Mutation and its role in evolution: A beginners guide

In the previous Natural Limitation to Evolutionary Processes (2/14/05) thread Faith expressed a desire to better understand the nature of mutation and to further discuss some specific examples of beneficial mutations which were raised in that thread.To that end I think we should have a mutation thread in the science forums where it belongs, and perhaps Faith can start an accompanying thread in the Theology and ID forum if she wants to develop her own ideas about how what we are discussing could fit into her own ideas about the history of life on Earth.Mutation is not a highly specific term in and of itself. As a fundamental basis for evolution all mutation needs to be is some sort of heritable change.Obviously the major focus of research into such things focuses on genetic mutations since we have a large number of tools for investigating and manipulating genes and a reasonable understanding of how they operate. This does not mean that genetic mutation is the be all and end all of mutation in terms of evolution, but it is certainly the best starting point.All genetic mutations are by no means equal either, not in their extent, nature or frequency. While we can make general observations about the relative frequency of particular types of mutation, and of regions in the genome or sequences of DNA which are more prone to mutations than others, we cannot accurately predict any specific mutation occuring at a specific locus in any given organism.The best we can do is make estimates based on the various probabilities and study populations of organisms to see how well they reflect those estimates.Naturally the best targets for such experiments are organisms which can be grown from a single organism such as selfing plants or many types of bacteria or yeast.For animals it is harder to get a suitable experimental species. For years Drosophila was the standard model organism for developmental genetics, but now with the rise in transgenics mice and other species more closely related to our own are gaining prominence.To get around the issue of not having clonal populations derived from one individual many of these populations are kept as genetically homogenous as possible by inbreeding.Such conditions allow us to identify specific mutations when they present themselves. One of the perennial problems with the idea of reliably guaging rate of detrimental or beneficial mutations is the much more obvious nature of detrimental mutations.We can argue to the double muscled cows come home over whether a mutated myostatin gene leading to muscular hypertrophy is really beneficial, but no one is going to quibble that a gene which leads to a total failure to develop as an embryo, or to an early death before reaching a reproductive age, is anything other than detrimental. Similarly medicine focuses specifically on syndromes and diseases we consider largely detrimental. It is only very recently that research has really taken off looking for genetic bases for things such as resistance traits to various diseases.The only way to guage the beneficial nature of a newly arisen gene is to track its course through a population over a large number of generations. Unfortunately that has not really been tenable so far in human populations.What can be done is to look at the prevalence of certain alleles in particular populations and make some conclusions about how selection has worked on those alleles. Naturally for biologists the origin of these alleles is ascribed to mutation, obviously that is something that Faith might wish to contend with on a thread other than this one.This is rather a high level overview of certain isues that might be relevant to ones understanding of mutation. Ideally this thread should be a venue for others, particularly Faith, to ask specific questions about the nature of mutation and the science surrounding it.TTFN,WK

Epigenetic mutations such as those that affect the methylation of DNA (Rakyan et al., 2003) or the acetylation or methylation of histones (Cheung and Lau, 2005) but which do not change the actual primary nucleotide sequence of the DNA.TTFN,WKEdited by Wounded King, : No reason given.

The first paper deals with an example where certain mice show a distinct kink in their tails. This phenotype is associated not with distinct allele but with distinct levels of DNA methylation at a specific locus.DNA methylation is when the Cytosine of CpG doublets become methylated, either spontaneously or due to the action of a methyltransferase enzyme. In geeral the more highly methylated a sequence of DNA the less likely itis to be transcribed. Methylation also tends to lead to the recruitment of histone modifying enzymes which act to further suppress expression by compacting DNA to a heterochromatic state.So the only difference between the mice with kinked tails and those without was the methylation status of the Axin locus.the second paper deals mostly with the chromatin remodelling enzymes and does not cover transgenerational heritability but only the epigenetic equivalent of somatic mutations.As I suggested before my own definition of a mutation would be any heritable change, and this could be subdivided into at least genetic and epigenetic mutation although there may well be other subdivisions with which we are not yet familiar.TTFN,WK

I appreciate that those sections were a bit arcane, my only defense is that I was responding directly to Jazzns questions about non-genetic mutations rather than trying to frame something in simpler terms as in the OP.Sometimes it is hard to explain a concept without first providing considerable background information, and if I did that in any depth for epigenetics it could take up pretty much a whole thread on its own.I think that a lot of discussion of epigenetics and other more abstruse topics is only likely to derail this thread. I was really hoping to focus more on straightforward genetic mutation since that is the most exstensively studied.TTFN,WK

I'm not sure how valuable a list of all known causes of mutation would really be to this discussion. As far as the more specific questions go common environmental factors and common properties inherent in the processes of DNA replication and repair are common sources of mutation. Excessive mutational loads due to abnormal envionmental states, such as very intense radiation exposure or exposure to high levels of chemical mutagens, are far more likely to produce large scale damage to DNA leading to health problems, such as cancer or sterility or death in the case of very high levels of radiation.The major source of background radiation exposure is atmospheric radon and in terms of the cell the largest source is radioactive ⁴⁰K, there is research showing that that this ⁴⁰K does not significantly vontributr to the rate of spontaneous mutation (Gevertz et al., 1985).The university of Kansas has a page from some lecturer's notes detailing various sources of mutation, here.TTFN,WK

No. That isn't right. As Aegist pointed out you don't need methyltransferases to get methylation of DNA, they are just the enzymes that actively methylate or demethylate the DNA in the cell as a normal part of development. In many cases it is epigenetic modification of DNA which leads to the specific patterns of gene expression characteristic of a particular cellular lineage.You might as well say that it is basically genetic because there has to be DNA to methylate in the first place.There are some genetic sequences which have an effect on methylation and specifically on the waves of demethylation and re-methylation which occur in the early embryo in mammals which are associated with imprinting.But in the case of the Axin fused example the DNA is exactly the same and only the methylation status has changed. If it were the result of a difference in the methyltransferase enzymes then that should have been revealed by the genetic methods used to identify the locus of the mutation.Why are you so fixated on everything just being genetic?TTFN,WK

The methyltransferases are proteins produced the same way as any other protein. The methyltransferases themselves are not what supresses the expression of the genes but presence of the methyl groups at the CpG sites.TTFN,WK

The only difference, although a very important one, between this example of AnInGe's and the mouse example I gave is that in the case of the mice the inheritance operated transgenerationally rather than simply being inherited in the differing somatic lineages of the organism.A particularly well studied epigenetic mutation is associated with the Agouti viable yellow allele which affects coat colour in mice. While epigenetic inheritance at this locus has previously been ascribed to methylation (Morgan et al, 1999) a recent paper suggests that in fact the allele is demethylated during early embryonic development and that the actual inherited epigenetic mark is something else (Blewitt et al, 2006). It may be that the actual transmitted epigenetic marker at the Axin-fused locus is similarly something other than the methylation but it is the methylation which is mediating the effect and the marker is still thought to be epigenetic rather than genetic.TTFN,WK

Bumping this for TheWay should he return.TTFN,WK

Hoot I can't tell from this if you even have the faintest idea what you are talking about. There is no such thing as an epigene nor epigenetic material. histones and methyl groups clearly don't undergo the same processes as nucleotide bases during meiosis or mitosis.If your point is that these are concerns of molecular genetics then it is a trivial one. If you don't think that there is a useful purpose in distinguishing between genetic factors centred around the primary sequence of DNA and epigenetic modifications of genetic material then you need to provide some rationale for why you don't see the distinction. What is your evidence for this? In fact what does this even mean? the whole point about the somatic lineages was that those were changes ocurring in a developed organism, not an embryo. How can it make any sort of sense to talk about somatic lineages following from fertilization, anything affecting the genetic makeup of a newly formed zygote is clearly going to affect all of the subsequent cells in the body.TTFN,WKEdited by Wounded King, : No reason given.Edited by Wounded King, : No reason given.

Can you explain, since you are so allele centric, just what you think an allele is? Because from what you are saying it sounds like you are using it in a very bizarre way.TTFN,WK

See this is why I get so frustrated when you try and make out I don't know what I'm talking about. An epiallele is any gene which has had some epigenetic modification substantially affect its expression to the extent that it has a phenotypic effect, i.e. a gene silenced in a particular lineage due to heavy DNA methylation could be considered an epiallele of that gene. The modifications could occur in introns or exons or upstream regions they principally serve to change the local DNA structure in such a way that the expression of the gene is altered. To ask if an epiallele is an intron just suggests that you don't know what either of these things is. He does, but an epiallele is neither an epigene nor epigenetic material. It is in fact the reason why I asked you to explain what you understood by the term allele and which you somehow managed to come to the completely wrong conclusion about despite your 'allele centric' view.By changing the way a gene is expressed epigenetic modification essentially creates a further allelic variation of that gene, although the primary genetic sequence is not directly changed, unless you count DNA methylation You were not too 'allele' centric but too 'primary sequence of DNA' centric.TTFN,WK

But what constitutes an allele is open for discussion, hence why I asked you what you meant. What you said suggested that you only thought of alleles in terms of variations of primary DNA sequence.Please be clear on the distinction. This form of 'allelic' variation is not the traditional genetic form, hence the qualifying term 'epi'.If you think I am agreeing with you but you have a different understanding than I of what is meant by an 'allele' then you might be mistaken. You saying 'That is what I thought all along.' worries me when you have so clearly had no idea what you are talking about 'all along'.TTFN,WK

In this case, given the usual understanding of what consitutes a gene, no. The gene, as represented by a sequence of nucleotides, is not changed. That is why the term epiallele is used, to distinguish it from the normal conception of an allele. An epiallele is formed by a set of extragenomic factors which act upon the gene causing a change in its expression sufficient to impact the phenotype. In principle no, in practice yes since you seem to only ever add more ambiguity by bringing up totally irrelevant concepts, i.e. introns. Its funny, because it seems like you just did. Yeah, like I said, you don't seem to understand at all what we have described to you, even after a couple of pages. If you understood the idea that DNA methylation and histone changes were key components of epigentic modification why would you ask if introns are epialleles. You seem to have at least a tenuous idea what an intron is, in as much as you can distinguish it from an exon, but you still don't seem to understand epigentic modification or the concept of epialleles as distinct from traditional genetic alleles.TTFN,WK

How could they? For a start they are clearly genetic differences. What epigenetic effect do you propose silent mutations may be having? It it is not inconceivable that a regulatory region for one gene might reside in the coding region of another, in that case such a mutation that was silent in the coding gene might affect the regulation of the other gene, but that would just be a plain old genetic effect. Not, because they are Genetic. There is certainly a case to be made that as we understand more about long distance regulatory sequences the traditional conception of a gene and consequently an allele as occurring a specific discrete loci is malleable as mutation megabases away can affect the regulation of a gene to the extent that they could produce a null allele of that gene in some cases. But this widening of the concept does not make them epialleles it just shows that a genetic allele is more complicated than it was traditionally thought to be. Similarly microRNAS, another one from the 'Junk' pile, clearly have regulatory roles and should be considered genes in their own right even thought they don't conform to the traditional idea of a gene being a sequence coding for a protein.Now those questions weren't bad, nice and simple and not introducing any totally irrelevant and random concepts.TTFN,WK