Innate Typos
Most point mutations occur in the human brain before birth
Polina Loseva, "The Attic"
A team of American scientists carried out a delicate and painstaking work: they extracted DNA from individual neurons of human embryos and looked for the smallest, "one-letter" differences in them. It turned out that more than half of the point mutations appear already in the early stages of embryo development, that they occur much faster than in adults, and that some of them are similar to mutations in cancer cells.
Not all cells are equally useful
It is generally believed that all non-sex cells in a healthy person's body are genetically identical. Roughly speaking, this means that if we take two skin cells, we will find the same DNA sequences in them. However, this statement is true only to some extent. If the aliens who first came to Earth looked at a crowd of people, they would also probably decide that all people are the same. But we know that this is not the case.
That's the same with the cells. The cells of our body accumulate genetic differences throughout life. This phenomenon is called mosaicism. The differences can be global – for example, if extra chromosomes remain in the cell as a result of unsuccessful division. There are smaller differences – for example, the movement of mobile parts of DNA (mobile elements) from one region of the genome to another. But some changes are so small that they cannot be detected every time. These are single–nucleotide variations - differences in a single letter (nucleotide) among a large DNA text. They are referred to as point mutations.
Even a minimal change in the sequence of a gene can lead to disruption of its work. The most famous example is sickle cell anemia, in which the replacement of one (!) nucleotide in the globin gene affects the sequence of the hemoglobin protein. Hemoglobin does not fold properly, which is why the erythrocytes carrying it take the form of a sickle and carry oxygen worse. According to the same principle, a tumor transformation can occur: a change in one nucleotide can lead to the fact that the protein will work worse or, conversely, better. And if this protein controls, say, cell division, then this can cause the development of a tumor.
Damaged phone
Where do these microscopic errors come from? Firstly, they inevitably occur when copying DNA. Imagine that they put a sequence of three billion letters in front of you (that's how many nucleotides make up the genome of one cell) and offered to sign a pair to each (A opposite T, G opposite C and vice versa) for a limited time. How many mistakes will you make due to inattention? DNA polymerase, which replicates DNA, is wrong on average 6 times per 10 billion nucleotides. That is, one or two errors occur with each cell division.
In addition, DNA can be damaged by the action of other substances, such as reactive oxygen species (these aggressive molecules accumulate in the cell during oxidative stress). Proteins of the repair system are designed to cope with these injuries. As a rule, they cut out the damaged nucleotide and complete a new one, focusing on the second, intact DNA chain. But sometimes there can be errors in both chains, so the mutation remains in the genome.
The transmission of hereditary information is somewhat like playing a broken phone. By transmitting the same message of billions of nucleotides from generation to generation, cells strive to keep it intact. But those who have played a damaged phone remember that the most exciting thing in this game is to compare what happened at the exit with what was at the entrance. This is what a group of scientists from the Mayo Clinic, Stanford and Yale Universities were doing: they decided to see how quickly errors accumulate in the developing human brain. Their results are published in the journal Science, and many unexpected facts can be found there (Bae et al., Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis).
A diagram showing an example of a mutation, as a result of which cytosine was replaced by thymine. Image: NHS National Genetics and Genomics Education Centre / wikimedia commons.
Will we wash this one or will we get a new one?
The researchers worked with the brains of human embryos aged 15 to 21 weeks (abortive material). They isolated the progenitor cells of neurons from the cortex of the large hemispheres of embryos and grew a separate colony (clone) from each. Then DNA was isolated from each clone, sequenced and compared with each other. It turned out that by the 20th week of embryo development, 200-400 single-nucleotide variations (ONV) are already accumulating in each of its neurons. In the same issue of Science, another group of researchers publishes data on the counting of ONV in human nerve cells during life (Lodato et al., Aging and neurodegeneration are associated with increased mutations in single human neurons). For comparison: in the nerve cells of newborns, about 1000 ONV are found, in an adult (about 45 years old) – 1500 ONV, and by old age (80 years) their number reaches about 2500.
These results overturn our ideas about the accumulation of errors in the genome. Contrary to popular belief, according to which most errors in DNA appear during a person's life and lead to inevitable aging, it turns out that at least a third of point mutations occur even in the embryonic period. Now we have reason to believe that we are all born already spoiled in some way, and we begin to age from the very first division of a fertilized egg.
Comparing sets of ONV in cells, we can conclude how early in the course of development they arose. So, the authors of the study decided to compare the detected ONV in neurons with "typos" in the cells of the spleen. Why the spleen? The fact is that the divergence of the precursors of the nervous tissue and the spleen occurs quite early – about the 12th day of development. This event, during which neurons and spleen cells "part", is called gastrulation. And the precursors of the nervous tissue remain in the outer layer. Among the single-letter errors in the genomes of neurons and spleen cells, only 1.4% were common. That is, approximately four ONV occurred in each cell before gastrulation. On the one hand, it's not that much. On the other hand, these errors appeared in the first 12 days of development! Whether it will still be.
And then the situation develops even more interesting. If immediately after fertilization errors occur at an average rate of 0.33 ONV per day (4 errors in 12 days), then after gastrulation – already 1.3 errors per day. In the period from the 15th to the 20th week, active neurogenesis takes place in the embryo, that is, the precursors of neurons are often divided. And here the rate of error occurrence already reaches 5.1 ONV per day.
At this rate, by the time of birth, a thousand errors are running in each neuron. Then, fortunately, the process slows down, because the precursors of neurons divide less and less. From the moment of birth to old age, errors accumulate evenly, according to various estimates – about 23-36 per year, that is, 0.06–0.1 ONV per day.
Image: Anatoly Lapushko / chrdk.
It is interesting to think about what caused the jump in the appearance of point mutations after the fourth month of development. The authors of the study believe that the reason for this may be oxidative stress: vessels are actively sprouting into the developing brain. Consequently, the oxygen concentration increases. And at the same time, there are more reactive oxygen species that attack DNA. Probably, brain cells are not ready for oxidative stress and launch their defense systems against it more slowly than they should. It is also worth noting that data on the number of errors in the DNA of neurons in newborns are similar to data previously obtained by other groups of researchers about errors in the DNA of other cells, for example, intestinal stem cells. So neurons are not the only ones accumulating errors in such numbers. In other organs, probably, the same processes occur as in the brain.
Butterfly Effect
The scope of these discoveries has yet to be realized. Most children are born neurologically healthy. Does this mean that the 1000 errors that each of their neurons carries are absolutely harmless? Unfortunately, no. Some of the detected ONV turned out to be similar to mutations found in cancer cells. There are about 3% of them, that is, in each precursor cell of a neuron, a five-month-old embryo can have up to 12 malignant errors. It is clear that not all of them will inevitably lead to the formation of tumors later – some will be unsuitable for survival, some will die under the onslaught of immunity, but one way or another, they all pose a threat.
In addition, not so long ago it was discovered that some sets of ONV correlate with the development of autism, schizophrenia and bipolar disorder. On the one hand, it is too early to draw conclusions from this discovery, since the correlations are too weak for each individual ONV. And we cannot unequivocally say that we have found the same nucleotide, the replacement of which leads to autism and schizophrenia. But on the other hand, do not forget that the search for ONV in living people is carried out on blood cells, not the brain. That is, in this way, it is possible to identify only those ONV that arose at the earliest stages of development, before gastrulation, when there was no division into cells of the nervous and circulatory systems. In other words, our blood does not always allow us to judge what is going on in our head. And, according to the results of recent studies, our inner world – in every sense of the word – appears much richer and more diverse than it seemed until now.
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