Reading Genomes
What can be learned from the Neanderthal genome?
Slon publishes an abridged version of this lecture.
Bioinformatics is a newly emerged field of genetics. We look at the data that biologists produce, the simplest thing is genomes. As long as the genome in a cell or test tube is a molecule. When its sequence has been determined, deciphered, it turns into text in a computer, and at this moment you can do all sorts of interesting things with it, for example, even understand what is written there – where are the genes, how they determine the properties of the organism, and so on. This is bioinformatics. "Decoding the genome" is actually not a very accurate metaphor, because decoding involves understanding. And in our case, if, for example, you score "decoding the human genome" in Google, then tens of thousands of links will pop up, but none of them will say what is in the genome.
In the early nineties, they thought about whether it was possible to read the mammoth genome. By this time, methods for reading genomic sequences had already appeared, a lot of work was done with them, and a human genome project was launched – to determine the DNA sequence. People began to think whether it was possible to determine its sequence for archaeological materials. The first article on this subject was published in 1993, and the author, a well-known scientist, said that, of course, nothing would work simply because the chemical decomposition of DNA had gone so far that it was no longer possible to work with it. And DNA is a very long molecule, photons hit it all the time, it is attacked by reactive oxygen species, it spoils a little all the time. When DNA is in a living cell, there are special mechanisms that treat it. And when the body dies and already lies, so to speak, in the form of decomposing bones, then these mechanisms, of course, do not work, and chemical damage begins. It seemed that in the case of archaeology, this damage would be so severe that nothing could be read. Fortunately, this turned out to be untrue, because already in 1996 the first sequence of mammoth DNA was read, a very small piece. The first thing that people were interested in understanding was the relationship between mammoths, mastodons and two elephants: Indian and African. But in this sequence, there was not enough data for such a determination.
The sequence can be used to figure out the evolutionary relationships between modern organisms. This idea, which belongs to Francis Crick, was proposed by him in 1959 in the form of a comment to an article devoted to something completely different. The idea is very simple: as long as we have a single species, the genomes of its individuals are mixed, and there is a mechanism to maintain the uniformity of the genome within the species. And when species diverge – for example, a mountain has grown, and individuals of the same population have stopped meeting on both sides – random changes accumulate there and there, which are already beginning to occur independently. When the species have diverged far enough, we see a certain amount of differences in their genomic sequences. It is clear that if the species have diverged recently, there will be few differences, if for a long time – a lot. By taking a sequence of the same gene from different living beings, you can determine by the degree of sequence discrepancy who is the closest relative to whom and who is more distant. It is drawn in the form of evolutionary trees.
This picture shows a living cell. Pay attention to the mitochondria. They have their own genome. They are actually former bacteria and are in every cell of every creature that has a nucleus in the cell (people, animals, fungi, plants, protozoa). Mitochondria, being bacteria, settled into the protocell when our ancestors were still unicellular. This, by the way, was also found out by analyzing sequences. So what are mitochondria good for? Firstly, they have their own genome, and secondly, there are several of them in the cell. That is, the dose of the mitochondrial genome is ten times greater than the dose of the nuclear one. In situations where you are dealing with negligible amounts, this turns out to be significant.
And one more important property, we will need it in the future – the mitochondrial genome is inherited strictly through the maternal line. Every man has it from his mother, his mother has it from his grandmother, and in children the mitochondria of the paternal grandmother disappears. In general, the mitochondrial genome is quite short. The human genome is three billion letters, and the mitochondrial one is somewhere in the tens of thousands. In 2005, three articles about the mammoth mitochondrial genome appeared at once, and it really was a technical achievement, quite amazing – it was the first reconstruction of the mitochondrial genome of an extinct creature. Here's the surprising thing: these three articles, published by three different groups of scientists, appeared with a difference of weeks, less than a month, so it was also, among other things, a terrible race to see who would do it first. In general, it is very good to write a novel about the history of works with ancient DNA, because there is, say, "Santa Barbara".
What can you do when you have a complete genome? You can try to understand the history of mammoths. There are two elephants, Asian and African, and a mammoth: who is the closest relative to whom? There are three scenarios. First: two elephants are sister groups, and the mammoth is their cousin. Second: the mammoth is close to the Asian elephant, the African elephant is a cousin. Third: the mammoth is close to the African elephant, and the Asian is a cousin. So, we will determine: if in the first condition two elephants have the same letters from the genome, and a mammoth has a different one, this method speaks in favor of the relationship of elephants against a mammoth. If two letters are the same for an Asian and a mammoth, and an African has a different one, then this position speaks in favor of the relationship of a mammoth and an "Asian". If all the letters are different, this position says nothing, however, as if all three letters are the same. And then the conclusion is unfortunate: until the mastodon genome comes to us, we will not be able to find out who is the closest relative to whom. An article about this was published on March 29, 2007. And already in August, an article about the mitochondrial genome of the mastodon was published. Again, there are a lot of similar stories - when one article is published, and the other one responding to it is at that moment in a different editorial office.
But back to the elephants. Since changes in DNA initially occur randomly and evenly over time (this is not entirely true, but let's forget about the lie for now), then simply by measuring the number of differences, we can tell when the common ancestor of two creatures lived. And indeed: the mammoth and the Asian elephant are sister groups and they diverged about six to seven million years ago. A little earlier, about eight million years ago, the African elephant separated. And a mastodon lived quite a long time ago. When all this was investigated, it turned out that the savanna African elephant and the forest African elephant are two different species. They were slightly different, and everyone considered them subspecies, and then it turned out that they were two completely different species.
This picture is in order to understand what kind of data people are dealing with. You determine the DNA sequence of someone severely degraded, these are all small pieces. The fact that orange is really mammoth DNA, but, say, the fact that yellow is bacterial DNA, and gray is generally unknown.
There is, among other things, a serious problem that besides mammoth DNA there is a lot of someone else's DNA. But people, fortunately, know how to deal with this. When did mammoths become extinct? Most recently, the last one died, apparently, on Wrangel Island 5 thousand years ago. In Alaska, mammoth sequences were found, the age of which is 10.5 thousand years, and there were not bones, not frozen corpses, but just residual rocks. It turns out that if you know what to look for, then you can isolate DNA from residual rocks.
Here's a piece of the work I'm taking part in. Just to show what else you can do, firstly, and, secondly, to show that I am related to this activity, and not telling stories from someone else's life.
This is the mammoth Lyuba, she drowned in the mud on the riverbank 40 thousand years ago. Thanks to the silt, she was very well preserved, and it turned out that you can see not only her sequence, but also the sequence of bacteria that lived in her stomach.
This is a separate topic. A person has about a hundred times more bacterial cells than his own.
What did they do – they took a piece of the contents of the intestine of this mammoth and looked at the bacterial sequences that are there. It turned out that the E. coli, which were 40 thousand years ago, are exactly the same as the baby elephant in the Moscow zoo. However, they are the same as humans (elephants and humans have the same). The bacteria have not changed during this time.
Now cave bears. Why are they? Because, unlike mammoths, bears' material is found in very large quantities in caves. It's not so cold there, but it's dry. And these are the same caves where the Neanderthals lived. Why not make Neanderthals right away? Because Neanderthals are like humans. More precisely, they are just people. We are descendants of Cro–Magnons who lived in Africa. And the Neanderthals lived in Europe, they are a separate branch of humanity. And it is clear that the genome of a Neanderthal will be very similar to the genome of a modern Cro-Magnon man. If you take a Neanderthal bone, separate a DNA fragment from there, isolate its sequence, then you will never know whether it is the sequence of the Neanderthal from whom the bone remained, or that archaeologist who grabbed it with his hands, or your own laboratory assistant.
In order to show that, in principle, it is possible to isolate a "pure" sequence from these bones, we worked with a cave bear. The idea was this: if you determine a DNA sequence from the bones of a cave bear that does not look like a person, but looks like a bear or at least a dog, then you did everything right. If you single out a person, give up. Svante Peebo and Edward Rubin are the authors of those articles about cave bears. And it was an obvious preparation to work with Neanderthal bones.
Looking at bear bones of different ages, we noticed that there is a correlation of genetic diversity with the climate – the colder, the less diverse the cave bears were, the smaller their population was. It is clear that the colder it is, the worse it is to live, the population is declining. However, the brown bear has nothing of the kind. He is the closest relative of the cave, their difference is that the brown one lives in the forest, and the cave one, respectively, in a cave. It would seem that the climate should act even more strongly on brown, but this does not happen. One possible explanation is competition with humans for caves. At this time, a modern man appears in Eurasia, he lives in caves and expels bears from there. They have nowhere to live, and they die. This is actually not true. People write such things in articles so that there is something striking, so that everyone remembers.
An interesting story about a polar bear. When we looked at the mitochondrial DNA, it turned out that the polar bear is not a separate species, but a group inside the brown ones. About brown bears, when they looked at not only mitochondria, but also nuclear genomes, they found out that the history that is reconstructed from mitochondrial DNA does not coincide with the one that is reconstructed from nuclear. According to the nuclear DNA, the polar bear is a completely separate species. And according to the mitochondrial, all modern polar bears are descendants of one bear, a brown one, who lived in Ireland about 30 thousand years ago. This is called introgression – when some fragment of the genome, brought from outside, spreads throughout the population.
Now about the Neanderthals. The methodology is the same. In 1997, mitochondrial sequences were determined, two articles were published about this with a difference of one day in the journals Nature and Science. There is a tradition: if people do not want to engage in rat racing and publish two weeks earlier than a neighbor, then they simply agree and publish materials at the same time. In the first article, a million letters from the Neanderthal genome were identified, and in the second – only 65 thousand letters, but more accurately. In one article it was written that the Neanderthal contribution to the genome of modern man is zero, and, of course, additional data is needed. And in another – that they observe the flow of Neanderthal gene variants in modern men. Why men? Because there is a Y-chromosome that is transmitted only through the male line, respectively, on this chromosome you see a genealogy along the male line, and, of course, additional data is also needed. The contribution of the modern human genome to the Neanderthal DNA was apparently made by male laboratory assistants from that laboratory, because it was pure pollution. Moreover, the Neanderthal subsequently turned out to be a girl, and this was a very good criterion, because when you determine a Neanderthal by DNA, by the Y chromosome, it is immediately clear that rude men grabbed her with their hands and ruined everything (meaning bone).
It turns out that 1-4% of modern gene variants that we observe in the genome of modern Europeans and Asians are exactly of Neanderthal origin. I was talking to a racist before the lecture and scared him off, it was my mistake. He explained to me that Americans are stupid because they are descended from Neanderthals, and Slavs are smart because they are descended from Cro-Magnons. I was very disappointed with him, because pure, unalloyed Cro–Magnons are just African Negroes, and white and yellow Euroasians have 2.5% of the genetic material that we inherited from Neanderthals, with which I congratulate us all. In my opinion, this is an important ideological conclusion. What genes have we inherited? There is a variant of the immune system gene, which is not found in Africa at all, but is present in a noticeable amount in Eurasia. And in Eurasia – exactly the option that the Neanderthal has. Therefore, the immune system of us who are lucky has a Neanderthal component. That's how it was. More precisely, this is the most likely scenario, and it was described in an article published in early 2010.
And then a wonderful thing happened – a phalanx of a thirteen-year-old girl's finger was found in an amazing preservation in the Denisova cave in Altai. Moreover, it is not the phalanx itself that has been preserved, but the DNA in it. And they determined the mitochondrial sequence first, and then the nuclear sequence – literally with a difference of six months. And then something quite amazing happened: Cro-Magnons and Neanderthals diverged 300 thousand years ago, and Denisov's DNA is a million years behind them. And this is a disaster, because according to paleontological data, there is no person who would have departed around that time. Neanderthals were separated from half a million years ago, and the next relative is homo erectus, they separated from him two million years ago. And this is some completely new branch of humanity. And if you look at the nuclear genome, it turns out that its preservation is much better than that of Neanderthals, the bones are much older, and the genome is perfectly preserved, but according to the nuclear genome it is still a Neanderthal.
This is a very big breakthrough in understanding the evolution of modern man. People from Denisova Cave are not found in the genomes of Eurasians. And this is absolutely amazing. This changes our perception of our place in the surrounding reality.
Portal "Eternal youth" http://vechnayamolodost.ru27.06.2012