What are the main evolutionary characteristics of mankind
Evolutionary human brain enlargement explained?
A large brain allows you and everyone else to read this text, do complex brain teasers, and solve problems. In current publications, two independent research groups describe the function of genes that are apparently a reason for the evolutionary enlargement of the human brain.
The genes of the NOTCH2NL family delay the differentiation of cortical progenitor cells in the cerebrum into mature neurons. The so-called basal progenitor cells can divide more frequently under their influence and therefore generate a larger number of nerve cells and thus of brain mass. In the human genome, the gene sequences for the NOTCH2NL genes are available in triplicate, i.e. as duplications.
The location of the NOTCH2NL genes in the human genome has apparently been incorrectly described so far, as one of the working groups discovered when they examined mutations in known neurological disorders for a connection with the genes found. Because they are apparently at exactly the point, the mutations of which are associated with diseases such as autism and ADHD. If, for example, there are too few or too many versions of the genes due to mutations, the clinical pictures microcephaly and macrocephaly arise - brains that are too small and too large.
- Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology, University Hospital Bonn
- Prof. Dr. Katrin Amunts, Director of the Institute for Structural and Functional Organization of the Brain (INM-1), Forschungszentrum Jülich (FZJ), and Director of the Cécile and Oskar Vogt Institute for Brain Research, Düsseldorf University Hospital, and Deputy Chairwoman of the German Ethics Council
- Prof. Dr. Frank Edenhofer, Deputy Head of the Institute for Molecular Biology, Chair of Genomics, Stem Cell Biology and Regenerative Medicine, University of Innsbruck, Austria
- Prof. Dr. Wieland Huttner, head of the group "Neural stem and progenitor cells and neocortex expansion in development and evolution", Max Planck Institute for Molecular Cell Biology and Genetics (CBG), Dresden
Prof. Dr. Oliver Brüstle
Director of the Institute for Reconstructive Neurobiology, University Hospital Bonn
“There are two very important pieces of work that give an insight into the evolution of the human brain. During brain development, there is a finely regulated balance between the replication of immature stem cells and their maturation in nerve cells. The NOTCH2NL gene family identified by both research groups intervenes in this process by lengthening the phase of cell reproduction and slowing down the maturation in nerve cells, which leads to an overall increase in the number of nerve cells and an enlargement of the cerebral cortex. The gene family described was created by duplicating an evolutionarily very old genetic make-up. This happened at the time of the development of the hominids, which suggests a causal effect in the enlargement of the cerebral cortex in the course of human evolution. "
“Interestingly, at the point in the human genome where the NOTCH2NL gene family is located, damage occurs in the sense of a loss or gain of DNA sequences. The results from the Haussler laboratory suggest that this damage is induced by gene segments that are duplicated in the course of evolution, which, due to their high similarity, can lead to recombinations in the genome. It can therefore be said that this evolutionary change in the genome, on the one hand, favored the formation of a larger cerebral cortex, but on the other hand, increased the risk of spontaneous genetic changes that are ultimately associated with diseases such as schizophrenia or autism can. Interestingly, and in accordance with the assumed role of the NOTCH2NL gene family in the evolutionary increase in size of the brain, a different size of the brain can also be determined in these patients. "
“When classifying the findings, it must be taken into account that a large number of genetic changes have occurred during human evolution that are relevant for brain development and function. This understanding is important in order to counteract any expectations or fears that, for example, artificial insertion of individual genes can easily induce 'humanization' in animal models. "
“Note: Conceptually, the findings fit well with a study published in 2016 in which a primate-specific long-non-coding RNA was described that leads to an amplification of the Notch signaling pathway by inhibiting the miR-143, which is directed against Notch . Incidentally, this long-non-coding RNA is also located in a gene segment whose deletion has been associated with reduced intelligence. In summary, all three studies indicate that the evolutionarily very old Notch signaling pathway was equipped with new regulatory mechanisms in the course of evolution, which could be the cause of the enlargement of the cerebral cortex in the course of human evolution. ,  "
Prof. Dr. Katrin Amunts
Director of the Institute for Structural and Functional Organization of the Brain (INM-1), Research Center Jülich (FZJ), and Director of the Cécile and Oskar Vogt Institute for Brain Research, University Hospital Düsseldorf, and Deputy Chairwoman of the German Ethics Council
"The study by Fiddes examines the influence of the three NOTCH2NL genes on the cellular development of the cerebral cortex, the cortex, in a methodologically very demanding, interdisciplinary approach."
“The analysis of the cortex organoids as a model of an anatomically very simplified cerebral cortex is particularly noteworthy. The organoids grew from human embryonic stem cells and made it possible to study the effects of the NOTCH2NL genes on the differentiation of cell types in different stages of development. "
“The study by Suzuki et al. is methodologically similarly comprehensive and supports the central importance of NOTCH2NLA, -B and -C in human cortical development. The unique selling point of the Suzuki study is that the authors found an activity pattern of 35 genes which, in addition to NOTCH2NL genes, seem to play an important role in human cortex development. These hominid-specific genes are said to have arisen in the course of evolution from an 'primordial gene' through gene duplication and conversion in the genomes of hominids and humans. The experimental data indicate that these events did not occur in chimpanzees, gorillas and orangutans. "
“The findings of the two studies confirm and complement each other. They underpin the key role of the NOTCH2NL genes in the NOTCH signal transduction pathway for the evolutionary expansion of the human cerebral cortex. "
"The data are important to elucidate the complex, multifactorial interplay of various molecular factors and to contribute to species-specific phenotypes such as cortical thickness and cell number."
“It stands to reason that subsequent studies will further characterize the cortical thickness as a fundamental phenotype and also consider its variation in the cerebral cortex and changes during ontogeny. The proportion of nerve cell bodies in comparison to the surrounding neuropil, which contains dendrites, axons and synapses, is a main factor in the brain's blueprint. All of these phenotypes ultimately contribute to brain function, dysfunction, and behavior. The considerations derived from this on the mechanism for the microduplication and microdeletion syndrome at the 1q21.1 locus in humans, where the NOTCH2NL genes are located and which contribute to macrocephaly and microcephaly, appear very plausible. "
"It is important to better understand the pathomechanisms of such syndromes in order to ultimately develop therapeutic options for them."
“At the same time, the development of the blueprint of the brain in evolution, but also in individual development, is subject to a complex dynamic of various genetic and non-genetic factors, of which we have now got to know another building block. Organoids are ultimately an extremely simplified model for certain characteristics of an organism and extensive follow-up studies are necessary to further clarify the role of NOTCH2NL, as the studies also make clear. "
"An ethically responsible handling of such studies requires weighing up the chances of developing new therapies and diagnostics with the possible risks that can arise from the transfer of genes from one species to another or from organoids."
Prof. Dr. Frank Edenhofer
Deputy Head of the Institute for Molecular Biology, Chair for Genomics, Stem Cell Biology and Regenerative Medicine, University of Innsbruck, Austria
"Both studies are groundbreaking in the systematic search and functional analysis of a group of closely related human-specific proteins that could explain the rapid pace of human brain development measured on an evolutionary scale."
"The work must, however, be viewed in the light of another study published in March by a Dresden working group, which has already described the essential findings on the neurodevelopmental significance of the protein family ´NOTCH2NL´ [1.]"
“In fact, it is very difficult to identify such human-specific genes because they are extremely similar to those of non-human primates. In the current study by Fiddes and co-workers, a total of eight new NOTCH2NL protein variants were found in 15 of the human genomes they examined. Suzuki and co-workers used a tailor-made sequencing of RNA for the particularly specific and sensitive detection of the activity of the NOTCH2NL gene variants in the human genome. "
“The three genes coding for NOTCH2NL lie close to a kind of 'genomic predetermined breaking point' on the long arm of human chromosome no. 1. This genetically fragile environment enabled the development of the gene duplication of NOTCH2NL, which is important for the cognitive function of the human brain, as a kind of evolutionary one Innovation."
“Interestingly, genetic changes in this area are also associated with neurological-psychiatric developmental disorders such as autism, epilepsy or schizophrenia. This genomic region of around 6 million base pairs, which is associated with developmental disorders, is collectively referred to as the '1q21.1 deletion / duplication syndrome'. "
“The studies that have now been published suggest that the human species has to pay a high price for accelerated brain development. In the form of a genomic compromise, in which several copies of NOTCH2NL enable a gain in the fetal development of the brain, but at the same time the likelihood of undesirable genetic changes increases, which predisposes us humans to neuro-psychiatric developmental disorders. "
“The outstanding importance of the work by Fiddes et al can also be seen in the fact that the authors used so-called brain organoids ('mini-brains') to model the species-specific effects of NOTCH2NL in cell culture. An experimentally increased activity of NOTCH2NL in brain organoids of the mouse led to a delay in the differentiation of neuronal progenitor cells. "
“In addition, the authors used the CRISPR / Cas gene scissors system to switch off the NOTCH2NL genes in human brain organoids. This enabled them to accelerate differentiation into cortical neurons. This type of genome modification by CRISPR / Cas is technically also possible in the primate model, as was recently shown. "
“From a basic research-oriented point of view, we don't have to fear any 'humanized apes'. The published studies already show that the brain organoids produced in the cell culture are sufficient to analyze the essential developmental differences between humans and monkeys in detail. "
Prof. Dr. Wieland Huttner
Head of the group "Neural stem and progenitor cells and neocortex expansion in development and evolution", Max Planck Institute for Molecular Cell Biology and Genetics (CBG), Dresden
“The two studies published in Cell by the working groups led by Haussler and Vanderhaeghen, as well as our work published in eLife in March 2018 , show that NOTCH2NL can multiply the so-called basal progenitors in the developing cerebrum - neocortex. There are basically two classes of progenitor cells in the developing neocortex: first, the so-called apical progenitor cells in the ventricular zone - the primary germ layer - which produce the basal progenitor cells. And secondly, the basal progenitor cells in the subventricular zone, the secondary germ layer, which migrated there from the ventricular zone and there produce the cortical nerve cells of the growing fetus. "
“The evolutionary enlargement of the neocortex is based on an increased ability of the basal precursor cells to initially multiply and thus ultimately to be able to produce more nerve cells. In this respect, the ability of NOTCH2NL described in the first sentence is consistent with a role in the evolutionary neocortex expansion, even if none of the three studies actually showed an expansion of the neocortex. "
"And: The fact that NOTCH2NL is a human-specific gene has been known for around eight years, first shown by Evan Eichler and colleagues in 2010 , and is not a result of the studies now to be treated."
When asked what the results can contribute to understanding diseases such as autism, ADHD, etc.
“We don't know enough about this yet, and it is far too early to answer these questions. It should be emphasized that there are a number of human-specific genes that are primarily active in cortical progenitor cells, which promote their proliferation, and which are therefore candidate genes for having contributed to the evolutionary expansion of the human neocortex. The first human-specific gene characterized in this context is ARHGAP11B . Indeed, ARHGAP11B has been shown to be able to enlarge the mouse neocortex and even induce its folding. None of this has yet been shown for NOTCH2NL. "
In response to the question: How do you rate ethical questions that could arise from the results, e.g. in relation to research into evolutionary cortical processes, for example through the "humanization of primates" with NOTCH2NL?
“First of all: I am not yet aware of any work in which NOTCH2NL is expressed in cortical progenitor cells of non-human primates. Personally, I consider it ethically irresponsible to allow such 'humanized' non-human primates to be born without prior investigation. First of all, the fetal phenotype after caesarean section during fetal development and before birth should be examined in such non-human primates. "
Information on possible conflicts of interest
All: None specified.
Fiddes IT et al. (2018): Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis. Cell, 173. DOI: 10.1016 / j.cell.2018.03.051.
Suzuki IK et al. (2018): Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta / Notch Regulation. Cell, 173. DOI: 10.1016 / j.cell.2018.03.051.
References cited by the experts
 Florio M et al. (2018): Evolution and cell-type specificity of human-specific genes preferentially expressed in progenitors of fetal neocortex. eLife; 7, e32332. DOI: 10.7554 / eLife.32332.
 Sudmant PH et al. (2010): Diversity of human copy number variation and multicopy genes. Science; 330, 6004: 641-6. DOI: 10.1126 / science.1197005.
 Florio M et al. (2015): Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion. Science; 347, 6229: 1465-70. DOI: 10.1126 / science.aaa1975.
 Rani, N. et al. (2016). A Primate lncRNA Mediates Notch Signaling during Neuronal Development by Sequestering miRNA. Neuron 90, 1174-1188. DOI: 10.1016 / j.neuron.2016.05.005.
 Pratt, T., et al. (2016). Junk DNA Used in Cerebral Cortical Evolution. Neuron 90, 1141-1143. DOI: 10.1016 / j.neuron.2016.06.007
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