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Author Topic:   How Many Mutations Does Each Human Have?
NosyNed
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Posts: 8838
From: Canada
Joined: 04-04-2003


Message 1 of 20 (348220)
09-11-2006 8:36 PM


I'ver read here (and other places) and even posted that each individual human has from around 5 to maybe 100 mutations.

But how do we know that?

For here a mutation is a difference in genetics in an individual from his parents that is not a result of the meiosis processes.

I would accept mouse studies as being applicable to humans. Perhaps fruit flies but might consider bacterial studies to be rather a large extrapolation.

This belongs in bio evol or miscelaneous I think.


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AdminAsgara
Administrator (Idle past 380 days)
Posts: 2073
From: The Universe
Joined: 10-11-2003


Message 2 of 20 (348222)
09-11-2006 8:43 PM


Thread moved here from the Proposed New Topics forum.
    
Codegate
Member (Idle past 725 days)
Posts: 84
From: The Great White North
Joined: 03-15-2006


Message 3 of 20 (348338)
09-12-2006 10:20 AM
Reply to: Message 1 by NosyNed
09-11-2006 8:36 PM


The numbers that I've always seen are with regard to the average number of copy errors in humans/mammels. Here are a couple of snippets from sites.

Mutations

Mutations are rare events.

This is surprising. Humans inherit 3 x 109 base pairs of DNA from each parent. Just considering single-base substitutions, this means that each cell has 6 billion (6 x 109) different base pairs that can be the target of a substitution.

Single-base substitutions are most apt to occur when DNA is being copied; for eukaryotes that means during S phase of the cell cycle.

No process is 100% accurate. Even the most highly skilled typist will introduce errors when copying a manuscript. So it is with DNA replication. Like a conscientious typist, the cell does proofread the accuracy of its copy. But, even so, errors slip through.

It has been estimated that in humans and other mammals, uncorrected errors (= mutations) occur at the rate of about 1 in every 50 million (5 x 107) nucleotides added to the chain. (Not bad — I wish that I could type so accurately.) But with 6 x 109 base pairs in a human cell, that mean that each new cell contains some 120 new mutations.

On average,how many mutations take place every minute?

There are many types of mutation which can occur in the 3 billion base
pairs which make up the human genome. The largest changes which can occur
are chromosomal translocations and deletions affecting millions of base
pairs, but these are fortunately very rare. The most frequent type of
mutation is a single nucleotide substitution, where at a particular
position in the genome one of the nucleotides is replaced by one of the
other three nucleotides. In humans it has been determined that between
generations approximately one out of one billion base pairs is substituted
in this manner, for an average of three new germ line mutations carried by
any given individual.

These 2 alone give a range of 3 to 120 per generation in humans. I've been trying to track down some info from an actual published paper but haven't had any luck yet. Hopefully someone can point me at one.


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jerker77
Inactive Member


Message 4 of 20 (348359)
09-12-2006 11:26 AM
Reply to: Message 1 by NosyNed
09-11-2006 8:36 PM


Hi!

A figure I can give for the spontaneous mutation rate for most organisms is between 10^-8 to 10^-10 base per cell division. This has been tested in a multitude of organisms.
Further reading see Drake, J. M. (1970) "The molecular Basis for cell Mutation" Holden Day, San Francisco.

Edited by jerker77, : Spelling


/jerker
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fallacycop
Member (Idle past 3598 days)
Posts: 692
From: Fortaleza-CE Brazil
Joined: 02-18-2006


Message 5 of 20 (348362)
09-12-2006 11:33 AM
Reply to: Message 4 by jerker77
09-12-2006 11:26 AM


"The molecular Basis for cell Mutation"
Interesting that mutation in the word mutation in your post...
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NosyNed
Member
Posts: 8838
From: Canada
Joined: 04-04-2003


Message 6 of 20 (348375)
09-12-2006 12:04 PM
Reply to: Message 3 by Codegate
09-12-2006 10:20 AM


Determing the number
In humans it has been determined that between
generations approximately one out of one billion base pairs is substituted
in this manner, for an average of three new germ line mutations carried by
any given individual.

"It has been determined" -- how?

All I've seen in some googling is that there are comparisons between human and chimps done to calculate a mutation rate. This is, to me, in this context, circular. Until we determine that the mutations are happening we can't assume that they are the sources of differences.


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Ben!
Member (Idle past 1699 days)
Posts: 1154
From: San Diego, CA
Joined: 10-14-2004


Message 7 of 20 (348378)
09-12-2006 12:14 PM
Reply to: Message 1 by NosyNed
09-11-2006 8:36 PM


Does it matter how many mutations we have in regular cells? The only mutations / changes that would would be in offspring are only due to mutations that exist in sex cells, right?

Does that mean that this topic should really focus on mutation rates in sex cells only, or am I not understanding something properly?


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jerker77
Inactive Member


Message 8 of 20 (348400)
09-12-2006 12:56 PM
Reply to: Message 7 by Ben!
09-12-2006 12:14 PM


Does that mean that this topic should really focus on mutation rates in sex cells only, or am I not understanding something properly?

As far as I understand the subject matter it’s of no importance what cell type we discuss. The percentage of base pair mutations are of the same order in all. But in Darwinian terms it’s of cause only sex cells that, in higher organisms, give rise to mutations that can be the basis for selection.

Edited by AdminJar, : close quotebox


/jerker
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crashfrog
Inactive Member


Message 9 of 20 (348403)
09-12-2006 1:06 PM
Reply to: Message 6 by NosyNed
09-12-2006 12:04 PM


Re: Determing the number
Well, a simple experiment would be to take a single cell, culture it through several generations (sequencing a particular gene out of one of the immediate daughter generations), and then examine the content of that gene in subsequent generations. The number of point substitutions divided by the number of cell divisions and the length of the genome is a rough estimate of the number of point substitutions per number of base pair replications, absent any environmental mutagens.

An estimate is all we can get, of course. Mutation is a random, stochiastic process. And obviously we're aware of the fact that some genes mutate more than others. But as a rough estimate it's servicable. I mean, think about it. Any mole or birthmark you have represents a mutation in your skin (that was passed on, as you developed, to the daughter generations of that single skin cell.) Any time you're out in the sun you're accruing mutations, too. Or any time you eat cooked red meat.

It's all but trivial to establish that mutations are occuring. I can't see how this basic scientific point could possibly be under dispute. Once again it's going to be something fairly hard to point to one paper proving it because it's such a trivially obvious scientific fact that it isn't worth writing a paper on.

Until we determine that the mutations are happening we can't assume that they are the sources of differences.

Where else are the differences coming from? Pluto?


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NosyNed
Member
Posts: 8838
From: Canada
Joined: 04-04-2003


Message 10 of 20 (348404)
09-12-2006 1:06 PM
Reply to: Message 7 by Ben!
09-12-2006 12:14 PM


Sex Cell Mutations
Does that mean that this topic should really focus on mutation rates in sex cells only, or am I not understanding something properly?

Yes, sort of.

When a new individual is born they have a number of mutations. These may have come from mutations in the sex cells of their parents and bee incorporated into the egg and sperm produced by those. Or they may have come about at the moment of creation of the particular egg and/or sperm that gave rise to that one individual.

I guess I'm interested in both. The result is an indivdual with genetics that are NOT in most of the cells of either of it's parents. If the mutation occured in the gamet producing cells of it's parents I'm willing to count that even if maybe that is a slight twist on the theme.


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NosyNed
Member
Posts: 8838
From: Canada
Joined: 04-04-2003


Message 11 of 20 (348405)
09-12-2006 1:08 PM
Reply to: Message 9 by crashfrog
09-12-2006 1:06 PM


Re: Determing the number
I would like to see anything that does that kind of direct measure of the DNA copying mechanisms error rate.
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NosyNed
Member
Posts: 8838
From: Canada
Joined: 04-04-2003


Message 12 of 20 (348406)
09-12-2006 1:10 PM
Reply to: Message 9 by crashfrog
09-12-2006 1:06 PM


Source of differences
Where else are the differences coming from? Pluto?

I was pointing out that the studies I found assumed that the differences between us and chimps came from mutations. That can't be used, yet, as a back up for the mutations being a source of those differences.

We are arguing about where the source of differences comes from in other threads.


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Wounded King
Member (Idle past 2172 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 13 of 20 (348453)
09-12-2006 2:56 PM
Reply to: Message 11 by NosyNed
09-12-2006 1:08 PM


Re: Determing the number
Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases
Kondrashov AS.
Hum Mutat. 2003 Jan;21(1):12-27

I estimate per nucleotide rates of spontaneous mutations of different kinds in humans directly from the data on per locus mutation rates and on sequences of de novo nonsense nucleotide substitutions, deletions, insertions, and complex events at eight loci causing autosomal dominant diseases and 12 loci causing X-linked diseases. The results are in good agreement with indirect estimates, obtained by comparison of orthologous human and chimpanzee pseudogenes. The average direct estimate of the combined rate of all mutations is 1.8x10(-8) per nucleotide per generation, and the coefficient of variation of this rate across the 20 loci is 0.53. Single nucleotide substitutions are approximately 25 times more common than all other mutations, deletions are approximately three times more common than insertions, complex mutations are very rare, and CpG context increases substitution rates by an order of magnitude. There is only a moderate tendency for loci with high per locus mutation rates to also have higher per nucleotide substitution rates, and per nucleotide rates of deletions and insertions are statistically independent on the per locus mutation rate. Rates of different kinds of mutations are strongly correlated across loci. Mutational hot spots with per nucleotide rates above 5x10(-7) make only a minor contribution to human mutation. In the next decade, direct measurements will produce a rather precise, quantitative description of human spontaneous mutation at the DNA level.

While this paper doesn't do any direct measurement of mutational rates itself it uses a number of directly observed mutational rate studies on specific genes to estimate average rates for mutation. Their rate works out to around ~100 'new' mutations per diploid human genome per generation, while some of these 'new' mutations may have been seen before they occur de novo in these cases.

TTFN,

WK


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NosyNed
Member
Posts: 8838
From: Canada
Joined: 04-04-2003


Message 14 of 20 (348471)
09-12-2006 4:23 PM
Reply to: Message 13 by Wounded King
09-12-2006 2:56 PM


Translating the Abstract
Ok, maybe. Let me try to translate the abstract. I hope you and others can confirm my translation.

They mutation rate was estimated by using other studies that have rates at specific loci (positions in the genes) and other studies that looked directly at new (because they weren't causing illness in the parents I presume -- the point of the "dominant" in the note) mutations that are seen because they cause disease.

From these they arrive at an estimate of the mutation rate.

A reason why this might be taken as meaningful is because the independent result matches with the 'historic' extrapolation in the differences between us and chimps.

The results also show that there is agreement (I don't know the stats well enough to say how well it agrees) between different loci.

The rest discusses the kinds of mutations and how they are related.

The fact that the simpler mutations (and less likely to result in a non-viable) organisms are far more common also supports the conclusion.

I don't know the significance of: "Rates of different kinds of mutations are strongly correlated across loci."


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AnswersInGenitals
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Posts: 509
Joined: 07-20-2006
Member Rating: 3.4


Message 15 of 20 (348485)
09-12-2006 5:38 PM
Reply to: Message 1 by NosyNed
09-11-2006 8:36 PM


Its all chemical kinetics
You and I are both mutants. In fact, every cell in our body (including our sperm or egg cells) is a mutant, differing from the original egg that we started from and from all the other cells in our body by a few hundred base pair changes, as I explain below.

It is very helpful here to appreciate the kinetic environment that the molecules in our cell are experiencing (and actually all molecules everywhere). Educational animations usually show molecules moving around very lazily and purposefully, but in reality they are jiggling and jumping around like first graders let out for recess. The average speed of those molecules is several hundred miles per hour and they are banging, spinning, flipping, and banging into each other some more at a rate of about one trillion times a second.

When the chromosomes are duplicated for cell division (the S phase mentioned before), a molecular complex named DNA polymerase moves along the DNA strand attaching base pairs that compliment the base pairs on the adjacent strand (As for Ts, Cs for Gs and vice versa) to give a complete compliment strand. To do so, a complimentary base has to be in the vicinity of the DNA polymerase and has to be a good geometric and energy fit to the base pair being complimented. However, geometric and energy fitness a somewhat fuzzy due to all that thermal jiggling and occasionally the wrong base will get attached to the growing strand. The rate that this happens can be determined form chemical kinetics and measurements on the selectivity of the DNA polymerase. The error rate turns out to be about 1 error in 10,000 bases.

If there were no correction mechanism, this would limit the useful length of the genetic code to just a few thousand base pairs. This is exactly what is found in most viruses and messenger RNAs. However, the DNA polymerase has a simple 'proof reading' error correction technique. If the wrong base is inserted, it causes a 'lump' in the DNA chain that stalls the DNA polymerase and causes it to back up several base pairs. As it does so, it removes the bases it has inserted over that short length of DNA, removing the error. This is not a strange or surprising way for the polymerase to act. All catalysts that accelerate a chemical reaction in one direction are able to perform the reverse reaction if the conditions are right. Once removing the errant base, the polymerase continues on in the forward direction for about another 10,000 base pairs until another error is created, which is then corrected in like fashion. This process is not perfect. If there is a 1 in 10,000 chance of creating one error, there is a (1 in 10,000) squared chance of creating two errors. If these two errors give a potentially correct base pairing (a A-T being replaced by a C-G base pair, for example), the polymerase will accept them and just continue on, leaving the error.

The four types of base pairs yield 16 possible pairings, four of which are valid (A-T, T-A, C-G, and G-C). Thus, one fourth of the double errors will be accepted as valid, only one of which is actually valid, giving three potential errors out of the 16 combinations and thus an uncorrected error rate of 1 in 500,000,000. This will give about a dozen errors in each duplication of a human cell with 6 billion base pairs, whether these cells are somatic (body) cells or germline (egg and sperm).

As the fertilized egg grows to an adult individual, the cells duplicate over and over, averaging 10 to 100 duplications per cell, and almost every cell now in your body is the result of several dozen duplications, and thus averages several hundred errors or mutations. The question then arises: With all these mutant cells, why aren't we just a puddle of mush? How can our specie survive with all these errors? To answer this, we must first realize that the frequent anti-evolutionist argument that the vast majority of mutations are detrimental is pure hogwash. (Well, maybe not so pure. Hogwash always seems to come contaminated with bovine fecal material.) The vast majority of mutations, probably over .9999 are totally inconsequential. This is essential for evolution to occur in life forms more complex than bacteria, which have their genomes pretty much limited to a few million base pairs (but that is a pretty extensive topic in its own right and deserves its own thread).

This post is already getting too long, so I won't go into detail, but the reasons so many mutations are inconsequential are 1) only a few percent of our DNA is used to code for anything or to control the coding process, 2) almost all the coding component of our DNA codes for protein amino acid sequences, and only about 10 percent of each proteins amino acids are actually involved it the protein function, i. e., actually contacts the molecules the protein interacts with. When I read creationists arguments that evolution, being a random process, can't produce a typical 300 amino acid (AA) protein because each AA must be exactly right for the protein to work, I often wonder if the author is a diabetic. If so, he probably takes daily insulin shots using insulin derived from cattle or sheep pancreases (pancreae?) which differ from human insulin by several AAs, but still work just as effectively. 3) Even if the mutation affects the operation of a coded protein, it will most likely occur in a cell that doesn't even use that protein (e. g., disabling insulin in a muscle cell). Their are further reasons why we are unaffected by mutations, but enough for now. Also, the point mutations discussed are just one of several evolutionarily important forms of mutation.

I'm sorry I didn't include references for the above, but looking up references is work, which would defeat the main function of these forums: work avoidance. Googling on some of the terms I used might get to the right sources.

Regards, AnInGe

---------------------------------------

I think. Therefore, I post.


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