Environmentally directed mutations

Some species are capable of generating a greater number of mutations under certain, usually stress conditions. This allows them to overcome the unfavourable conditions. Some authors are of the opinion that the organism is capable not only of  generating a suitable number of mutations, but that it is also capable of generating just those mutations that allow it to overcome the currently active unfavourable environmental factor. In other words, according to these concepts, organisms are capable of environmentally directed mutations. The results of fluctuation tests, replica plating tests and our knowledge of the mechanisms of the formation of mutations indicate that, in general, organisms mutate randomly, and not in an environmentally directed manner.(see Fluctuation tests and Replica plating tests).  However, in a great many organisms, there exist specialized genetic mechanisms through which the organisms generate a certain, momentarily advantageous type of mutation in specific situations.These mechanisms permit the population of organisms to react adaptively in situations in which they find themselves repeatedly, although not very frequently.Contemporary evolutionary biology assumes that, similar to other adaptive processes or structures encountered in organisms, these mechanisms and necessary molecular apparatuses arise gradually through random mutations during evolution through the action of natural selection.

The hypervariability of the surface protein in the African trypanosome is an example of such a mechanism (Borst et al. 1997).During their life cycle in the organism of their host, these parasitic protozoa regularly and repeatedly encounter attacks by the immunity system.Most of these attacks are directed against the main antigen of the surface coat and the individual trypanosome is practically defenseless against them and is thus rapidly and reliably killed.  The defensive strategy of the protozoa lies in the fact that it has approximately 1000 genes for very different variants of this protein in its genome and, through mutations in the regulation regions of the individual genes, such as duplication translocation to the expression site, ensures that synthesis of the surface antigen is switched from one gene to the other in some individuals in the population.These events occur with relatively low frequency; at every instant in the body of the host, almost 100% of the protozoa express the same surface antigen.However, it is sufficient for at least several mutated cells with the minority antigen to survive the immunity response of the organism against the majority surface antigen.These again multiply in the host so that, sooner or later, it again develops a strong immune response against them.Less than 0.1% of the protozoa mostly survive the individual waves of immune response; however, the host is not able to completely rid itself of the parasite.A similar parasite strategy is also known for bacteria of the Borrelia and  Neisseria genera (Seifert & So 1988; Meyer 1987) and it can expected with certainty that it will be even more widely spread in nature.

Experiments have shown that antigen variability in parasites is actually ensured by hypermutability of specific DNA sections.The molecular mechanism of these mutations is quite well known and it is known that, for example in trypanosomes, they occur with a frequency of 0.01 and in borrelia with a frequency of 0.0001 – 0.001 per cell division.However, in some cases, the increased frequency of certain mutations can be only an apparent cause of a similar  phenomenon and the entire mechanism can function on the basis of some form of natural selection.An example could be the case of the formation of resistance against methotrexate through the multiplication (number of copies) of certain genes.If a gradually increasing amount of this inhibitor enzyme dihydrofolate reductase is added to long-term passage cultures of the protozoa Leishmaniamajor, or even to in vitro passage cultures of mammalian cells, in time a species of the protozoa (mammalian cells) is obtained that will be very resistant to this inhibitor.Study of the genome of these resistant species demonstrated that they have a multiple copies of the gene for dihydrofolate reductase (Schimke 1984; Grondin et al. 1998).A similar mechanism of formation of resistance is active for mosquitoes of the Culexgenus resistant to organophosphate insecticides (Callaghan et al. 1998).It is possible that this multiplication of genes occurs in the cell as a random mutation and is only anchored through natural selection under the condition of selection pressure from the inhibitor.However, it is also possible that a specific mechanism exists in the cells,which is capable of multiplying any genes whose transcription and subsequent translation to the protein molecule occurs at a velocity approaching the maximum velocity for the given gene.For example, if the enzyme dihydrofolate reductase is inhibited by the presence of methotrexate, the cell must synthesize a much greater number of molecules of the enzyme than a cell under normal conditions.Most of the molecules of the enzyme are immediately inhibited, so that transcription of mRNA from the relevant gene is regulated up to maximum possible rate.If the cell is capable of multiplying the gene for dihydrofolate reductase sufficiently so that it manages to compensate the inhibiting effect of methotrexate, transcription of mRNA will no longer have to occur at the maximum velocity and further multiplication of the gene will stop.

A very interesting situation can occur in the case of hypermutability of the variable part of the chains of immunoglobulins in B-lymphocytes (Berek 1992; Berek & Ziegner 1993).Here, the relevant processes occur at the intra-organism level and the relevant mutations are somatic mutations; however, all the processes are controlled by the same laws as similar processes at the inter-organism levels.

If the organism of a mammal encounters a foreign protein, at least some of its B-lymphocytes will bear, on their surfaces, immunoglobulin molecules with a certain, although frequently very low affinity for this protein.However, during a few days, the progeny of these lymphocytes begin to appear in the organism; they have individual mutations in the variable part of the genes for immunoglobulins that, as they regularly accumulate in the genes, gradually increase the affinity of the immunoglobulins for the given protein.It is said that the affinity of the antibodies matures through hypermutability of the genes for immunoglobulins.

It was originally assumed that, in this case, the immune system employs the classical mechanism of Darwinistic evolution, i.e. generation of quite random mutations in the relevant regions of the immunoglobulin genes and selecting mutants with immunoglobulins with greater affinity for a foreign protein.However, there are two unexpected facts.The generation time for lymphocytes is many hours, while the actual process of affinity maturation lasts only a few days.Simultaneously, the number of selective intermediate stages and the number of mutations that must be gradually fixed is so large that it is practically impossible for the whole process to take place during a few cell generations, during which the process of antibody affinity maturation occurs (Manser 1990).In addition, when the individual mutants were studied as they were formed during affinity maturation, it began to be apparent that every mutation that was fixed increased the affinity of the immunoglobulins compared to the former state (Lavoie, Drohan, & Smithgill 1992).If the Darwinistic mechanism were active, we would expect that a substantial percentage of the mutations would be neutral, at the very least.

At the present time, there is only one model that has attempted to explain this paradox in the behaviour of the immune system during antibody affinity maturation (Manser 1990).The affinity matures in the germinal centres of the lymphatic nodes (Fig. III.9).At these sites are located populations of B-lymphocytes and auxiliary T-lymphocytes and also a certain amount of the antigen, for example a foreign protein bound to the surface of the dendritic cells in the follicles.The B-lymphocytes bind the antigen released gradually from the dendritic cells to their surface immunoglobulins and transport it to their lysosomes.There, they split it enzymatically into the individual peptides, bind these to II class MHC (major histocompatibility complex) molecules and, together with them, transport it back to their surface.The T-lymphocytes “feel out” the surface of the B-lymphocytes and provide a growth factor to those that present the greatest number of foreign peptides on their surface.Only B-lymphocytes that have obtained the growth factor can divide.If all the B-lymphocytes have molecules of the same immunoglobulin on their surface, then they bind them all, internalize them, split them and present the foreign antigens on their surface to approximately the same degree.The assistance that is provided by the T-lymphocytes is thus also evenly divided and all the cells can divide only very slowly or do not divide at all.In contrast, if there is amongst the cells a mutant that produces immunoglobulins with greater affinity for the antigen, they preferentially capture this antigen from the other B-lymphocytes, present more foreign peptides on their surface and thus obtain more growth factor from the T-lymphocytes at the expense of the other B-lymphocytes and can thus divide more rapidly.

So far, this was an example of classical Darwinistic evolution of which we have, however, already stated that it cannot adequately explain the process of affinity maturation because of the inadequate number of generations of lymphocytes and absence of neutral mutations.The authors of the alternative model (Fig. III.10) assume that the cells must mutate in the quiescent state, i.e. when they are not dividing and, in addition, those mutations that do not lead to increased antigen affinity must be repaired.One of the mechanisms through which the lymphocytes could achieve these goals is as follows:The lymphocyte is capable of somehow generating mutations solely in the (+)-chains of the DNA of the gene for immunoglobulin, i.e. in the chain from which the mRNA for immunoglobulin is transcribed.After some time, both DNA chains are fitted together and the sequence of nucleotides in the (+)-chain is repaired according to the sequence in the (-)-chain.However, if one of the mutations is manifested in an increase in the affinity of the immunoglobulin for the antigen, then the B-lymphocyte obtaines the growth factor from the auxiliary T-lymphocyte and divides before the mutation in the (+)-chain can be repaired.As soon as replication occurs in the given DNA section, the mutation is definitively fixed in one of the two daughter cells and cannot be repaired.

This hypothetic model is only one of a number of possible models (Steele, Rothenfluh, & Blanden 1997).It will be interesting in the future to learn which mechanism was actually chosen by evolution to enable the immune system to avoid the greatest drawbacks of Darwinistic evolution, the inability to generate targeted (environmentally directed) mutations.

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The classical Darwinian theory of evolution can explain the evolution of adaptive traits only in asexual organisms. The frozen plasticity theory is much more general: It can also explain the origin and evolution of adaptive traits in both asexual and sexual organisms Read more