human neural cell types and cell culture systems, including organoids, have provided much-needed tools for comparative studies of neurodevelopment in humans and NHPs Gallego Romero et al.

Recently, Prescott et al. The authors compared genome-wide enhancer and promoter activity and identified a novel motif enriched in regions with species-biased activity. The functional studies discussed above are encouraging attempts to provide experimental evidence of the molecular mechanisms involved in human brain evolution and underscore the challenges of experimentally testing such evolutionary hypotheses. While mouse models provide the most powerful tools for genomic manipulation in mammals, lineages leading to humans and mice diverged 75 million years ago Mouse Genome Sequencing Consortium et al.

This difference in genetic background complicates the interpretation of functional studies, as genes evolve in concert with the rest of the genome and an alteration or loss of function can be due the absence of any number of unknown players. Thus, while a positive experimental result provides support for a given interpretation, a negative result is ambiguous. Aside from the difficulties of interpreting the results of mouse models specifically, demonstrating that a mutation has a functional consequence that may have been evolutionarily selected is a necessary step to supporting adaptive evolution, but by itself does not provide strong evidence that the mutation was selected in the context hypothesized Nielsen, Therefore, these experimental studies, while far from conclusive, should be viewed as sources of information that serve to either increase or decrease the probability of a given hypothesis.

Multiple lines of evidence show that key aspects of human brain organization and development scale as expected, while cognition does not. Even though the way our brain is built is not exceptional, we differ by a unique combination of mental abilities, combined with higher general intelligence. While higher general intelligence compared to NHPs may likely be the product of increased relative and absolute neuron number, especially in the neocortex, our superiority in specific cognitive abilities is likely the result of mosaic structural rewiring and molecular reorganization of specific neural circuits and cell types.

These observations, as well as the study of brain size and organization in extinct primates Falk, ; Neubauer, ; Pearce et al. It is also likely that these changes have affected many, if not all, brain structures and levels of organization. Advancements in high-throughput molecular biology and biochemistry technologies have enabled unprecedented identification of human-specific features that may contribute to unique aspects of human brain development.

For example, several recent studies have mapped gene expression to specific cell types during brain development, using various single-cell sequencing approaches Johnson et al. The cellular-level resolution of differential expression possible through these approaches, both among neural progenitor cells and subsequent postmitotic populations, allows a better understanding of the myriad fine-tuned processes governing early brain development.

High-throughput techniques also permit, to some degree, the systematization of key aspects of the functional characterization of human specific genomic elements. This is the case for the massively parallel reporter assays, which enable simultaneous testing of the regulatory activity of hundreds of thousands of putative regulatory elements Shlyueva et al. Continued efforts are both important and critical in many areas, including characterizing the extent of human diversity, expanding high-quality annotations of NHP genomes, and increasing the coverage of gene expression profiles across more tissues and time points.

Therefore, within the context of human CNS development and evolution, it will be valuable to profile transcriptional dynamics in developmental NHP samples from an extended number of CNS regions. Most of the recent efforts have focused on a few regions of the forebrain and cerebellum, while almost no data are available on the majority of other regions of the human or NHP CNS.

Furthermore, there is an obvious lack of comparative studies on diverse types of neuronal and glial cells across primates. So far, most of the effort has been largely focused on neocortical neurons. However, astrocytes, oligodendrocytes, and microglia are relevant in many aspects of CNS function and represent half of the cellular composition of the nervous system. It is thus a promising and almost uncharted field that must be explored to generate a more complete and integrated picture of the human CNS specializations.

In addition to NHP comparisons, advances in the acquisition and processing of genomic material from archaic humans Neanderthals and Denisovans can improve temporal resolution of human-specific sequence change. These changes gave rise to only 87 proteins containing amino-acid substitutions. In addition, around 3, of the changes, including both single nucleotide changes and indels, exclusively found and fixed in Homo sapiens were predicted to have an effect on gene regulation.

Some of them, for instance, are found in an intronic HAR of AUTS2 , a gene associated with several neurological phenotypes, in a region also showing strong evidence of a selective sweep that occurred in modern humans after the split with Neanderthals Green et al. Recent studies offer other intriguing observations, such as the fact that genes expressed in developing cortex and adult striatum are significantly depleted in introgressed archaic genetic material Vernot et al.

One of these regions of introgression deserts includes FOXP2. Finally, the emerging field of imaging genetics, which allows the identification of genetic loci explaining variation in brain structures and functions among extant humans Hibar et al. Furthermore, it will be necessary to develop in vitro cellular systems that are able to model the complexities of human neurodevelopment more accurately.

Building on work that has characterized human-specific changes at multiple levels, it will be important for future work to integrate this information and shift focus to detailed experimental studies in order to gain a better understanding of the mechanisms underlying the development and evolutionary specializations of the human nervous system.

We thank members of our laboratory for thoughtful discussions and comments on the manuscript and Amanda Gautier for illustrating the primate brains in Figure 1. Also, we would like to thank reviewers for their insightful comments, as these comments led to an improved manuscript. We apologize to all colleagues whose relevant studies were not cited because of space limitations, the broad scope of this review, and the emphasis on recent studies.

McDonnell Foundation, and the Simons Foundation. Author manuscript; available in PMC Jul Sousa , 1, 8 Kyle A. Meyer , 1, 8 Gabriel Santpere , 1 Forrest O. Kyle A. Forrest O. Author information Copyright and License information Disclaimer.

Copyright notice. The publisher's final edited version of this article is available at Cell. See other articles in PMC that cite the published article. Evolutionary Perspective on Human Nervous System Structure Humans Have the Largest Brain among Extant Primates The overall size of the CNS has been correlated with general intelligence and other indicators of cognitive capacities Jerison, ; Williams and Herrup, , but this relationship is neither robust nor mechanistically understood.

Open in a separate window. Figure 1. Figure 2. Humans Have Specialized Neuronal Connections Myriad neuronal cell types and their specific synaptic connections comprise the core components of neural circuits and networks, which are collectively referred to as the connectome van den Heuvel et al. Figure 3. Developmental Mechanisms Underlying the Evolution of Human Nervous System We have thus far reviewed phenotypic similarities and differences between gross brain features, as well as smaller structures and cell types in human and non-human brains.

Figure 4. Genetic Basis and Molecular Mechanisms Underlying Human Brain Evolution Given a phenotypic difference, identifying underlying genomic changes is a challenging task. Protein-Coding Mutations While many of the genetic differences between species lie outside of protein-coding regions, focusing on amino-acid substitutions makes it easier to identify changes that likely have a functional consequence for example, when an amino acid with very different properties is substituted or a mutation leads to a stop codon.

Figure 5. Mouse Models of Human-Specific Genomic Features Each row presents a study that investigated a different type of human-specific change in a mouse model, with the right column highlighting a specific finding of the study. Mutations to Noncoding Regulatory Regions Many phenotypic differences between humans and NHPs, including those involving the nervous system, may be rooted in regulatory variation.

Changes in Patterns of Developmental and Adult Gene Expression Transcriptome profiling of tissues provides an additional level of information that can be used to prioritize genes for functional studies of human-specific gene regulation during neurodevelopment. Changes in Patterns of Developmental and Adult Regulatory Marks In addition to transcriptome data, several contemporary techniques provide valuable information for comparing gene regulation across species.

Functional Modeling of Human Brain Development and Evolution There are a number of methods available for investigating these findings in experimental systems, many of which have been discussed above. Conclusions and Future Directions Multiple lines of evidence show that key aspects of human brain organization and development scale as expected, while cognition does not. Acknowledgments We thank members of our laboratory for thoughtful discussions and comments on the manuscript and Amanda Gautier for illustrating the primate brains in Figure 1.

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Unraveling the evolution of uniquely human cognition.

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Combining and investing functions of the nervous system Estimates on the number of de novo protein-coding genes present only in humans vary widely, with up to 60 genes proposed Knowles and McLysaght, ; McLysaght and Guerzoni, ; Guerzoni and McLysaght. The strategies that neuroscientists have adopted for studying the nervous system have varied over the years as new techniques and methods have been developed. The gray matter of the ventral horn initiates somatic reflexes while the gray matter of the lateral horn initiates autonomic reflexes. Neuroscientists are now applying the new biochemical, anatomical, and physiological techniques to study these animals, and there is reasonable hope that they may solve some of the remaining mysteries of Parkinson's disease in the near future. Second messengers typically diffuse within the cell to deliver the information from the receptor to various target proteins, modifying these proteins' activities and thereby modulating the physiological responses of that cell. Evolutionary history and genome organization of DUF protein domains.
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Combining and investing functions of the nervous system But it is not only in the morphology of the processes that nerve cells differ. Contact us Submission enquiries: alyzza. It should be possible, therefore, to build a bridge between the study of simplified learning and behavior and more general studies of cell biology. Circular representation of human cortical networks for subject and population-level connectomic visualization. Most axons do not grow in isolation but in association with other axons from the same neuronal population, and it is becoming clear that they can use a variety of strategies to find their way. A natural history of the human mind: tracing evolutionary changes in brain and cognition. Gritsch, S.
Uk forex reviews and ratings The von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans. Berer K, et al. A minor inappropriate activation of VN results in excessive activation and elevation of neurotransmitters, thereby impairing the digestive process and influencing gastric motility []. The nerve tract projecting from the top continues the pathway, making a ninety degree turn to the right and continuing to the right border of the image. And research may find much more about them in the future. The first task, known as stereognosisinvolves the naming of objects strictly on the basis of the somatosensory information that comes from manipulating them. TABLE 3.
Combining and investing functions of the nervous system Matcovitch-Natan O, et al. But there is a third function that needs to be included. Takada, M. Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health? Stem Cell Res Amst. It is the organized and coordinated activity of the nervous system that ultimately manifests itself in the behavior of the organism. Quantitative relationships in delphinid neocortex.

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