How important genes turned out to be unimportant

The absence of many genes considered important does not affect health.

Kirill Stasevich, "Science and Life" based on Science: Human 'knockouts' reveal genes we don't need.

Although we already know how many genes a person has (according to various estimates, from 20 to 25 thousand), their functions still remain largely uncertain. This can be compared to a text typed with unknown characters: first you try to understand where one word ends and another begins, and then you comprehend the actual meaning of the words.

The same thing happened to the human genome: we can only guess at the meaning of most of the "words" so far (although many genes have already been studied quite well). In addition, do not forget that the meaning of "words" can change when interacting with each other – the molecular genetic context affects the work of genes.

Usually, when they want to find out why a particular section of the chromosome is needed (not necessarily a coding protein, it can be a regulatory DNA sequence), it is either turned off by mutations, or simply cut out of the genome, in general, one way or another it is not allowed to work. This method is good with animals, but no one will turn off genes in humans specifically for experimental purposes. However, it is possible to use an experiment set up by nature itself and analyze the genomes of those whose ancestors live in closed, closed communities from generation to generation and whose parents often turn out to be relatively close relatives – for example, cousins.

To understand what's going on here, you need to remember the simplest genetics. As you know, in each of our cells there is a double set of chromosomes, one copy of which we got from our father, the other from our mother. That is, each gene is in the maternal and paternal variants (alleles), and if the gene from one of the parents came inoperable, being spoiled by accumulated mutations, then the cell (and the whole organism) can still live happily ever after thanks to the second copy inherited from the other parent. (We are not discussing here more complex – and quite common – cases when the same gene itself exists in several copies: for example, there may be two, three, etc. copies of it on both chromosomes, some of which may work, and some may not. In addition, genes may have such abnormal variants that continue to work, but work incorrectly, and by their irregularity they suppress, dominate over the variant that is normal, healthy.)

But if the broken variants of the gene from both parents come together in the embryo during fertilization, then it is worth waiting for some kind of disease - if, of course, the embryo survives until birth at all. In this case, we can conclude why this gene is needed, what it does in the cell and how important it is for humans in general. Such cases when two "breakdowns" converge in one organism are quite rare if the population is large. But if the population is small, if reproduction takes place within a relatively narrow "circle of persons", if people (or animals) who are related to a fairly close relationship enter into marriage, then the probability of meeting mutant genetic alleles increases.

Richard Durbin from the Sanger Institute, David A. van Heel from Queen Mary College and their colleagues analyzed the genomes of 3,222 adult Pakistanis living in the UK (only protein coding sequences were selected for analysis, no attention has yet been paid to purely regulatory sequences). People from Pakistan were chosen precisely because they traditionally marry not with "strangers", but with someone from "their own". It turned out that they were missing quite a few genes, some of which are believed to be associated with quite serious diseases.

One would expect that in the absence of such genes, a person would be very ill, but there were really a minority of those who were ill; in addition, some physiological disorders that should have occurred did not manifest themselves as much as could be expected. Some cases were particularly curious: for example, one of the women who managed to have children did not have the PRDM9 gene at all, about which it is known that it is necessary for shuffling genes between chromosomes during the formation of germ cells.

Correct chromosome sorting is an absolutely necessary process, and mice with PRDM9 turned off are sterile in experiments. But on the other hand, dogs tolerate the PRDM9 shutdown normally – and, apparently, humans too. (More recently, we recalled about this gene in connection with an article about speciation and infertility of hybrids – they also talked about human and mouse variants of PRDM9.) The full results of the study are published in Science; now the authors are going to do similar work, but with people from South Asia.

That is, let's repeat once again, people who lacked the same gene in both the maternal and paternal chromosomes were not just born, but also managed to live for quite a long time, have their own children, and generally felt good. However, this does not mean that the harm from closely related crossing is far-fetched. Even if we do not take experiments and observations of animals, there are very instructive examples in human history of how maintaining the "purity of blood" gave exceptionally sickly, ugly, feeble–minded descendants (those who are curious may be interested in the clinical history of the Spanish king Carlos II, who was called "Bewitched" because of his numerous diseases, "Enchanted" and "Possessed").

What the new data really says is that we don't yet fully know how our genes work – even those about which we already seem to know enough. Many of them, of course, are vital for us, and their complete absence can have an extremely negative impact on the development of the human body. But here it should always be remembered that the genome is a system with a sufficiently high reliability, that genes can "back up" each other, and that the influence of genes may depend, as we said above, on the current context.

Recall that recently a research group from the Broad Institute tried to estimate the number of genes absolutely necessary for a person – there were 3230 of them. Many of them are indeed associated with serious diseases, but most of these three thousand plus are functionally terra incognita. Genetic studies like the one described above should speed up the process of deciphering the functions of human genes.

Portal "Eternal youth" http://vechnayamolodost.ru  10.03.2016