Secrets of the "dark DNA"
An attempt to explain everything incomprehensible at once
Alexey Aleksenko, "Snob"
There are two approaches to problems. The first approach – the author is not a sexist, but let's call him "male" – is to solve problems one by one, gradually. The second approach is more interesting: you just need to dump all the problems into one pile, cry a little, and then they will probably somehow solve themselves. Usually science goes the first way, but now we will analyze an example when the second, integral method turned out to be closer to it.
By the way, there is nothing new here for the general public: if we assume that the Easter Island idols were erected by the passengers of flying saucers (who had recently exterminated the dinosaurs), you will not get an answer to any question ... but the formal reduction of the list of secrets brings some emotional relief.
A similar plot twist occurred recently in the molecular genetics of animals. The mystery that lay at the heart of this story is as follows. In 2004, Gil Bejerano, a graduate of the Hebrew University of Jerusalem, together with his colleague David Hausner discovered very strange sequences in the human genome. They were about several hundred base letters long, and there were about five hundred of them in total. The strange thing about them was that exactly the same sequences were found in the genomes of rats and mice, and very, very similar - in dogs, chickens and even in some fish.
We have a dime a dozen pieces of the genome that are somewhat similar to rat or fish. The genes of the alpha chain of hemoglobin, for example, are very similar in all vertebrate animals: we are separated from the horse by only 25 significant substitutions (that is, those that led to a change in the amino acid in the corresponding protein), and from the gorilla – a single one. However, there are much more synonymous differences – not leading to a change in protein – even between different people. The genes of rRNA – the structural framework of the cellular factory for the production of protein, ribosomes – are generally similar to each other in all living creatures of the earth.
But the hemoglobin or rRNA genes are exactly the genes: they encode quite understandable components of a living cell, and therefore are changeable exactly within the limits that can be expected from the details of the mechanism performing a given function. The sequences discovered by Bejerano were not genes in the usual sense. Some of them fit entirely into introns – nothing coding pieces that the cell cuts out of the gene product and throws away. Others were on the border of introns. And with all this, their similarity in different animals was stunning. Between a human and a rat, for example, one hundred percent, in other vertebrates – about 95 percent. The strange, short pieces of DNA scattered everywhere turned out to be much more conservative than the genes of the most important cellular proteins, and this mystery seemed to have no solution. Bejerano and his co-authors noted only that "dark DNA" (it is quite logical for us to call it that by analogy with "dark matter", over the riddle of which physicists are struggling) is usually found inside and in the vicinity of genes that regulate the work of other parts of the genome and, in particular, control the processes of development.
If something managed to change so little in the half a billion years of evolution separating us from fish, it means that selection mercilessly punished for any step left or right. And if so, then, if these pieces of the genome are artificially removed or even slightly changed, then instead of the usual chicken or mouse, a terrible non-viable freak will be born, and most likely will not appear at all, having died at the stage of the first divisions of the egg.
This experience was done in 2007 by researchers from Berkeley (California). And the result disappointed them terribly. Mice whose several pieces of "dark DNA" were deliberately corrupted were born healthy and happy. It was not possible to detect the slightest difference from ordinary mice. The researchers had to make an absurd conclusion: perhaps some parts of the genome do not change during evolution, not because selection does not allow them, but for other, completely incomprehensible reasons. For what reasons?! It is said: "by the incomprehensible," and that's it.
But scientists really don't like to put points at such moments of the narrative. If you can't solve the mystery, you can at least try to connect it with others – well, for example, with the mystery of the development of consciousness on the way from the same fish to man. And the idea of linking the mystery of "dark DNA" with the mystery of brain development turned out to be unexpectedly fruitful.
An article published a couple of weeks ago in the journal Cell (Dickel et al., Ultraconserved Enhancers Are Required for Normal Development) has a solid list of authors, it includes many of those who in 2007 tried to breed mutant mice with impaired ultraconservative fragments and made sure that these are not mutants, but ordinary mice. This time, the CRISPR technique was used to manipulate mouse DNA – fortunately, over the past decade it has gone from a laboratory curiosity to a powerful research tool. The mice obtained by the researchers were still not very different from the usual ones. But biologists were not satisfied with this superficial observation, but immediately got into their brains. And there they finally found what they were looking for.
The result depended on which DNA sequences were deleted. One of the lines showed a sharp decrease in the number of cells known to be somehow involved in the development of Alzheimer's disease. The other line had a visibly altered area of the forebrain involved in the formation of long-term memory. The same site is believed to play an important role in the development of epilepsy. It is not surprising that in 2007 no one paid attention to such subtleties: nevertheless, the life of mice in a laboratory vivarium is not so eventful as to make too high demands on their brains. But in the wild, a forgetful mouse, or, for example, a mouse prone to epileptic seizures, is doomed to everyday failures and bitter disappointments.
Of course, the answer simply puts the problem in the context of a broader mystery, since scientists' ideas about memory formation, Alzheimer's disease or epilepsy are still quite fragmentary. However, to find out that several burning mysteries of biology are actually connected with each other is already a lot.
Gil Bejerano himself, who once discovered "dark DNA" (or can we already call it "ultraconservative enhancers", as serious people put it?) the work caused difficult feelings: "Then <in 2004> someone urged us to wait with the publication until it becomes clear why these things are needed. Now I can tell them, hey dudes, it took fourteen years!"
Is this data enough to explain the amazing, almost one hundred percent preservation of ultraconservative enhancers in the process of evolution and divergence of vertebrate classes? At first glance, this is not too obvious. But now at least there is a clear break in the continuous veil of secrets. There, in this gap, other secrets loomed, compared to which the former ones will seem like childish jokes, like a fairy tale about a bun before a Stephen King novel. We and our dear readers risk simply not living up to the moment when everything is clarified; that's why we had to tell this story right now, without waiting for the final catharsis. And if we ever find out the final answer, we can arrogantly say: "Oh, I read about it somewhere back in 2018!"
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