Three nearly identical genes could help explain how 0.5 liters of gray matter in early human ancestors became the 1.4-liter organ that made our species so successful and distinctive , The newly identified genes could also help explain how brain development sometimes goes awry and leads to neurological disorders.
The genes, descendants of an ancient developmental gene that has multiplied and changed in the course of evolution, contribute to a growing list of DNA in the expansion of the human brain. But they are characterized by learning so much about how they work their magic, says James Noonan, an evolutionary genomic student at Yale University. Researchers have shown that this trio increases the number of potential nerve cells in the brain tissue and a team even determines the likely responsible protein interactions. "These are new proteins that are potentially very effective in changing a very important pathway in brain development," adds Noonan.
Until now, the four genes were thought to be one NOTCH2NL a spin-off of the NOTCH gene family, which controls the developmental stages from fruit flies to whales. But two studies in the May 31 issue of Cell track a series of genetic accidents in recent evolutionary history that revealed four very closely related NOTCH2NL genes in humans (see chart below). ,
David Haussler, a bioinformatics scientist at the University of California, Santa Cruz, and his colleagues have been on the trail of genes after discovering that the NOTCH pathway in human and macaque brain organoids – test tube models of the developing brain is different is working . NOTCH2NL was missing in the macaque organ and, as later analyzes showed, also in other nonhuman monkeys. The NOTCH2NL could have played a unique role in human evolution.
By comparing NOTCH2NL -related DNA in the genomes of humans and other primates, Haussler's team reconstructed the evolution of genes history. They concluded that during DNA replication, perhaps 14 million years ago, part of an ancestral NOTCH2 gene was mistakenly copied. The new "gene" was incomplete and non-functional, but some 11 million years later, just before the brains of human ancestors began to expand, an additional piece NOTCH2 was inserted into this copy, rendering the gene functional , "This event marks the birth of NOTCH2NL genes that we now have in our brains," says Frank Jacobs, a co-senior author on paper and an evolutionary genomist at the University of Amsterdam.
Subsequently, the active NOTCH2NL gene was doubled twice, yielding three active NOTCH2NL genes in a row at one end of human chromosome 1 and an inactive copy at the other end. Gene copies can be potent evolutionary forces because a copy continues its necessary work and gives others the freedom to do something new.
Pierre Vanderhaeghen, a developmental neurobiologist at the Free University of Brussels, discovered the same set of genes when he found a way to study human fetal brain tissue on duplicated genes. To find out what they are doing, his team increased their activity in cultured brain tissue. The tissue produced more stem cells, they report in the second Cell Paper
The finding supplements a spring earlier by Wieland Huttner, a neurobiologist at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany , He and his team had decided to focus on NOTCH2NL (which they took to be a single gene) after discovering that it was highly active in fetal brain cells. When they introduced a human NOTCH2NL gene from mouse embryos into the incipient brain tissue, more stem cells developed. This suggests that the human gene retards the specialization of these cells so that they have a chance to produce many more copies of themselves, the researchers reported in eLife on March 21
Cell describes Vanderhaeghen and his colleagues molecular details on how NOTCH2NL promotes neuron formation. They found that a NOTCH2NL protein blocks a key step in a signaling pathway that causes the stem cells to differentiate and stop the division. As a result, the cells persist and continue to produce offspring, ultimately leading to a greater amount of neurons. "These are really convincing biological data," says Noonan. "In other studies of genes involved in human evolution, it has been very difficult to draw a line from genetic difference to phenotype to a biochemical mechanism responsible for it."
The location of the three active NOTCH2NL genes also says, says Haussler. They are involved in the middle of DNA in autism, schizophrenia and a developmental delay syndrome. Such duplicated DNA tends to be copied extra times or lose DNA during replication, and instability is a hallmark of these disorders. For Greg Wray, an evolutionary developmental biologist at Duke University in Durham, North Carolina, this indication of brain disease is the most compelling new finding. "These genes probably play an important role in cortical development, and dysregulation leads to disease."
Wray is less convinced that genes play a unique role in human evolution, because the chromosomal region in which they are located is complex and complex, difficult to sequence, and because of the evidence for an evolutionary difference in human evolution Gene function is indirect between humans and other species.
But Haussler believes that these genes will be key players in the expansion of the human brain. "One change has not made it alone, but some will be found more fundamental than others," he says. " NOTCH2NL has a chance."