Why do we need "unnecessary" genes
Alexander Markov, "Elements"The yeast genome contains about 6000 genes, of which only 1000 are absolutely necessary for survival in standard laboratory conditions.
Why yeast needs the remaining 5,000 genes was still not entirely clear. Having conducted more than 6 million tests, geneticists from the USA and Canada came to the conclusion that the vast majority of these supposedly "unnecessary" genes are useful in certain non-standard conditions. In particular, many of them increase the resistance of yeast to various poisons.
To find out why a particular gene is needed, the easiest way is to spoil it with a mutation or turn it off altogether and see how this affects the phenotype (that is, the structure, physiology or behavior of the organism). It is in this way that geneticists often find out the functions of genes. You can also move in the opposite direction: having discovered an altered (mutant) phenotype, try to find out which gene (or genes) changes led to such consequences. Previously, geneticists almost always went the second way, and recently, due to the development of genetic engineering and other modern techniques, the first way is increasingly being used.
At the same time, it is surprisingly often found that one or another gene (or a non-coding section of DNA) does not seem to be needed for anything: its removal does not lead to any visible consequences and does not at all reduce the viability of the organism.
"Elements" have already told about several such cases (see: After removing 15% of genes, bacteria become completely tame, "Elements", 24.05.2006; Removal of the most important parts of the genome does not harm the health of mice at all, "Elements", 14.09.2007). Recently, an interesting new article was published in the journal PNAS with similar results. Not being able to write a separate note on this article, I will tell you about it here in a nutshell. It turned out that disabling the SREB2 gene, which is actively working in brain cells, not only does not harm the health of mice, but even leads to a slight increase in brain size and improves memory. Meanwhile, this gene is ultraconservative: the protein encoded by it is absolutely the same in all mammals — not a single amino acid has changed in it in the entire history of the mammalian class. Minor changes in the non-coding regions (introns) of this gene in humans are associated with a tendency to schizophrenia, and a slight increase in the expression (activity) of this gene in the same mice caused them serious mental abnormalities, very similar to the aforementioned mental illness. All indirect signs, it would seem, suggest that this gene should be vital — however, mice with the SREB2 gene disabled feel great and even learn various mouse tricks faster than their non-mutant girlfriends.
How to explain such strange results? Are the numerous "unnecessary" genes found in the course of such experiments really not needed by their owners at all? But if a gene becomes unnecessary, then, in theory, it should quickly fail and break down under the influence of random mutations that are not eliminated by selection. How then to explain the high conservatism, that is, the evolutionary stability of many of these genes, which is manifested in the high level of their similarity in species of organisms that are far from each other?
The most obvious (and in many cases, probably the only possible) answer is as follows. Probably, these genes are still needed for some reason, but not in the greenhouse conditions of a scientific laboratory, but in nature, where living organisms have to deal with infinitely diverse, sometimes dramatically changing and unpredictable environmental factors. It is quite logical to assume that the more constant and predictable the living conditions, the more the genetic "program" of the behavior of a cell (or a multicellular organism) can be simplified. This explains, for example, the radical reduction of genomes in intracellular symbiotic bacteria (see: The smallest genome has been read, "Elements", 16.10.2006). The conditions in which laboratory organisms live and are studied are usually extremely standardized (standard environments, feeds, cells, illumination, etc.), which makes their existence — from an evolutionary point of view — little different from the life of intracellular parasites.
This theoretical reasoning, however, needs experimental verification. This is exactly the task set by geneticists from the USA and Canada, who published the results of their research in the latest issue of the journal Science. The authors studied the "unnecessary genes" of a classic laboratory object — the fungus Saccharomyces cerevisiae (this is a well-known yeast). In yeast, up to 65% of genes can be removed or disabled without any reduction in viability. However, with one small clarification: we are talking about viability in standard "rich" laboratory environments saturated with all the necessary substances.
The authors used existing collections of mutant yeast, where each strain contains one deletion (one deleted gene) in a homozygous or heterozygous state (that is, either both copies of this gene or only one are deleted). Yeast can reproduce both sexually and asexually (budding), and the method of reproduction depends on environmental conditions. Therefore, heterozygous strains can be propagated asexually for a long time without fear that they will cease to be purely heterozygous.
The collections used include about 6000 heterozygous strains — that's how many genes are contained in the yeast genome. For each gene, therefore, there is a strain on one of the chromosomes of which this gene is removed. The number of homozygous strains, that is, those in which one or another gene is removed on both chromosomes, is somewhat less — about 5000. There are a thousand fewer of them than heterozygous strains, because that's how many genes — 1000 — are "vital". Their removal on both chromosomes is fatal for yeast even when grown in a rich environment.
Each of these strains was tested under a variety of non-standard conditions. All kinds of chemicals were added to the medium, including drugs that inhibit the growth of microorganisms, or some important components were removed from the medium (for example, amino acids or vitamins). Each heterozygous strain was tested in 726 different environments, and each homozygous strain was tested in 418.
Scientists have done a truly titanic job: the total number of tests performed exceeded 6 million! In each of the tests, the growth of yeast in a non-standard environment was compared with the growth of the same strain in "normal" laboratory conditions.
It was previously known that homozygous deletions of 19% of genes are lethal (this is the "vital thousand"); another 15% of genes increase viability in a standard rich environment (in other words, their deletion in a homozygous state reduces viability). There were still 66% of the genes, it is not clear why they were needed.
The researchers found that the vast majority of these "unnecessary" genes turn out to be useful (that is, they increase the viability of yeast) in at least one of the tested environments. Only 205 genes (3% of the total) they never revealed their secret: among the tested variants of the conditions, there was no one in which the presence of these genes would be useful. A significant part of the genes, as it turned out, increases the resistance of yeast to the effects of various poisons, including all kinds of drugs used to combat pathogenic microorganisms. The authors paid special attention to these genes, highlighting among them an extensive group of multifunctional genes that provide yeast with protection from many types of toxic substances at once. Further study of these genes will help to better understand the mechanisms of resistance of microorganisms to drugs.
A curious situation has developed with transcription factors (TF) — proteins that regulate the activity of genes depending on certain external factors or signals. There are about 160 TF genes in the yeast genome, but only 5 of them are vital when growing in standard "ideal" conditions. Almost all TF proved to be useful in various non-standard conditions, and 16 of them were among the multifunctional "defenders" that increase the resistance of yeast to many toxic substances at once. Transcription factors form the basis of the cell's response system to external stimuli — together with other signaling and regulatory proteins, they can be likened to the sensory organs and nervous system of multicellular animals. The fewer transcription factors, the "stupider" the cell. It is quite natural that in ideal greenhouse conditions, complex response systems become unnecessary — this principle is based on the rapid reduction of TF genes in intracellular symbiotic bacteria, and a natural decrease in brain size and a decrease in mental abilities in domestic animals compared to their wild ancestors.
The study thus fully confirmed the theoretical expectations based on the classical Darwinian principle: "if a gene exists, then it is needed for some reason." The number of supposedly "unnecessary" genes in the yeast genome has now decreased from 66% to 3%, and these remaining genes with an unknown function are most likely also needed by yeast in vivo for something. Those of them that have really become unnecessary may be in one stage or another of degradation. The authors note that more than a third of these 205 genes, apparently, no longer function, that is, they do not encode proteins and are not expressed.
Source: Maureen E. Hillenmeyer et al. The Chemical Genomic Portrait of Yeast: Uncovering a Phenotype for All Genes // Science. 2008. V. 320. P. 362–365.
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22.04.2008