The cause of dozens of hereditary diseases
DNA with circular motion
American scientists of Russian origin have shown the mechanism of occurrence of serious diseasesGalina Kostina, "Expert" No. 40-2012
Two years ago in Boston, in a scientific laboratory, I was shown a picture of an American family: a healthy grandmother, next to her daughter with a face frozen due to partial paralysis and a grandson who can no longer hold his head. The rest of the boy's numerous problems are not visible in the photo. This is an example of a terrible neurodegenerative disease, Friedreich's ataxia, which is incredibly progressing from generation to generation. The reason for this is a violation of the genome.
The recently published results of a large-scale ENCODE project have shown what the part of our genome that used to be called garbage is made of. Including in these 99% of the genome, there are often long repeats of the same groups of nucleotides. According to one version, these repetitions arose because of the inherent DNA "selfishness": she likes to copy herself about and without. It is believed that in the non-coding part of the genome, repeats do not do anything special. However, they often come across in the genes encoding proteins, and can lead to quite dramatic consequences. The question is the number or length of such repetitions. If there are no more than three or five dozen of them, they do not seem to affect the work of genes in any way. If two hundred – there may be problems in old age. But if even more – then trouble. Lengthening from two hundred repetitions to several thousand leads to illness. Young people under 25 suddenly begin to suffer from unsteadiness when walking, frequent falls, then heart problems arise. Another nuisance is connected with the fact that in the next generation the disease may take a more severe form.
The mechanism of occurrence of this disease was solved by American scientists – our compatriots: Professor of Boston Tufts University Sergey Mirkin in collaboration with Professor of the Georgia Institute of Technology Kirill Lobachev, as well as professors of the Eppley Cancer Research Institute at the University of Nebraska Medical Center Yuri Pavlov and Polina Shcherbakova. Part of the research was published in October in the prestigious scientific journal Molecular Cell (a sequel is due to be published soon in the journal Cell Reports). According to one of the reviewers, the genetic power of the research is staggering.
Solid ha-ha-haRepeats of only three GAA nucleotides, which turn into a long chain of GAA GAA GAA GAA GAA triplets, etc. as part of the gene encoding the protein frataxin, every person normally has.
Frataxin performs a transport function – it removes trivalent iron from the mitochondria. If the function is disrupted, for example, by super-long repeats from GAA, the mitochondria overflows with iron cations and, as a result, free radicals that affect the most metabolically active cells – neurons, as well as cells of the myocardium, retina, and bone system. Sergey Mirkin shows a photo of the family. Parents are practically healthy: each has an intermediate (about 150) number of copies of GAA repeats. And two of the three children inherited an elongated version of the repeat from each parent and as a result received an incurable neurodegenerative disease.
Why do repetitions increase so dramatically with hereditary transmission? This question has been worrying molecular biologist Mirkin for many years. Actually, he became interested in the structure of repeats in DNA when he was still working in Russia. Mirkin continued to deal with this topic in the USA, where he moved in 1989, although it was not easy: the lion's share of NIH (National Institutes of Health) grants are issued for projects that can then be converted into medicine, and there was no such bundle for his favorite repeats. So at first Mirkin studied the properties of repetitions at the University of Illinois for small "fundamental" grants. And only when it was possible to link a common disease – the syndrome of the brittle X chromosome - with similar repeats, NIH grants went.
By this time Mirkin had already thoroughly studied the unusual structures formed by DNA repeats, and he was increasingly interested in the mechanism of their elongation. The answer, in his opinion, could be given by understanding the genetics of repeat instability. For obvious reasons, it is impossible to obtain directed mutations that affect this process in humans, but it can actually be done in a model organism, for example in baker's yeast. But such rapidly dividing unicellular organisms as yeast throw repetitions out of themselves so that they do not interfere with their growth. And Mirkin came up with an elegant solution – to force a long repeat to turn off the work of the gene that prevents yeast growth, thereby making the lengthening of the repeat profitable. The idea was so beautiful that no one dared to test it with an experiment. As Mirkin jokes, beautiful ideas often do not justify themselves. Alexander Shishkin, a postdoc from Russia, believed in it, and he conducted relevant research at Tufts University, where Mirkin received a prestigious position as a named professor.
Despite the success of the study, many questions remained unresolved. For example, why is there a sharp elongation of repetitions in one family from generation to generation, and in another, where parents are also carriers of the disease, there is no elongation of repetitions in the offspring. This indicates the presence of other factors affecting the process. To find out which ones, Mirkin called two more geneticists from the same St. Petersburg school – Yuri Pavlov and Polina Shcherbakova. "Yuri is a phenomenal geneticist, with the broadest erudition and philosophical mindset," says Mirkin, "He suggested studying mutations in the genes of DNA polymerase, one of the participants in the replication fork that reads information from a DNA strand." New scrupulous experiments were required. Point mutations were introduced into the genes encoding DNA polymerase. "Polina, a specialist in mutant DNA polymerases and their role in the occurrence of cancer, suggested using three specific mutations, and, as it turned out later, she guessed one hundred percent," Mirkin admires his colleagues. – All three point mutations introduced into DNA polymerase genes led to a dramatic increase in the length of repeats!" Studies have helped explain why in some families the disease develops and progresses in generations, while in others it does not: if there are also hidden mutations in the genes of one of the main actors of replication - DNA polymerase, – there will be trouble.
There are targets, you can look for bulletsAll these processes were tested on model organisms – yeast.
But scientists believe that their results can be safely extrapolated to other organisms, including humans, since the mechanisms of such basic cellular processes as replication and transcription are conservative and similar in all organisms. They also suggest that the results of their work concerning one disease – Friedreich's ataxia, can be attributed to other genetic diseases associated with the elongation of nucleotide repeats. There are at least thirty such diseases. Among them are brittle X-chromosome syndrome, Huntington's chorea, myotonic dystrophy, some forms of Lou Gehrig's disease and others. But the syndrome of the brittle X chromosome, which leads to mental retardation, occurs in one out of a thousand newborns, despite the fact that every two hundredth person is its potential carrier. Huntington's chorea manifests itself after 35 years, when the patient, as a rule, already manages to pass on the terrible genetic heritage to his children.
The fundamental knowledge gained in the course of many years of research, after some time, can be used in medicine. First, when diagnosing. "The day is not far off," says Mirkin, "when we will know the genome sequence of every person living on Earth." Analysis of the identified mutations will reveal the risks of the appearance or development of diseases and, if necessary, discuss whether it is worth having offspring with unfavorable forecasts. Secondly, knowing the mechanisms means knowing the targets that pharmacists can target. "We know which genes are involved in the process and which products of these genes can be targets for drugs. Accordingly, we can begin to search for drugs against diseases caused by the lengthening of repetitions. We are now groping for such approaches, but this is a completely different area of activity, which is still at the origins. In any case, the fundamental knowledge we have gained gives hope," says Sergey Mirkin.
Portal "Eternal youth" http://vechnayamolodost.ru08.10.2012