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Meet NOTCH2NL, the human genes that our big brains gave us



  Learn about NOTCH2NL, the human-specific genes that may have given us our big brains
This illustration shows the evolutionary history of the NOTCH2NL genes in the large monkey line. Credit: Fiddes et al./Cell

The development of larger brains in the past 3 million years has played an important role in our ability to think as a species, solve problems, and develop culture. But the genetic changes behind the expansion that made us human were elusive. In an article published in Cell on May 31

, two research teams identified a gene family, NOTCH2NL, which appears to play an important role in the development of the human cortex and was possibly a driving force in research Evolution of our great brains. NOTCH2NL genes delay the differentiation of cortical stem cells into neurons, producing more neurons in the course of development. The genes are found exclusively in humans, are strongly expressed in neural stem cells of the human cerebral cortex and are located on a part of the genome that is involved in neurological developmental disorders.

"Our brains have grown three times as large, especially through the extension of certain functional areas of the cerebral cortex, and that must be a fundamental substrate for us to become human." There is really no more exciting scientific question I can come up with genetic changes that have made us what we are, "says David Haussler, co-senior author of one of the papers and bioinformaticians at the University of California, Santa Cruz, and the Howard Hughes Medical Institute

The team at Haussler and authors Frank Jacobs of the University of Amsterdam and Sofie Salama of the University of California at Santa Cruz and the Howard Hughes Medical Institute compared genes expressed during human and macaque brain development in stem cell models when they realized that they were NOTCH2NL in could detect human cells, but not in which the Ma kaken. Looking at the DNA, they also did not see it in orangutans and found only truncated, inactive versions in our nearest relatives, gorillas and chimpanzees.

Reconstruction of the evolutionary history of NOTCH2NL genes revealed that a process called gene conversion was probably responsible for repairing a non-functional version of NOTCH2NL that originally appeared as a partial duplication of an essential neuronal development gene known as NOTCH2. This repair only happened to humans – and they estimate that it happened 3-4 million years ago, around the same time as the fossil record indicates that human brains began to expand. After it was repaired, but before we turned away from our common ancestor with Neanderthals, NOTCH2NL was duplicated twice more.

The team behind the other paper, led by developmental biologist Pierre Vanderhaeghen of ULB and VIB-KU Leuven, came from a related direction to NOTCH2NL and looked for human-specific genes that are active during fetal brain development using primary tissue. "One of the sacred crickets of researchers like us is to find out what is responsible for a larger brain, especially the cerebral cortex, during human development and evolution," says Vanderhaeghen. "Given the relatively rapid development of the human brain, it is tempting to speculate that newly developed, human-specific genes can help shape our brain species-specific."

<a rel = "lightbox" href = "https://3c1703fe8d.site.internapcdn.net/newman/gfx/news/2018/1-meetnotch2nl.jpg" title = "A human skull overlaid with an illustration of the Human brain: Credit: Fiddes et al / Cell ">
 Meet NOTCH2NL, the human-specific genes that may have given us our big brains
A human skull overlaid with an illustration of the human brain. Credit: Fiddes et al./Cell

The search for human-specific genes involved in the development of the brain proved to be difficult, as these genes are poorly annotated in genome databases and difficult to detect from more abundant genes different species are different. The Vanderhaeghen team developed tailor-made RNA sequence analysis for the specific and sensitive detection of human-specific genes in the human fetal cerebral cortex. This enabled them to identify a repertoire of 35 genes specific to humans active in the development of the cerebral cortex in humans, including NOTCH2NL genes.

They used NOTCH2NL in particular because of the importance of its predecessor NOTCH2. in signaling processes that control whether cortical stem cells produce neurons or regenerate more stem cells. And they found that artificial expression of NOTCH2NL in mouse embryos increased the number of precursor stem cells in the mouse cortex. To better understand what genes do to humans, the team turned to an in vitro model of cortical development of human pluripotent stem cells to explore NOTCH2NL function.

In this model, they found that NOTCH2NL can significantly expand the population of cortical strain cells, which in turn generate more neurons, a feature that should distinguish between human and non-human cortical neurogenesis. "From a stem cell, you can either regenerate two progenitor cells, generate two neurons, or generate a precursor stem cell and a neuron, and what NOTCH2NL does is easily influence that decision toward regenerating precursors that can go on later." early effect with long-term consequences, as is often the case in evolution, "says Vanderhaeghen.

The team at Haussler investigated what happened when NOTCH2NL was not expressed: they deleted it from human stem cells and used it for cortex In the organoids derived from NOTCH2NL-depleted stem cells, differentiation was faster, but the organoids were smaller. "Losing NOTCH2NL leads to premature differentiation of cortical stem cells Neurons, but at the same time the very important stem cell pool is brewed ht, "says Jacobs.

NOTCH2NL's position in the genome, which until recently has been mapped incorrectly, further supports its role in the size of the human brain. Duplications or deletions in a genome region known as 1q21.1 are known to cause macrocephaly or microcephaly and are associated with a number of neurodevelopmental disorders, including ADHD, autism spectrum disorder and mental retardation. The Haussler team examined 11 patients with errors at this locus and found that NOTCH2NL was actually duplicated and deleted in the relocation events associated with larger and smaller brain sizes. "We really wanted the gene to be in the 1q21.1 disease interval because it made logical sense, but it was not in the wrong reference genome, and then we found new data and we found it was a mistake The Reference Genome It rarely happens that when something that seems wrong is true, it is actually true, I do not think anything of that level will ever happen again in my career, "says Haussler.

<a rel = "lightbox" href = "https://3c1703fe8d.site.internapcdn.net/newman/gfx/news/2018/2-meetnotch2nl.jpg" title = "Human cortical cells in vitro. Suzuki et al. Cell ">
 Meet NOTCH2NL, the human-specific genes that may have given us our big brains
Human cortical cells in vitro. Credit: Suzuki et al./Cell

This part of the genome is simply difficult to sequence and read. "We looked under the lamppost in human genetics by looking only at the regions that were easy to sequence, in these other regions there is a lot of information, and there is a reasonable case that they are the true cauldron fast Change in the last few million years, "he says.

Since NOTCH2NL is something of an evolutionary compromise between larger brains and 1q21.1 disease susceptibility, researchers are quick to draw attention to the fact that there are many healthy variation here too. "It's a blessing that has allowed us to get a big brain, and yes, it's a curse because we can have these recombination events that can be bad, but what we found when we developed the technology was really to sequence them into individuals. " that there are several different alleles of this gene, and that this variation creates the subtlety and plasticity that is important to make human beings human, "says Salama.

There are still many unknowns when it comes to NOTCH2NL, the Haussler The team points out that they were only able to look at the genomes of a small sample of patients, and that their organoid models did not address the later stages of cortical development at a time when NOTCH2NL could be even more important Another important question, the Vanderhaeghens Team wants to answer is the question of what other human-specific genes identified here (especially those that also occur in the 1q21.1 region or other genomic regions associated with brain diseases) during brain development, and although both teams were able to show that NOTCH2NL at the Vanderhaeghen admits that the exact mechanism is involved in a well studied Notch signaling pathway us, according to which NOTCH2NL establishes the balance between differentiation and regeneration, is still uncertain.

"What is amazing is that there are many signaling pathways that control the development of the embryo and are fully conserved between the species. The Notch signaling pathway is the oldest. You can find it in any animal you look at It has been used on developing embryos for as long as there are animals, and yet there is a whole new innovation in NOTCH2NL, especially in the human lineage, "says Vanderhaeghen.

"The site was unstable during evolution, so repairing these functional NOTCH2NL genes could have happened at any time," says Jacobs. "It could have happened earlier in the primate line and had a major impact on the brain's development, but it did not, it's a matter of luck or chance that fascinates me: how you come from something that's pretty neutral to us Genome to something that has such an important function and is used by our species to search for such important properties. "


Further information:
Mutant ferrets provide clues to the size of the human brain

Further information:
Cell Fiddes et al.: "Human-specific NOTCH2NL genes influence notch signaling and cortical neurogenesis" https://www.cell.com/cell/fulltext/S0092-8674 (18 ) Suzuki et al.: "Human-specific NOTCH2NL genes expand cortical neurogenesis by delta / notch regulation." 30383-0 DOI: 10.1016 / j.cell.2018.03.051

https://www.cell.com/cell/fulltext/S0092-8674(18)30399-4 DOI: 10.1016 / j.cell.2018.03.067

References in Journal:
cell

Provided by:
cell Press


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