21 replies to this topic

[olaf.larsson]

Are there any investigations of mutationrate in difrent animals? It would be interesting to see if animals that live long have less mutations than animals that live short.

[Lazarus Long]

There are such studies and we mention a few here in biotech if you look around. There also does appear to be a relationship between mutation rate, cancers, telomere shortening, and life expectancy.

Some reptiles and arthropods (ie. tortoises and lobsters, some birds too BTW) live a very long time and do not experience severe telomere shortening with mitotic cell division, or at least at a comparatively protracted rate.

They also do not appear to mutate particularly fast and that is why they seem to be *prehistoric* in their physiology because they have adapted like fish (or even Darwin Finches) to adjust to available food supply with their size (or beak structure) but have not particularly altered their basic structures in millions of years.

Should we consider them less evolved?

Why, if like a shark they have succeeded in finding an optimal physiology for the environmental niche they occupy?

BTW the relationship of cancer and mutation rate is simple, cancer is the result of mutation. Remember most mutation is destructive not positive.

Also when you discuss mutation it is also necessary to look at mitochondria.

There are living fossil species that have not significantly mutated in response to environment for tens if not hundreds of millions of years. This is an aspect of the discussion we have had elsewhere with respect to aging and evolution.

Loons, sharks, lobsters, tortoises and sea turtles are just a few such examples of species that have far slower rates of mutation and the fossil record supports this.

[olaf.larsson]

"There are living fossil species that have not significantly mutated in response to environment for tens if not hundreds of millions of years. "

As I see it its not an evidence of low mutationrate. If a spieces is very well adopted to their eco-niche it could be so that almost no mutations can be fixed becouse they will always cause loss of fitness instead of gain. So even if mutations happen they quickly disapear from the gene-pool.

[Lazarus Long]

As I see it its not an evidence of low mutation rate. If a species is very well adopted to their eco-niche it could be so that almost no mutations can accour becouse they will always cause loss of fitness instead of gain.

You are not grasping how mutation as opposed to adaptation works. A successful mutation in the wrong environment would still fail. The point is that some species do not appear to be undergoing the same rate of mutation as others. In particular this is definitely true between reptiles and mammals as we should be grateful.

There are two distinct vectors of evolution, convergence and divergence. Individual mutation drives divergence and creates the opportunity for a successful mutation that enhances fitness to be Selected for through group pressure resulting in *convergence* over generations into new environments or over competitors in the same environment.

I have said elsewhere and it applies here; Individuals Diverge through Mutation and Groups Converge through Speciation. IOW they are both forces that are simultaneously and constantly at work, in an ever adapting flux with environmental pressure through a dynamic of Individual AND Group Selection pressure.

After the K-T event that ended Cretaceous period 65 million years ago mammals mutated and diverged into all environmental niches so fast that reptiles were not given the chance of making a competitive comeback that is why I said we should be grateful for our bad fortune of being more genetically malleable, the downside of course is as we become more successful as individuals at living longer the legacy of what contributed to that initial success is that we suffer more from malignancy as a species because of cellular damage resulting from mutation.

This diaspora of life through divergence is seen a number of times in the fossil record in the aftermath of catastrophe as these events alter the dynamics of *fitness* dramatically.

We also see it as a result very early on when a bacterial mutation and subsequent symbiosis with other *prokaryotes* resulting in eukaryotic differentiation through the creation of chloroplasts and mitochondria. This advantage took a considerable period of time initially to supplant the competing species but the results were vastly more complex species possible through the advantages of energy provided to the cells by this mutation and symbiosis that make complex cell differentiation possible, making possible the Great Cambrian Divergence of adaptive forms of multicellular species.

The point is that mutation doesn't occur at constant rates even within any given species and definitely not for all species at the same rate. It also doesn't occur any guarantee of fitness but just being fit doesn't stop it and needing to doesn't make it happen. Mutation is also a response to environment as in radiation, chemical mutagens and viruses or bacterial episomes but it also appears to be the result of cellular damage to organelles like mitochondria and telomeres.

Evolutionary Timeline
http://www.talkorigi...o_timeline.html

[olaf.larsson]

I mean: The aging results in the same changes in diffrent animals; mouse, dog, horse, monkey, human; but in diffrent rate. If aging really is accumulation of mutations, it would be very easy to plot the mutationrate on a diagram and see a linear corelation to the lifeexpectancy of the animal. I suppose someone has done such studies already but I have not heard about them.

[Lazarus Long]

The aging results in the same changes in different animals; mouse, dog, horse, monkey, human; but in different rate.

This is a false assumption if taken too far and also all the examples you gave are mammals for good reason, it fails immediately as an assumption as you cross taxonomic distinctions between kingdoms and phyla.

In mammals the assumption is generally valid but the rate issue is not always different (whales, elephants and humans all age at roughly the same rate) and some species that age at faster rates don't necessarily show the same phenotypic results unless they are kept in laboratory conditions as their loss of fitness in natural environments would have resulted in mortality long before.

If aging really is accumulation of mutations, it would be very easy to plot the mutation rate on a diagram and see a linear corelation to the lifeexpectancy of the animal.

Coincidentally I made this same assumption and asked a geneticist this same basic question at our social the other evening. He reminded me that we have not mapped the genome of most of these other species. So your basic assumption is false again as we do not have the data to use to make such correlations; yet.

[olaf.larsson]

"This is a false assumption if taken too far and also all the examples you gave are mammals for good reason, it fails immediately as an assumption as you cross taxonomic distinctions between kingdoms and phyla."

Yes we are interested in aging in mamals ofcourse. When I say "animals" I ofcourse mean mamals. I dont think many people are very interested in developing anti aging treatments for aligators, sharks, insects, trees, slimemolds or other creatures which have nonmamal aging pattern. The experiment ofcourse is easy to perform, you dont need a whole genome sequenece to be able to compair some sequences at diffrent possitions from old and young animals. The sequences compaired would be assumed to be representative of the mutationrate in the whole genome.

Edited by wolfram, 06 December 2004 - 03:52 PM.

[Lazarus Long]

Again you are assuming that a distinct mutation is found in a single or small group of alleles. The odds are that at least 200 different genes are associated with aging in humans and not all of these are necessarily the same in different species of mammals even.

We do not have a good definition of aging mammals yet, so this is a work in progress. We are still unaware if the issue is a result of specific genes or a combination of gene interactions. Your question simply isn't as easily answered as you might like.

To use a metaphor, it is like suggesting that we can try to understand the ocean by studying a few beaches we have access to. The data you want is simply not yet out there, or frankly BEING FUNDED TO BE FOUND!

So if you want to fund the research, please endeavor to find those you trust to make the effort. If you seek to perform the research yourself all the better but please stop just insisting something should be easy because you do not grasp all the parameters of the problem. That is the difference between science and wishing.

If you want the answer I advise you to get to work. Simply saying it should be easy to obtain doesn't make it so.

[olaf.larsson]

mr. Lazarus why do you sound so angry to me? Please calm down. If a piece of DNA in a organism is associated itself to senescense or not is totaly unintersting, the thing you want to know to get a picture of the total mutationrate, is how many mutations there are in it compaired to the same piece nonmutated DNA. Maybee you have missinterpreted what I mean. I would like to here some other well informed persons opinion on this subject before you write another angry answer.
No Im not in the position to do this research myself right now, but maybee I will be soon.

[Lazarus Long]

I am not angry with you at all Wolfram . I am certainly calm [sfty] but I am trying to impress upon you the dire state of the science you seem to blithely take for granted. [:o]

Your questions are valid but the assumptions you go on to make aren't. More importantly you are taking science and research for granted as if all that can be studied has been and this is far from the case.

The areas you are suggesting have been investigated are losing funding for research not gaining it and the answers you seek are taking longer to find as a consequence. They are clearly solvable conundrums but require a careful balance of diligent study with activism in the face of growing repression.

If I am expressing any strong emotion, it is the frustration with my own government and exacerbation with a culture that favors soundbite silly-science instead of serious inquiry. A culture that in its atavistic, theistic cultural decay prefers the sanctimony of falsehood to the insecurity of possibilty from answers that might run contrary to their expectations and desires.

Did you glance at my other post called the War On Science?

I was writing that post when replying to your questions so perhaps some of my angst carried into my words but please be assured it wasn't directed at you. The answers to the kinds of questions you're asking are tantalizingly close but the possibility of them being answered is retreating away fast as the requisite funding is being stopped for this kind of broad scale genetic research and the available funds specifically for research into aging are actually diminishing under the Bush administration as antithetical to its policy.

BTW, you are not understanding that a *general* mutation rate is not in itself the cause of aging. It is precisely the mutation rate in specific alleles and genes and these are not clearly identified in general yet.

In particular as we have not mapped the genome of most other species even the kinds of general mutation rates you are discussing are not yet known except in some particular and limited instances.

Could they be known? [ang]

Of course, but as this type of research is not being funded to the extent required and in fact is now finding its funding sources drying up don't hold your breath that such answers will be easy to find and forthcoming.

And BTW, there is nothing in my words that is angry with you (I have just spent a few minutes reviewing my previous response) so I suggest you are simply misinterpreting them. )

How much do you currently understand about genetics?

[Lazarus Long]

And yes there is research going on still. The chimp genome is pretty well understood and dogs and many other domestic species are under investigation as well as some wild species but the kinds of concrete answers you seem to be assuming aren't there yet.

Mutation rates differ among regions of the mammalian genome
http://www.ncbi.nlm....9&dopt=Citation

 
Mutation rates differ among regions of the mammalian genome.

Wolfe KH, Sharp PM, Li WH.

Department of Genetics, Trinity College, Dublin, Ireland.

In the traditional view of molecular evolution, the rate of point mutation is uniform over the genome of an organism and variation in the rate of nucleotide substitution among DNA regions reflects differential selective constraints. Here we provide evidence for significant variation in mutation rate among regions in the mammalian genome. We show first that substitutions at silent (degenerate) sites in protein-coding genes in mammals seem to be effectively neutral (or nearly so) as they do not occur significantly less frequently than substitutions in pseudogenes. We then show that the rate of silent substitution varies among genes and is correlated with the base composition of genes and their flanking DNA. This implies that the variation in both silent substitution rate and base composition can be attributed to systematic differences in the rate and pattern of mutation over regions of the genome. We propose that the differences arise because mutation patterns vary with the timing of replication of different chromosomal regions in the germline. This hypothesis can account for both the origin of isochores in mammalian genomes and the observation that silent nucleotide substitutions in different mammalian genes do not have the same molecular clock.

MeSH Terms:
Animals
Base Composition
Cercopithecidae
Chromosome Mapping
Chromosomes, Human
Comparative Study
Genes, Structural*
Human
Mice
Mutation*
Rats
Species Specificity
Support, Non-U.S. Gov't
Support, U.S. Gov't, P.H.S.

PMID: 2911369 [PubMed - indexed for MEDLINE]

http://www.pubmedcen...gi?artid=117386
Mutation rates in mammalian genomes
Sudhir Kumar*† and Sankar Subramanian*

Department of Biology, Arizona State University, Tempe, AZ 85287-1501

Communicated by Calyampudi R. Rao, Pennsylvania State University, University Park, PA, 2001 November 27 (received for review 2001 November 7)

* S.K. and S.S. contributed equally to this work.
† To whom reprint requests should be addressed at: Department of Biology, Life Sciences A-371, Arizona State University, Tempe, AZ 85287-1501. E-mail: s.kumar@asu.edu.

This article has been cited by other articles in PMC.
 
Knowledge of the rate of point mutation is of fundamental importance, because mutations are a vital source of genetic novelty and a significant cause of human diseases. Currently, mutation rate is thought to vary many fold among genes within a genome and among lineages in mammals. We have conducted a computational analysis of 5,669 genes (17,208 sequences) from species representing major groups of placental mammals to characterize the extent of mutation rate differences among genes in a genome and among diverse mammalian lineages. We find that mutation rate is approximately constant per year and largely similar among genes. Similarity of mutation rates among lineages with vastly different generation lengths and physiological attributes points to a much greater contribution of replication-independent mutational processes to the overall mutation rate. Our results suggest that the average mammalian genome mutation rate is 2.2 × 10−9 per base pair per year, which provides further opportunities for estimating species and population divergence times by using molecular clocks.


Introduction 
 
Rates of point mutation can be determined indirectly by estimating the rate at which the neutral substitutions accumulate in protein-coding genes (1). Synonymous substitutions in protein-coding genes generally are free from natural selection and are used frequently for inferring neutral substitution rates (1, 2). In particular, the fourfold-degenerate sites are expected to harbor only the neutral substitutions, because all mutations at these sites are synonymous at the amino acid sequence level. By using estimates of evolutionary distances based on neutral substitutions, many studies have examined the null hypotheses of uniformity of neutral mutation rates among genes within a genome and among mammalian lineages and have come to conflicting conclusions (2–9). For example, significant differences in mutation rates among mammalian lineages reported over the last two decades led to the proposal of the generation-time effect hypothesis (10–13). However, Easteal et al. (14) have argued that previous results of substantial differences among lineages observed may have been caused by the use of incorrect fossil dates or inappropriate outgroups. Similarly, there is significant controversy regarding differences in mutation rate among genes within a genome (8, 9, 15) and over 10-fold differences in the estimates of the mutation rates among studies (1.1–12.4 × 10−9 substitutions per site per year; refs. 3, 11, 12, and 16–19).

One common feature of many of these studies is that they have either analyzed a small number of genes or only a few species. Analysis of a large sample of genes from a genome and diverse phylogenetic lineages is the key to testing the null hypothesis of equal mutation rates within and among genomes. A large number of genes is necessary, because only a fraction (≈15%) of codon positions in a sequence are fourfold-degenerate (see Fig. 1 legend) and we need to sample genomic regions extensively. Furthermore, mutation rate information from many inter- as well as intraordinal mammalian species pairs is necessary to test whether the observed differences, if any, among mammalian orders are likely to be tied significantly to differences in generation times and physiological attributes among groups. Therefore, we have assembled a data set of 17,208 protein-coding DNA sequences belonging to 5,669 different nuclear genes from a total of 326 placental mammalian species to characterize the extent of difference in mutation rates among genes in a genome and among lineages.
{excerpt, go to the page for the relevent links please}

[Lazarus Long]

From the second article above

Figure 6.
Relative evolutionary rate among different mammalian lineages. The relative evolutionary rate differences (Är) in a gene for two lineages (say, A and B) were computed as Är = [lA − ½(lA + lB)]/½(lA + lB), where lA and lB are the least-squares estimates of the branch lengths leading to the two lineages using the average distances between species/groups A and B and their distances with the outgroup(s). Är was computed for each gene, and the mean value taken over all genes for groups A and B. Negative values indicate that group B is evolving faster than group A. Only the genes passing the disparity index test were used in this analysis.

Proc Natl Acad Sci U S A. 2002 January 22; 99(2): 803–808.
Copyright © 2002, The National Academy of Sciences
http://www.pubmedcen...q0226298006.jpg
http://www.pubmedcen...pe=figure&id=F6


And this is the Figure the quote refers to:

http://www.pubmedcen...q0226298001.jpg
Figure 1.
Distribution of the number of fourfold-degenerate sites in the human-mouse orthologous genes. The average number of fourfold-degenerate sites from 3,722 genes of human-mouse comparison is 245, which is 15.7% of the average cDNA length (1,568).

Proc Natl Acad Sci U S A. 2002 January 22; 99(2): 803–808.
Copyright © 2002, The National Academy of Sciences

[Lazarus Long]

Another minor point wolfram; between chimps and humans there is very little difference in genome.

We share 98% of the same exact genes (not mere homologues) and the mutation rates are almost identical yet their life expectancy is less than half that of ours even when they are living domestically with almost the same advantages as humans.

Does that explain why I don't agree with your assumption as to how knowing the importance of general mutation rates can address the underlying issue of aging?

We most certainly do need to build an adequate general model for genetic aging and add to that a clear map of all the genes involved and their interaction.

BTW, my thanks to João Pedro de Magalhães because I remembered to borrow his example from the presentation the other night.

[olaf.larsson]

Here are papers supporting the thesis that mutationrate is correlated to life span.


1. Hart RW, Setlow RB, 1974. Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proceedings of the National Academy of Sciences of the United States of America, 71, 2169-2173.

2. Hall KY, Hart RW, Benirschke AK, Walford RL, 1984. Correlation between ultraviolet-induced DNA-repair in primate lymphocytes and fibroblasts and species maximum achievable life-span. Mechanisms of Ageing and Development, 24, 163-173.

3. Francis AA, Lee WH, Regan JD, 1981. The relationship of DNA excision repair of ultraviolet-induced lesions to the maximum life span of mammals. Mechanisms of Ageing and Development, 16, 181-189.

4. Treton JA, Courtois Y, 1982. Correlation between DNA excision repair and mammalian lifespan in lens epithelial-cells. Cell Biology International Reports, 6, 253-260.

5. Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J, 2003. Aging and genome maintenance: lessons from the mouse? Science, 299,1355-1359.

[John Schloendorn]

Wolfram and Laz, your misunderstanding seems to me that Laz, you're talking mostly about germ line mutations, and the rate at which they get evolutionarily accepted over multiple generations, while Wolfram, you're talking about somatic cell mutations and their rates within one generation.
The problem with the latter could be that they're technically difficult to assess because different mutations happen in every cell. One would have to do it cell by cell and average.

[olaf.larsson]

The problem with the latter could be that they're technically difficult to assess because different mutations happen in every cell. One would have to do it cell by cell and average.

Yes this is what I mean. One should do this if its technically possible. I dont think germline mutations is a very good measurement of general somatic mutations.

[John Schloendorn]

It would be interesting to see if animals that live long have less mutations than animals that live short. (Wolfram)

BTW the relationship of cancer and mutation rate is simple, cancer is the result of mutation (Laz)

This would suggest to take cancer rates as an approximation for mutation rates, in order to learn something about your question Wolfram. Then one could compare how mutations rates correlate with aging rates in different species. (One may have to expect some variance from different cancer defenses though)

[jaydfox]

I dont think germline mutations is a very good measurement of general somatic mutations.

No, neither do I. Germline cells like stem cells have better DNA repair mechanisms including the fact that they are telomerase positive so they are not in any way representative of the mutation rate in somatic cells.

How does that fit in with your theory that the rate of (somatic and stem cell) mutation enjoyed by most species is suboptimal in order to allow greater germline mutations for evolvability?

[olaf.larsson]

I would say Germ line mutations have to be to be lower. Somatic doesn't matter very much as long as they dont kill you before breeding.