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Author Topic:   Will mutations become less freqent?
Discreet Label
Member (Idle past 3580 days)
Posts: 272
Joined: 11-17-2005


Message 16 of 25 (334564)
07-23-2006 5:47 PM
Reply to: Message 15 by RAZD
07-23-2006 8:33 AM


I don't know where this actually fits into the whole mutation limitations. But currently i'm participating in a cross biology/chemistry internship. And one of the groups that is particupating is looking into DNA double strand breaks. From what little I understand about biology, and what has been described, is that double strand breaks, a single one is enough to kill a cell. At this point it is pretty much believed that double strand breaks occur at a rate of 10-60 times per cell...

So big question that arose out of that why aren't we dead?

And this is where DNA polymerases come in. These things act as a way to get double breaks to react with either the other end, or another double break. So basically dna strands recombining willy nilly all the time in our body (again to my bare understanding i don't know much about DNA). So 'mutation' rates in the sense that cell DNA in body is no longer initially the DNA that it started with is sounds like its a pretty frequent occurance no matter what way you look at it...


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RAZD
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Posts: 20714
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Message 17 of 25 (335875)
07-27-2006 9:48 PM
Reply to: Message 16 by Discreet Label
07-23-2006 5:47 PM


So big question that arose out of that why aren't we dead?

I would say either the model that predicts cell death in this scenario is faulty or you are missing some element in it (not necessarily your fault - your source may have missed it before passing it on to you).

From what little I understand about biology, and what has been described, is that double strand breaks, a single one is enough to kill a cell. At this point it is pretty much believed that double strand breaks occur at a rate of 10-60 times per cell...

The technical answer would need to come from a molecular biologist (bradcap1, WK, etc), but a google on {double strand DNA breaks} brings up these as the first two "hits" (note "DSB" means double strand break):

http://www.bio.brandeis.edu/haberlab/jehsite/resdsbr.html
http://carcin.oxfordjournals.org/cgi/content/full/23/5/687

The first fairly "layman friendly"

A number of models have been put forth over the years to explain how DNA recombination occurs. The basis of these models lies in what has been learned of recombination from yeast and other fungi. Fungi have been studied intensively because they possess certain properties such as the ability to yield four viable meiotic products (spores) that can be assayed and analyzed. For example, a mutation that is heterozygous will give rise to two mutant spores and two wild type spores, a 2+:2- pattern that is considered to be classically Mendelian. The appearance of non-Mendelian patterns such as 1+:3- (a "gene conversion") or the presence of "sectored" colonies (colonies with a divided phenotype) gave rise to a series of models to explain these events.

and the second more technical:

The DNA double-strand break (DSB) is the principle cytotoxic lesion for ionizing radiation and radio-mimetic chemicals but can also be caused by mechanical stress on chromosomes or when a replicative DNA polymerase encounters a DNA single-strand break or other type of DNA lesion. DSBs also occur as intermediates in various biological events, such as V(D)J recombination in developing lymphoid cells. Inaccurate repair or lack of repair of a DSB can lead to mutations or to larger-scale genomic instability through the generation of dicentric or acentric chromosomal fragments. Such genome changes may have tumourigenic potential.

The second also says:

DSBs are potent inducers of mutations and of cell death. In metazoa, just one DSB can kill a cell if it leads to the inactivation of an essential gene or, more commonly, triggers apoptosis (5).

So I would say that is part of the answer to your question -- where the DSB occurs makes a difference.

I don't know where this actually fits into the whole mutation limitations.

The question is whether this (and other kinds) of mutation can be prevented or restricted by some genetic shield process.

I don't see that happening to any great(er) degree -- the current mechanism (natural selection) removes the individual organisms where DSB's do cause (cell) death -- particularly in unicellular life, metazoa, so additional protection is not necessary.

Where the process is NOT lethal, the question then is whether or not it can be prevented. The chemical bond cannot be made any stronger or weaker, so the only way to reduce it being interrupted is to form either some kind of shield or to develop some kind of additional repair mechanism that is faultless -- both things evolution is notoriously incapable of (and we don't need to discuss the implications of this for "design" do we?)

After all it is the current repair mechanism that puts the strands together with the cross-over eh? And as long as the organism functions and passes on those genes to the next generation then the repair is "successful" so there is no need to modify the repair mechanism if it succeeds.

Can the rates of mutation change? Yes, it has been observed. I believe (quick scan of second paper) it is through changing the way the repair mechanisms react and respond.

Can mutation be eliminated? Yes, but I believe total extinction would be part of that "ultimate solution" as it would leave life with no safety position.

The problem is that life is not invested in just one or two species and that different species have different rates of mutations -- the selection of species is also part of the mechanism for selection of the mutation rate that suits the need for diversity in the global population -- in my humble (but sometimes arrogant) opinion anyway.

Enjoy.


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Discreet Label
Member (Idle past 3580 days)
Posts: 272
Joined: 11-17-2005


Message 18 of 25 (335878)
07-27-2006 10:29 PM
Reply to: Message 17 by RAZD
07-27-2006 9:48 PM


I'll go ahead and take a look, but heres the research group is working on a set of research projects with it.

DSB


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capeo
Inactive Member


Message 19 of 25 (335894)
07-28-2006 12:44 AM
Reply to: Message 18 by Discreet Label
07-27-2006 10:29 PM


The implication of the study would seem to suggest that DNA polymerases must have a simple way with dealing double strand breaks during synthesis more than just occasionally, to me anyway. From the amount of double strand break suggested the non-template nucleotides (which are stated to occur very often) would be intergrated at an amazing rate, more than is tenable except maybe in the case of a cancer. What am I missing?

More to the point of the OP, and since it has already been stated more thoroughly I'll express it more succinctly in my layman's terms: lower mutation rate = less basis for selection = extinction due to the slightest variance in environmental pressure. Which really isn't a very viable model.


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Wounded King
Member (Idle past 2611 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 20 of 25 (335961)
07-28-2006 6:20 AM
Reply to: Message 19 by capeo
07-28-2006 12:44 AM


From the amount of double strand break suggested the non-template nucleotides (which are stated to occur very often) would be intergrated at an amazing rate, more than is tenable except maybe in the case of a cancer. What am I missing?

I think once again the position of the break is critical. I'm not going to try and put any exact numbers on it, since our understanding of which genetic elements are important to normal cellular functional and organismal development are changing all the time, but most of our DNA seems to serve at best a structural function and is far less likely to be perturbed by the insertion of a few non-template nucleotides, certainly less so than by having a persistent DSB. In a coding region or a crtical regulatory region then such insertions certainly could be detrimental, but as a numbers game the chances are much higher that the insertion will have little effect.

TTFN,

WK


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RAZD
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Posts: 20714
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Joined: 03-14-2004
Member Rating: 2.5


Message 21 of 25 (335978)
07-28-2006 7:34 AM
Reply to: Message 20 by Wounded King
07-28-2006 6:20 AM


... most of our DNA seems to serve at best a structural function ...

One of the observations I have gleaned from the {Human Proteome Folding} project on the World Grid work,
http://www.worldcommunitygrid.org/projects_showcase/viewHpf2Research.do,
is that it is important what parts of the proteins are exposed to be active or able to be active -- the rest is "structure" to ensure the proper parts are exposed in the final folded molecule.

... and is far less likely to be perturbed by the insertion of a few non-template nucleotides, certainly less so than by having a persistent DSB.

Presumably DNA would have similar {structure} issues.

Common view (laypeople) is that there is one strand of DNA in each nucleus (mental picture of long twisting double chain of colored balls with toothpicks between ...) - but this view conflicts with the 22 (human) chromosomes we (laypeople) also "know" about (mental picture of 22 odd shaped lumps, of which one looks oddly like an "X" and another type looks oddly like a "Y" ... ).

Now it seems that DNA is rather randomly broken into smaller segments and reformed as\when necessary (when duplication is needed?), so the whole system may be much more dynamic than is commonly envisaged.

In a coding region or a crtical regulatory region then such insertions certainly could be detrimental, ...

When duplication is needed -- but may it also be necessary to {open up - access the 'internal' folded structure} the DNA for other functions? And then have some mechanism to recombine it?


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Wounded King
Member (Idle past 2611 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 22 of 25 (335995)
07-28-2006 8:46 AM
Reply to: Message 21 by RAZD
07-28-2006 7:34 AM


Now it seems that DNA is rather randomly broken into smaller segments and reformed as\when necessary (when duplication is needed?), so the whole system may be much more dynamic than is commonly envisaged.

I don't think this is an accurate characterisation of what happens during a DSB, there is a lot more to the structure of a chromosome than merely DNA. DNA in a chromosome is wrapped around nucleosomes which are structures composed of several proteins known as histones, both the packing of the DNA to the nucleosome and further modifications of the organisation of nucleosomes themselves can produce tighter packing of DNA into what is known as heterochromatin. Therefore even if DNA undergoes a DSB the two 'fragments' are not floating dissociated from one another but still joined together by the larger superstructure of the chromosome.

When duplication is needed -- but may it also be necessary to {open up - access the 'internal' folded structure} the DNA for other functions? And then have some mechanism to recombine it?

Not only when duplication is needed. If the break or insertion is in the coding region of an important housekeeping gene then a cells function may be severely compromised. Indeed this sort of damage to a tumour supressor gene could well be an important step towards the development of cancer.

Dna must normally be opened up from its compacted heterochromatic state if a gene is to be transcribed prior to protein synthesis. There is a constant dynamic restructuring of chromatin as and when certain genes are no longer required. Much of the regulation of this is provided by modifications to the histone proteins, specifically methylation and acetylation of the histones.

As well as the histones to fully 'open' the structure for transcription there are a number of enzymes which actively manipulate the DNA such as Helicases which seperate out the strands and Topoisomerases which actually cut the DNA in order to reform it topologically. Some Topoisomerases actually produce double stranded breaks in order to untangle chromosomes.

TTFN,

WK


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RAZD
Member
Posts: 20714
From: the other end of the sidewalk
Joined: 03-14-2004
Member Rating: 2.5


Message 23 of 25 (336171)
07-28-2006 7:07 PM
Reply to: Message 22 by Wounded King
07-28-2006 8:46 AM


... and further modifications of the organisation of nucleosomes themselves can produce tighter packing of DNA into what is known as heterochromatin. Therefore even if DNA undergoes a DSB the two 'fragments' are not floating dissociated from one another but still joined together by the larger superstructure of the chromosome.

Thanks, yeah the common mis-impression of free-floating DNA strands in a liquid "egg yolk" nucleus is more due to "popular news" than reality eh? And what is even less understood popularly (if even thought about) is the structure of the chromosomes.

So the DNA is pretty much held in place by other molecules within the chromosome, molecules that are also responsible for the overall shape of the chromosome?

Would not segments on the outside be more vulnerable to damage? And breaks on the outside areas would be less tied down close to each other? (is this (one reason) why some segments are more prone to mutations than others?)

Overall sounds like a mechanism to minimize random recombinations and to stabilize the genetic structure.

Some Topoisomerases actually produce double stranded breaks in order to untangle chromosomes.

I would guess that these are the more common DSB's that were mentioned above, and would (by 'choice') be non-lethal to the cell.

Dna must normally be opened up from its compacted heterochromatic state if a gene is to be transcribed prior to protein synthesis. There is a constant dynamic restructuring of chromatin as and when certain genes are no longer required. Much of the regulation of this is provided by modifications to the histone proteins, specifically methylation and acetylation of the histones.

Pretty dynamic. And a sequence of such operations ends up with cell specialization via chemical communication with adjacent cells to determine which sequence to open when?

Thanks.


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This message is a reply to:
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Theus
Inactive Member


Message 24 of 25 (339786)
08-13-2006 12:16 PM
Reply to: Message 19 by capeo
07-28-2006 12:44 AM


How to make baby cells
While it can be debated the relative benefits and costs of mutation, the existence of mutations is not so much a consequence of evolution as it is a consequence of mechanics. The cell cycle is a short, nasty process and mitoses must take place in the S phase of a cell, which itself lasts only a couple hours (if that). But the length of one strand of cellular DNA is somewhere between 2 - 3 meters for humans, and must be straitened out and copied within the confines of the cell's nucleus in the period of an hour. And, this DNA is very, very thin, only a few molecules wide.

So, analagy: the developed northern half of New Jersey is the size of a single cell. Take a shoelace that is about the length of the width across the United States (New York to LA) and roll up most of it around some golf balls (twice around each, specifically). Give one end to a gas-guzzling SUV (this takes energy), and the other to a hummer. Expose about a mile of it and drive 100mph down the New Jersey Turnpike (our site of DNA replication) going two opposite directions. With the ball of yarn next to you, weave out the sequence you see on the shoelace as it races past you while you dodge the traffic of other molecules. It's semi-conservative replication, so two of these are happening at the same time. And we have some 24 chromosomes to do. You have an hour, and for simplicity we'll leave out the bit about Okazaki fragments.

This is where mutations come from.


אם אנחנו מאמינים דברים מהעבר יחיד אז אנחנו נישאר לנצח בהוה

This message is a reply to:
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mick
Member (Idle past 3502 days)
Posts: 913
Joined: 02-17-2005


Message 25 of 25 (339921)
08-14-2006 3:09 AM
Reply to: Message 1 by Elliot
07-16-2006 4:41 PM


Elliot writes:

This also offers a small explaination to the dinosaurs, because if they had less DNA mutations then they would be less likely to survive a major climate change.

It's worth bearing in mind that any perfecting or optimizing of the dna replication mechanism would have been selected for extremely early in the history of life, if you are correct in saying that more accurate translation is a selective benefit.

It seems likely that some optimal balance between accuracy and "evolvability" would be reached long before the origin of metazoa.

Mick


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