Not all mutations are equally harmful
Harmful mutations in human populations
Alexey Kondrashov, Post-science
Mutations occur in all organisms. There is such a theorem: if an organism tried to make sure that there were no mutations at all (that is, it indefinitely increased the accuracy of DNA replication and repair), then the "price" of these processes would tend to infinity, since nothing can be done without mistakes. The price refers to the time that these processes would take, and the energy that would be spent on them. Therefore, some errors in the work of the cell with genetic texts inevitably arise.
1. Causes of mutationsMutations occur very rarely and mainly for two reasons.
Firstly, due to errors in DNA replication. Secondly, due to errors in the repair. DNA needs to be doubled all the time, because when a cell divides, both daughter cells must receive all the DNA. And this doubling cannot be done infallibly.
Sometimes DNA breaks down, because it is quite a fragile thing. The length of the entire DNA in each human cell is a meter. It is quite compactly packed. Since DNA is a molecule of very small thickness, it constantly breaks down even under thermal influences. And it needs to be repaired. And if it is repaired carelessly, then a mutation will occur. With DNA replication, the probability that a new letter will be "attached" incorrectly is only 10-10 – this is one chance in ten billion.
This process takes place in two stages: first the DNA "attaches" the letter, and then immediately tries to tear it off. Accordingly, if the letter was attached incorrectly, then, most likely, it will be torn off (this is the so-called 3’ > 5’-exonuclease activity). Then comes the third stage of activity – the third "line of defense". If the letter was attached incorrectly and not torn off, then DNA arises, in which two strands contain letters that are not complementary to each other. Then enzymes begin to crawl there, which recognize such inconsistencies and throw out the wrong new letter, replacing it.
2. Mutations are harmful and harmlessDespite the fact that there is a persistent struggle for accuracy in the process of DNA replication, some mistakes are inevitable.
In this sense, man is no different from animals. In humans, the mutation rate is approximately 10-8 per nucleotide per generation. Since the human genome is three billion nucleotides long and each of us has two genotypes, it means that 10-8 per letter per generation is about 60 new mutations for each newborn. Of course, of these 60 new mutations, a large proportion are neutral. The human genome is stuffed with various "garbage", and if the letter A is replaced by the letter B in some far corner, then nothing will happen to the person. But about 10% of our DNA is important. And if a mutation affects something important, it is most likely harmful, because when you change something that works, it gets worse.
3. History of the study of harmful mutationsThe first observation of mutational variability in humans appeared almost immediately after the rediscovery of Mendel's laws.
In 1909, the English physician Archibald Garrod published a work on genetic diseases of metabolism called "Congenital errors of metabolism". In particular, he studied a disease known as alkaptonuria, a disorder of tyrosine metabolism in which homogentizic acid is present in the urine. Garrod noticed that patients are usually descendants of marriages between relatives. This is caused by the fact that alkaptonuria is a recessive disease. That is, to get it, you need to get mutant alleles from both mom and dad, which is much more likely if mom and dad are relatives. This was the first advance in the study of harmful mutations in humans.
And in 1912, the German doctor Wilhelm Weinberg noticed that hereditary diseases are more common in the last children in the family. And he concluded that mutations are more often transmitted to children from elderly parents. In 1935, the great geneticist John Haldane made an absolutely amazing discovery. He studied the disease "hemophilia", which is linked to gender. That is, the gene whose breakdown can lead to hemophilia is sitting on the X chromosome. In order for the disease to occur in a girl, it is necessary that both of her X chromosomes carry a broken allele, which happens very rarely. And the boy has only one X chromosome. Therefore, one broken allele is enough for the appearance of the disease. Therefore, hemophilia occurs almost only in boys. Haldane noticed that if a boy is sick with hemophilia, then often his brothers are also sick. And I made this conclusion. Imagine that the boy is a hemophiliac, because his mother has a mutation. Then it would be a unique mutation: there would be only one sporadic patient. And they usually arise in families. That is, if the boy is a hemophiliac, then his brother is also a hemophiliac with a probability of almost 50%. This means that it's not Mom's fault. And this mom's dad is to blame. Mom is already a heterozygous carrier. That is, the mutation did not occur in mom, it occurred earlier. From this, Haldane concluded that men transmit newly emerged mutations much more often than women. This means that mutations occur much more often in the germ cells of men than in the germ cells of women.
It doesn't seem surprising now. We know that a girl has about thirty cell divisions from zygote to zygote. In the embryonic path of a girl, when she is still an embryo, all the eggs are already formed. And men produce sperm all their lives. And therefore, not thirty divisions pass from zygote to zygote in the male line. If a man reproduces at the age of 18, then about 150 divisions, and if at the age of 60, then even 500 divisions. And since the main source of mutation is a DNA replication error, we see such a sharp difference in the rates of mutation occurrence between men and women.
4. Mildly harmful mutationsApproximately 2% of newborns carry some kind of clear simple Mendelian pathology.
Accordingly, 98% of children are healthy – in the sense that they do not have Mendelian disease. Until the early 30s, it was believed that mutations were something rare. However, the first one who showed that this was not the case was Timofeev-Resovsky. In 1935, he discovered mildly harmful mutations – mutations that do not kill and do not cause any obvious phenotype like non-coagulability of blood, but simply slightly reduce fitness. He showed that there are more mutations that only quantitatively spoil the fruit fly than those that can be fixed and said that their carrier is a mutant.
After 35 years, the Japanese Terumi Mukai began to study weakly expressed mutations already on a very large material. And it turned out that there are more such mutations than obvious ones, not twice, but a hundred times. It turned out that most of the mutations are something that we do not detect by simple methods. And then modern (new generation) sequencing methods appeared, which allow for several thousand dollars to completely decipher the human genotype. If we call the human genome a statistical population norm, it turns out that the genotype of each person carries about ten thousand deviations from the genome, which cause the replacement of an amino acid in a protein.
5. Methods of mutation researchThere are methods that allow you to tell by replacing an amino acid in a protein whether it is harmful or harmless.
The basis of these methods is also evolutionary. We compare a protein in humans with similar proteins in a variety of mammals. Let it be normal for a person to have the amino acid glycine in some place, but some other mammals have alanine there. Then, probably, alanine in this place is also not harmful to a person. There can be no complete certainty here, but it is likely. And if glycine is in some place in everyone's protein (in humans, dogs, horses, mice), then replacing it with alanine in humans will probably be harmful, because no one does that.
These and other considerations allow us to estimate what proportion of mutations in humans is harmful. Here it is useful to distinguish between new mutations that have arisen now and mutations that have arisen earlier, and are now also present in the form of rare alleles. Out of ten thousand differences from the genetic norm, about a thousand are harmful.
6. Consequences of accumulation of mutationsThis means that each person in the genotype has from 900-1100 weakly harmful mutations replacing the amino acid.
The number of such mutations increases by about one per generation due to the spontaneous mutation process. Now, natural selection practically does not work against weakly harmful mutations in humans – it only works against very strong disorders. If, for example, a person's blood pressure rises by one percent, he will eat an extra pill and live happily until the age of 70. No one knows what will become of the human population due to the accumulation of these mildly harmful mutations. Clearly, nothing good. But how quickly the consequences of this accumulation will become visible, no one knows yet.
About the author:
Alexey Kondrashov – Candidate of Biological Sciences, Professor of the Department of Ecology and Evolutionary Biology at the University of Michigan (USA)
Portal "Eternal youth" http://vechnayamolodost.ru01.07.2014