Adaptive mutation
Encyclopedia
Evolutionary theory describes that mutagenesis
occurs randomly, regardless of the utility of a genetic mutation to the organism. If it is beneficial or neutral, the organism will survive to reproduce and pass on the mutation. However, molecular biologist John Cairns has proposed that "when populations of single cells are subject to certain forms of strong selection pressure, variants emerge bearing changes in DNA sequence that bring about an appropriate change in phenotype." This suggests that there exists a particular physiological pathway that responds to a specific selective pressure to produce a mutation conferring the correct phenotype that will alleviate this pressure.
Such evidence was first produced by Cairns et al. in 1988. The original experiments involved a strain of E. coli
that has a frameshift mutation
in the lactose
(LacZ) operon
, inactivating the proteins needed for utilization of this sugar. The bacteria
were then spread on an agar
medium in which the only carbon source was lactose. This meant that a cell could grow only if a second mutation occurred in the lactose operon, reversing the effects of the mutation and therefore allowing the enzymes to be synthesized. Mutations with this effect appeared to occur significantly more frequently than expected, and at a rate that was greater than mutations in other parts of the genomes of these E. coli cells.
There is however a serious flaw in this experiment, as Cairns does not distinguish between selection and detection of LacZ revertants. If he is testing to see if the presence of lactose as the selective agent causes mutations that confer the ability to eat lactose, then he should not detect this mutation with lactose present (i.e. looking for cells that grow with lactose as the only carbon source.) He will never know, in this case, if cells have acquired this ability without the presence of lactose - a possibility that his theory cannot reconcile. In fact, the acknowledgment of fundamental limitations on our ability to separate between mutation selection and detection has lead Vasily Ogryzko to suggest that for the proper description of the Cairns' experiments, the formalism of quantum theory would be required, with the phenomenon of adaptive mutations naturally following from such an approach.
Furthermore, when looking for additional mutations only in cells that have already reverted to Lac+, it would certainly be the case that other, unnecessary mutations would be less numerous - especially since most are deleterious. However, Barry Hall has provided evidence that the mutation rate in bacteria under environmental stress increases across the board, most likely indiscriminately. When testing for tryptophan revertants (trp− → trp+, i.e. cells that have regained the ability to make tryptophan), he found that occurrence of auxotrophic mutants increased as well. Tryptophan revertants, which had been exposed to the environmental stress of lacking the amino acid, saw a 1.8% rate of auxotrophy for any other amino acid. When testing for auxotrophy in cells in non-stressed colonies, he found a rate below 0.01%. From these data, Hall hypothesized that cells under stress enter a "hyper-mutable state," where cells increase their general rate of mutation, increasing the overall probability that they will acquire a mutation conferring a phenotype that aids their survival. Hall later determined that his mutants were the result of transposon activity, and concluded that his results were in fact about transposon biology, and not mutagenesis.
Similar results have been observed in other experiments. These experiments suggested that mutations in bacteria are influenced by the selective pressures that the bacteria are placed under.
One possible explanation is that under conditions of stress the global rate of errors in DNA replication
and repair
mechanisms is increased, and hence the mutation rate is increased.
Another explanation stems from a similarity in cellular mechanisms underlying the acquisition of adaptive mutations in the bacterial stationary phase cells and in the mammalian tumor
cells. In both cases the adaptive mutations arise in response to a sustained stress environment and are promoted by high rate of genomic mutations. Cellular processes leading to the mutations are also surprisingly similar between both organisms and include silencing of differentiation, cellular senescence
, programmed cell death
, and DNA repair
on the one hand, and activation of the error-prone replication and transposons on the other. The similarity suggests that the adaptive mutations may be an output of activation in the stressed cell of a special survival strategy for quick adaptation to the stressful environment. This strategy that is also referred as the mutator phenotype is an alternative to other stress-induced strategies, such as senescence
and programmed cell death
, activated in majority of stressed cells. Continuing stress-induced proliferative and survival signaling may be an important prerequisite for epigenetic reprogramming of some cells to activate the mutator phenotype.
Mutagenesis
Mutagenesis is a process by which the genetic information of an organism is changed in a stable manner, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures...
occurs randomly, regardless of the utility of a genetic mutation to the organism. If it is beneficial or neutral, the organism will survive to reproduce and pass on the mutation. However, molecular biologist John Cairns has proposed that "when populations of single cells are subject to certain forms of strong selection pressure, variants emerge bearing changes in DNA sequence that bring about an appropriate change in phenotype." This suggests that there exists a particular physiological pathway that responds to a specific selective pressure to produce a mutation conferring the correct phenotype that will alleviate this pressure.
Such evidence was first produced by Cairns et al. in 1988. The original experiments involved a strain of E. coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
that has a frameshift mutation
Frameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
in the lactose
Lactose
Lactose is a disaccharide sugar that is found most notably in milk and is formed from galactose and glucose. Lactose makes up around 2~8% of milk , although the amount varies among species and individuals. It is extracted from sweet or sour whey. The name comes from or , the Latin word for milk,...
(LacZ) operon
Operon
In genetics, an operon is a functioning unit of genomic DNA containing a cluster of genes under the control of a single regulatory signal or promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo trans-splicing to create...
, inactivating the proteins needed for utilization of this sugar. The bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
were then spread on an agar
Agar
Agar or agar-agar is a gelatinous substance derived from a polysaccharide that accumulates in the cell walls of agarophyte red algae. Throughout history into modern times, agar has been chiefly used as an ingredient in desserts throughout Asia and also as a solid substrate to contain culture medium...
medium in which the only carbon source was lactose. This meant that a cell could grow only if a second mutation occurred in the lactose operon, reversing the effects of the mutation and therefore allowing the enzymes to be synthesized. Mutations with this effect appeared to occur significantly more frequently than expected, and at a rate that was greater than mutations in other parts of the genomes of these E. coli cells.
There is however a serious flaw in this experiment, as Cairns does not distinguish between selection and detection of LacZ revertants. If he is testing to see if the presence of lactose as the selective agent causes mutations that confer the ability to eat lactose, then he should not detect this mutation with lactose present (i.e. looking for cells that grow with lactose as the only carbon source.) He will never know, in this case, if cells have acquired this ability without the presence of lactose - a possibility that his theory cannot reconcile. In fact, the acknowledgment of fundamental limitations on our ability to separate between mutation selection and detection has lead Vasily Ogryzko to suggest that for the proper description of the Cairns' experiments, the formalism of quantum theory would be required, with the phenomenon of adaptive mutations naturally following from such an approach.
Furthermore, when looking for additional mutations only in cells that have already reverted to Lac+, it would certainly be the case that other, unnecessary mutations would be less numerous - especially since most are deleterious. However, Barry Hall has provided evidence that the mutation rate in bacteria under environmental stress increases across the board, most likely indiscriminately. When testing for tryptophan revertants (trp− → trp+, i.e. cells that have regained the ability to make tryptophan), he found that occurrence of auxotrophic mutants increased as well. Tryptophan revertants, which had been exposed to the environmental stress of lacking the amino acid, saw a 1.8% rate of auxotrophy for any other amino acid. When testing for auxotrophy in cells in non-stressed colonies, he found a rate below 0.01%. From these data, Hall hypothesized that cells under stress enter a "hyper-mutable state," where cells increase their general rate of mutation, increasing the overall probability that they will acquire a mutation conferring a phenotype that aids their survival. Hall later determined that his mutants were the result of transposon activity, and concluded that his results were in fact about transposon biology, and not mutagenesis.
Similar results have been observed in other experiments. These experiments suggested that mutations in bacteria are influenced by the selective pressures that the bacteria are placed under.
One possible explanation is that under conditions of stress the global rate of errors in DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
mechanisms is increased, and hence the mutation rate is increased.
Another explanation stems from a similarity in cellular mechanisms underlying the acquisition of adaptive mutations in the bacterial stationary phase cells and in the mammalian tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cells. In both cases the adaptive mutations arise in response to a sustained stress environment and are promoted by high rate of genomic mutations. Cellular processes leading to the mutations are also surprisingly similar between both organisms and include silencing of differentiation, cellular senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
, programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
, and DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
on the one hand, and activation of the error-prone replication and transposons on the other. The similarity suggests that the adaptive mutations may be an output of activation in the stressed cell of a special survival strategy for quick adaptation to the stressful environment. This strategy that is also referred as the mutator phenotype is an alternative to other stress-induced strategies, such as senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
and programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
, activated in majority of stressed cells. Continuing stress-induced proliferative and survival signaling may be an important prerequisite for epigenetic reprogramming of some cells to activate the mutator phenotype.