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How A New "Junk DNA" Gene In Humans Caused Us To Have Larger Brains
To story of a long non-coding RNA that began generating a helpful protein.
Humans, chimpanzees and bonobos, share most of our DNA. In fact, human and chimp genomes are nearly 90% exactly aligned in most regions… making not many unique genes between chimpanzees and human. As a result, little alterations can affect gene timing or activity levels and subsequently have an impact that is not proportional to the number of bases modified. However, this does not imply that recently evolved genes are unimportant to the evolution of humans.
In a report1, published this week, the evolution of a novel class of genes since our split from our simian forebears is examined. These areas in our genome has been known as ‘junk DNA.’ The research team examined one of these recently evolved genes and discovered that it is crucial for the development of larger brains after learning more about how this class of genes arose.
The majority of the genes encode proteins. A messenger RNA is produced from the information in DNA, and this RNA is subsequently translated into a protein. The gene is inactive if the protein is not produced.
But we've been aware that there are other options for almost 70 years. Many genes whose product is RNA are not translated into proteins. Instead, these RNA serve a crucial purpose. Since the first of these non-protein-coding functional RNAs was identified in the 1950s, the number of them being identified has continuously increased, and there are now numerous types of them. These carry out a variety of tasks, such as modifying the activity of protein-coding genes, safeguarding the ends of chromosomes, and splicing out extra messenger RNA.
lncRNAs, also known as long non-coding RNAs, are one of these classes. Similar to messenger RNAs, these often begin with portions of the original RNA being spliced out and being given unique caps on both ends to make them more difficult to degrade. But lncRNAs remain in the cell's nucleus with its DNA and are utilized to regulate the activity of other genes rather than being sent outside to be translated into proteins.
However, research on genes that are novel to the species revealed that the distinctions between messenger RNAs and lncRNAs might occasionally be lost during the course of evolution. It was discovered that several of the protein-producing genes in one species operate as lncRNAs in closely related species instead of encoding any proteins. This shows that some of the lncRNA genes have undergone mutations to become protein-coding genes.
The new research aimed to determine whether this played a role in human evolution.
The researchers compared the genomes of humans, chimpanzees, and the more distantly related macaques using public genome databases. They discovered 29 instances in which lncRNAs had transformed into protein-coding genes during the time when chimpanzees and humans diverged from macaques. Since humans separated from the ancestors of chimpanzees and bonobos, another 45 genes have gone through this process.
With this discovery in hand, the researchers questioned what made these recently produced genes unique. Not surprisingly, they discovered that exporting these RNAs from the nucleus to the area where they could be translated was a crucial step. Low levels of the majority of lncRNAs are found outside the nucleus, indicating imperfect control over their location. However, the ones that had acquired a protein-coding function were located at considerably greater levels outside the nucleus.
This seemed to be caused by a less strong connection with the complex that removes unneeded RNA segments from messenger RNAs. When lncRNAs evolved into protein-coding genes, their function in genetic networks also changed. It is common for many genes engaged in related processes to have coordinated activity, meaning that they all turn on or off at the same time.
Both protein-coding genes and lncRNAs may be present in those networks. These lncRNAs basically disconnected from the networks they were a part of when they transformed into new genes. This makes sense because the proteins they produce are highly unlikely to serve the same purpose as the lncRNAs.
So what does that role entail?
The group selected ENSG00000205704, which is active in brain cells and makes a tiny protein (107 amino acids) found in both the nucleus and cell body, as one example to concentrate on. The gene was altered in stem cells to produce cell lines that either completely lacked the gene or had it highly activated in order to study its function. Then, neurons were created from the stem cells.
More neurons were produced in the cells that had ENSG00000205704 activated. This is due to the fact that the protein it encodes seems to maintain neural stem cells' immaturity, allowing them to divide their cells more frequently before becoming neurons. By deleting the gene, fewer neurons were created overall and they matured early. But those are only cultured cells.
What takes place in real brains?
They activated ENSG00000205704 in the mouse genome and then examined the mice's brains to find out. It resulted in a longer neocortex (albeit interestingly, the width didn't alter much), supporting the hypothesis that the newly developed gene contributes to the development of larger brains by decreasing the pace of neuronal synthesis.
It undoubtedly sounds really thrilling that we developed a new gene specifically to produce huge brains. The more important query, however, for evolutionary biologists is, “what this can reveal about the emergence of new protein-coding genes?”
There are several steps involved in creating a new protein-coding gene:
An RNA must first be created
Then it must be processed to maintain its stability
Then sent outside the nucleus to be translated into protein
Last, the protein must carry out some sort of function, even if it is subpar
Only until the entire process is complete can evolution begin to use selection pressure to enhance everything. To ask so much of random mutations seems unreasonable.
Because it enables evolution to improve RNA production and processing before the last stages become problematic, the conversion of a lncRNA into a protein-coding one is an intriguing method.
As a result, if mutations result in the lncRNA coding for proteins, the ensuing proteins are already likely to be produced and can thus be subjected to increased evolutionary selection right away.
It's important to investigate how prevalent this mechanism is in species other than humans.
An, N.A., Zhang, J., Mo, F. et al. De novo genes with an lncRNA origin encode unique human brain developmental functionality. Nat Ecol Evol (2023). https://doi.org/10.1038/s41559-022-01925-6