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Written | November The current understanding of human evolution is mainly derived from the support of fossil evidence, which proves that there are multiple branches of ancient human lineages during the evolution process.
Among them, Neanderthals and Denisovans are similar to modern humans, so they can provide a comparison of the most subtle genetics and phenotypes that have emerged during human evolution.
The evolutionary highly conserved splicing regulator NOVA1 (Neuro-oncological ventral antigen 1) plays a key role in neurodevelopment and function.
However, in the modern human genome, NOVA1 has gradually evolved from Neanderthals and Danny during the evolutionary process.
Sovar protein coding variants.
In order to study the functional importance of amino acid changes in human evolution, the Alysson R.
Muotri research group of the University of California in the United States published an article in Science titledReintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopmen, using gene editing technology to make NOVA1 mutations in ancient humans The type allele was reintroduced into human-induced pluripotent cells, and then their neural development was tracked through cortical organoids, revealing the key role of the mutation site in the neural development process.
In order to summarize and analyze the evolutionary genetic variation, the authors analyzed the human genome information from the 1000 Genomes Project [1] and the Simons Genome Diversity Project [2] and found 61 non-synonymous amino acid variants.
It is unique to mankind and is preserved stably in the present mankind.
This result provides an experimentally easy-to-handle candidate gene for the genetic variation that may constitute a specific human phenotype.
As a result, the authors discovered that the candidate RNA binding protein NOVA1 contains a fixed non-synonymous variant, which does not exist in Neanderthals and Denisovans (Figure 1).
This has aroused the research interest of the authors.
Through structural analysis, the authors found that the I200V mutation of NOVA1 in modern humans appeared on the second of the three KH (K homology) structures and was related to the interaction of RNA molecules (Figure 1).
Figure 1 There is an I200V mutation in NOVA1 in modern humans.
In order to study the function of this ancient mutation in human evolution, the authors constructed an induced pluripotent stem cell line containing the ancient NOVA1 variant.
The authors used CRISPR-Cas9 gene editing technology to construct modern human versions of NOVA1Hu/Hu and NOVA1Ar/Ar, which contain ancient mutants.
In addition, in order to construct a control experimental group, the authors also established a non-functional NOVA1NOVA1Ko/Ko knockout group and a NOVA1Ko/Ar with a copy of the ancient mutant NOVA1 supplemented on the knockout version.
After confirming that there is no off-target effect through sequencing, the authors used the above four induced pluripotent stem cell lines to induce different genotypes of cerebral cortical organoids.
The authors found that the cortical organs of NOVA1Ar/Ar and NOVA1Ko/Ar are significantly smaller than NOVA1Hu/Hu in the proliferation and maturation stages (Figure 2).
Through the analysis of cell proliferation, cell cycle, cell apoptosis, and cell types, the authors found that cerebral cortical organoids containing ancient mutations are smaller because they contain more apoptotic cells, and the proliferation ability of cells is also certain.
Change.
Figure 2 Bright field diagrams of different genotypes of NOVA1 cortical organoids in the induction, proliferation and maturation stages.
Further, considering that NOVA1 is a splicing regulator, the authors performed RNA analysis in cortical organoids of different developmental stages and different genotypes.
Sequencing, hoping to detect changes in potential gene expression and alternative splicing. Compared with NOVA1Hu/Hu, most of the genetic changes in NOVA1Ar/Ar are related to cell development, cell proliferation, neural tissue and connections.
In addition, through the eCLIP (enhanced cross-linking and immunoprecipitation) technology [3], the authors explored the binding preference of NOVA1 in the mutant cortical organs of modern humans and ancient humans, and found that the two types of NOVA1 binding peaks have 2/ 3 is coincident, but NOVA1 in cortical organs with ancient mutants will be more inclined to bind in the short 3'UTR region.
In addition, since many genes with altered expression in the ancient mutant NOVA1 organoids are related to synapse formation and neural networks, the authors used electron microscopy to observe the synaptic ultrastructures of modern humans and ancient humans NOVA1 cortical organs.
It was found that the number of synaptic vesicles in the ancient mutant cortical organoids was significantly reduced.
Further through the detection of synaptic-associated network proteins and electrophysiological properties, the authors found significant differences between the two organoids.
Therefore, the results indicate that the expression of the ancient NOVA1 variant can cause changes in synaptic protein interaction network proteins, affect glutamatergic signals, trigger differences in neuronal connections, and neuronal electrophysiological heterogeneity.
Figure 3 Working model.
In general, this work has established cortical organoids with different variants of the NOVA1 gene in modern humans and ancient humans, and identified the key role of ancient variants of NOVA1 in the process of neurodevelopment.
This may It is an important functional impact caused by the differences between modern humans and Neanderthals and Denisovans in the evolutionary process.
It is worth mentioning that in the discussion section at the end of the article, the authors state the limitations of this work.
First of all, the ancient mutant NOVA1 was genetically manipulated in specific, modern human induced pluripotent stem cells.
The difference in genetic background between modern humans and ancient humans may also be the cause of downstream genetic changes. Secondly, although the authors ruled out possible off-target effects caused by CRISPR-Cas9 through large-scale sequencing, it is still possible that some undetected and untargeted genetic variants may affect the activity of NOVA12.
But in general, the results of this work support the hypothesis that the ancient NOVA1Ar/Ar gene mutation changes the development of cortical organoids in the context of modern humans, and provides important evidence for the evolution of modern human neurodevelopment.
Original link: https://doi.
org/10.
1126/science.
aax2537 Platemaker: 11 References 1 Auton, A.
et al.
A global reference for human genetic variation.
Nature 526, 68-74, doi:10.
1038/ nature15393 (2015).
2 Mallick, S.
et al.
The Simons Genome Diversity Project: 300 genomes from 142 diverse populations.
Nature 538, 201-206, doi:10.
1038/nature18964 (2016).
3 Van Nostrand, EL et al.
Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP).
Nature methods 13, 508-514, doi:10.
1038/nmeth.
3810 (2016).
Instructions for reprinting [Original Articles] BioArt original articles, individuals are welcome Reposting and sharing, reprinting without permission is prohibited, the copyright of all published works is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
Among them, Neanderthals and Denisovans are similar to modern humans, so they can provide a comparison of the most subtle genetics and phenotypes that have emerged during human evolution.
The evolutionary highly conserved splicing regulator NOVA1 (Neuro-oncological ventral antigen 1) plays a key role in neurodevelopment and function.
However, in the modern human genome, NOVA1 has gradually evolved from Neanderthals and Danny during the evolutionary process.
Sovar protein coding variants.
In order to study the functional importance of amino acid changes in human evolution, the Alysson R.
Muotri research group of the University of California in the United States published an article in Science titledReintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopmen, using gene editing technology to make NOVA1 mutations in ancient humans The type allele was reintroduced into human-induced pluripotent cells, and then their neural development was tracked through cortical organoids, revealing the key role of the mutation site in the neural development process.
In order to summarize and analyze the evolutionary genetic variation, the authors analyzed the human genome information from the 1000 Genomes Project [1] and the Simons Genome Diversity Project [2] and found 61 non-synonymous amino acid variants.
It is unique to mankind and is preserved stably in the present mankind.
This result provides an experimentally easy-to-handle candidate gene for the genetic variation that may constitute a specific human phenotype.
As a result, the authors discovered that the candidate RNA binding protein NOVA1 contains a fixed non-synonymous variant, which does not exist in Neanderthals and Denisovans (Figure 1).
This has aroused the research interest of the authors.
Through structural analysis, the authors found that the I200V mutation of NOVA1 in modern humans appeared on the second of the three KH (K homology) structures and was related to the interaction of RNA molecules (Figure 1).
Figure 1 There is an I200V mutation in NOVA1 in modern humans.
In order to study the function of this ancient mutation in human evolution, the authors constructed an induced pluripotent stem cell line containing the ancient NOVA1 variant.
The authors used CRISPR-Cas9 gene editing technology to construct modern human versions of NOVA1Hu/Hu and NOVA1Ar/Ar, which contain ancient mutants.
In addition, in order to construct a control experimental group, the authors also established a non-functional NOVA1NOVA1Ko/Ko knockout group and a NOVA1Ko/Ar with a copy of the ancient mutant NOVA1 supplemented on the knockout version.
After confirming that there is no off-target effect through sequencing, the authors used the above four induced pluripotent stem cell lines to induce different genotypes of cerebral cortical organoids.
The authors found that the cortical organs of NOVA1Ar/Ar and NOVA1Ko/Ar are significantly smaller than NOVA1Hu/Hu in the proliferation and maturation stages (Figure 2).
Through the analysis of cell proliferation, cell cycle, cell apoptosis, and cell types, the authors found that cerebral cortical organoids containing ancient mutations are smaller because they contain more apoptotic cells, and the proliferation ability of cells is also certain.
Change.
Figure 2 Bright field diagrams of different genotypes of NOVA1 cortical organoids in the induction, proliferation and maturation stages.
Further, considering that NOVA1 is a splicing regulator, the authors performed RNA analysis in cortical organoids of different developmental stages and different genotypes.
Sequencing, hoping to detect changes in potential gene expression and alternative splicing. Compared with NOVA1Hu/Hu, most of the genetic changes in NOVA1Ar/Ar are related to cell development, cell proliferation, neural tissue and connections.
In addition, through the eCLIP (enhanced cross-linking and immunoprecipitation) technology [3], the authors explored the binding preference of NOVA1 in the mutant cortical organs of modern humans and ancient humans, and found that the two types of NOVA1 binding peaks have 2/ 3 is coincident, but NOVA1 in cortical organs with ancient mutants will be more inclined to bind in the short 3'UTR region.
In addition, since many genes with altered expression in the ancient mutant NOVA1 organoids are related to synapse formation and neural networks, the authors used electron microscopy to observe the synaptic ultrastructures of modern humans and ancient humans NOVA1 cortical organs.
It was found that the number of synaptic vesicles in the ancient mutant cortical organoids was significantly reduced.
Further through the detection of synaptic-associated network proteins and electrophysiological properties, the authors found significant differences between the two organoids.
Therefore, the results indicate that the expression of the ancient NOVA1 variant can cause changes in synaptic protein interaction network proteins, affect glutamatergic signals, trigger differences in neuronal connections, and neuronal electrophysiological heterogeneity.
Figure 3 Working model.
In general, this work has established cortical organoids with different variants of the NOVA1 gene in modern humans and ancient humans, and identified the key role of ancient variants of NOVA1 in the process of neurodevelopment.
This may It is an important functional impact caused by the differences between modern humans and Neanderthals and Denisovans in the evolutionary process.
It is worth mentioning that in the discussion section at the end of the article, the authors state the limitations of this work.
First of all, the ancient mutant NOVA1 was genetically manipulated in specific, modern human induced pluripotent stem cells.
The difference in genetic background between modern humans and ancient humans may also be the cause of downstream genetic changes. Secondly, although the authors ruled out possible off-target effects caused by CRISPR-Cas9 through large-scale sequencing, it is still possible that some undetected and untargeted genetic variants may affect the activity of NOVA12.
But in general, the results of this work support the hypothesis that the ancient NOVA1Ar/Ar gene mutation changes the development of cortical organoids in the context of modern humans, and provides important evidence for the evolution of modern human neurodevelopment.
Original link: https://doi.
org/10.
1126/science.
aax2537 Platemaker: 11 References 1 Auton, A.
et al.
A global reference for human genetic variation.
Nature 526, 68-74, doi:10.
1038/ nature15393 (2015).
2 Mallick, S.
et al.
The Simons Genome Diversity Project: 300 genomes from 142 diverse populations.
Nature 538, 201-206, doi:10.
1038/nature18964 (2016).
3 Van Nostrand, EL et al.
Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP).
Nature methods 13, 508-514, doi:10.
1038/nmeth.
3810 (2016).
Instructions for reprinting [Original Articles] BioArt original articles, individuals are welcome Reposting and sharing, reprinting without permission is prohibited, the copyright of all published works is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
