Notes On Genetic Variation study of mutagenesis

[mitchellmckain 0]

Based on doubts I had about the random nature of genetic variation and the origins of mutation, I did some library research and found some very intresting data and conclusions in books about Mutagenesis. My conclusions are preceeded by a ">" character.Friedberg, Walker and Siede, “DNA Repair and Mutagenesis” 1995“Once it was recognized that DNA is the informationally active chemical component of essentially all genetic material (with the notable exception of RNA viruses), it was assumed that this macromolecule must be extraordinarily stable in order to maintain the high degree of fidelity required of a master blueprint. It has been something of a surprise to learn that the primary structure of DNA is in fact quite dynamic and subject to constant change. For example, gene transposition is a well established phenomenon in prokaryotic and eukaryotic cells. In addition to these larger scale changes, DNA is subject to alteration in the chemistry or sequence of individual nucleotides.” This book out lines the process by which DNA participates in a constant cycle of damage and repair. The book describes 3 types of cellular responses to DNA damage (including errors): Reversal, excision and tolerance. The first is a reaction to fairly minor damage which can be repaired by the action of a single polypeptide enzyme. Excision is a much more elaborate process by which the damaged or mismatched pieces are cut away and the original sequence is restored. Tolerance mechanisms do no remove the primary damage and thus often results in a permanent change in the genome. There are at least 4 known mechanisms for reversing different types of DNA damage, the simplest of which is called photoreactivation of DNA by which a light activated enzyme removes the type of damage that is most commonly caused by UV radiation. Heterogeneity of excision repair chapter 7 Because some of the repair mechanisms are tied to the transcription process, there is a bias towards the repair of transciptionally active DNA sequences. But the existence of repair mechanisms for nonactive DNA has been shown to be of critical importance to the prevention of cancer. >This pheonmena of “heterogeneity of exicision repair” is another example that suggests that the whole process is anything but random. Mismatch repair chapter 9 Tolerance chapters 10-12 “For example, prokaryotic cells have evolved mechanisms for repairing single-strand gaps and double-strand breaks in their DNA that have arisen either directly from DNA damage or indirectly as the result of processing of the initial DNA damage. These mechanisms involve proteins that also play roles in the homologous recombination of undamaged DNA. Niether of these processes appear to be particulary mutagentic. In addition, prokaryotic cells have evolved another class of mechanisms for processing damaged DNA which, although not yet fully understood a biochemical level, appears to involve the polymerization of DNA past a lesion and is often referred to a translesion DNA synthesis. In contrast to other systems that act on damaged DNA, this type of processing can be highly mutagenic and, in fact is required for most UV radiation and chemical mutagenesis.” pg 407 “In the case of E coli, in which these alternative mechanisms for dealing with damaged DNA have been studied most closely it has become clear that their regulation and operation is intimately related to the complex SOS regulatory network. The expression of the more than 20 genes in this network is induced by DNA damage and is regulated by the LexA and RecA protiens.” pg 407 The book described the experiements, “that first suggested that an inducible system is required for mutagenesis,” where UV radiation failed to induce mutation in bacteriophages unless the host cell was also irradiated thereby activating the SOS system of the cell that allowed the translesion DNA sythesis process to occur in the DNA of both the host cell and the invading viral DNA. pg 466 “Studies of UV radiation-induce mutagenesis of the bacterial chromosome played a key role in the development of the notion that recA+ -lexA+-dependent functions are required for the specialized processing of damaged DNA that gives rise to mutations and that this process is inducible. Evelyn Witkin’s observation that lexA(Ind-) mutants were not mutable by UV radiation led her to postulate that the lexA+ gene might encode or control a new or modified DNA polymerase capable of inserting nucleotides oposite UV radiation lesions and that UV mutagenesis occurred by a mechanism of translesion replication.” pg 467 > So we have a set of genes for the express purpose of of bypassing the DNA repair system to allow mutations to occur! > No genetic alteration is external or random, because alteration is not due to random damage or replication error as much as it is due to a particular type of response to DNA damage. Edward A. Birge, “Bacterial and Bacteriaophage Genetics”“Transposons are units of DNA that move themselves from one DNA strand to another or to a new position on the same molecule, inserting at nearly random positions. They are also capable of catalyzing DNA rearrangements such as deletions or inversions.” pg 80. “One of the basic tenets of genetics is that indiscriminate exchange of genetic information is disadvantageous to a species. In eukaryotic cells, problems with chromosome pairing during mitosis and meiosis often prevent cells that have acquired foreign chromosomes from surviving. However, because segregation of the nucleoid in prokaryotic cells requires no such elaborate mechanism, other strategies must come into play. In particular, many bacterial cells and their viruses use a system of restriction and modification to tag their own DNA and disrupt any foreign DNA that may be present.”

[bricktamland 0]

SoCancer is caused by mutations in DNA isnt it?If we could turn off these genes, could we prevent cancer?Or at least make it less likely to occur?

[mitchellmckain 0]

So

Cancer is caused by mutations in DNA isnt it?

If we could turn off these genes, could we prevent cancer?

Or at least make it less likely to occur?

1064332536[/snapback]

The studies in the notes above were using E-coli and were in response to ultra-violet light. If we have a similar gene it would probably only apply to skin cancer but I doubt that it really applies directly to cancer in humans at all. I think that our cells are far more sophisticated than E-coli.

 

I believe it is somewhat well known that the human body deals with cancer all the time as a part of its immune response, and that cancer only threatens us when this fails. This is more likely to happen when we are exposed to more cancer causing agents like radiation and carcinogens. What we learn from the notes on mutagenesis in this regard is that even the immune system is only backup for a very efficient DNA repair system. Considering this, it seems that the best prevention is to reduce exposure to these cancer agents and to support a healthy immune system with proper nutrition.

 

If we have genes which bypass the genetic repair like E-coli, I would expect it to be much more limited and controlled than it is in E-coli. The point seems to be to maintain the evolutionary advantage of genetic variation and it seems that would only advantageous in reproductive cells. However, since we have our own means of producing genetic variation we might not have these bypass genes at all.

 

The main thing which I learned from this study of mutagenesis was that variation which is the driving force of evolution is not random or accidental but controlled and intentional. It would only have been random at some very early point in evolutionary history.

[illini319 0]

As mentioned in the post before me, please keep in mind that the study was done in a bacterium. Having said that, DNA damage sensing/repairing proteins are so critically important to life that it is highly conserved all the way up to humans. It is not their job to directly generate mistakes. The generation of genetic mistakes should not be equated to genetic diversity. The bulk of 'mistakes' that are made are quickly, and faithfully, repaired. Then there is the question of where the genetic lesion occurs. Most of the time, these mistakes occur in regions of our DNA that does not encode any gene. Hence these are neutral mutations and do not contribute to some phenotypic change. On the off chance that DNA damage occurs on coding DNA, then there is STILL the question of which cell this damage occurred in. If it happens on some somatic cell, there is a chance that such a persistent DNA damage can give a selective growth advantage that can lead to cancer. Such an avenue is detrimental to the organism... but does not contribute to genetic diversity. Only when DNA damage occurs (and persists) in our germ cells (sperm or egg) does it ever contribute to genetic diversity, because these changes can actually propagate to the next generation.