Advocatus Diaboli

Yes sir. I've encountered the most ignorant creationist so far. I'll forget for a moment that he thinks natural selection does not happen(you read correctly).

What easy-to-understand study gives the accurate rate of harmfuf mutations?

TalkOrigins doesn't have what I'm looking for.
Thank you in advance.

charlie d

Well, it depends on what that person means. If he's talking about nucleotide substitutions, then in coding sequences about 1/3 are synomimous, and therefore neutral; in non-coding sequences the vast majority are.

If on the other hand he's talking about non-synonymous aa substitutions, a good fraction, if not the majority are neutral (but it depends on the protein of course). Here is a link to a paper that provides an estimate of the fraction of neutral alleles at human protein-coding genes at around 0.4 (40%) - I would start from there and work my way up the literature.

However, if he's just talking about non-neutral mutations, the ratio of harmful mutations may be even higher than 99%, but so what, that's what natural selection is about.

Oh wait - he doesn't believe in natural selection. I guess that's where his problem is.

Advocatus Diaboli

Isn't it strange that he hasn't given any study or scientific source to confirm his 99% of mutations are harmful claim?
Basicly he just said "they are, prove me wrong".
Logic won't help. Empiric evidence won't help. Scientific studies don't help. Maybe its time to ignore?

Wounded King

Is this related to the statistic by any chance?

charlie d

Well, there are plenty of studies on mutations and their effects, but it's hard to figure out which ones would be appropriate, and I doubt there is something as quantitative as you seem to be looking for.

For instance, all the old Drosophila mutagenesis from the 1920s and '30s show a high rate of deleterious mutations, but of course there is a bias there: the experimenter is likely to detect only major morphological changes, and all major morphological changes in a well-adapted organism are likely deleterious. On the other hand, there may have been hundreds of subtle improvements in the same irradiated strains that were lost precisely because they were subtle.

Similarly, we know of human mutations mainly because of genetic diseases they cause, but only rarely we become aware of polymorphisms that are selectively favored (for some we even can make the inference of selective advantage, but don't have evidence of the selective forces involved).

Finally, there are plenty of studies of random protein mutagenesis. Again here the majority are neutral, a bunch are harmful and very few are beneficial - but you run into the same bias as for Drosophila: you are unlikely to detect subtle advantages, or mutations that would benefit a protein in its complex physiological context (because these experiments are usually run in very specific, restricted conditions), or mutations that acquire new functions (because you wouldn't know what new function to look for).

In general, it does boil down to the intuitive statement that there are more ways to break an egg (i.e. a well-adapted organism or protein) than to put one back together.

Nevertheless, I would point out to your friend that the majority of mutations are neutral or quasi-neutral, and just by looking at the enormous variability within human populations, I'd suggest that there is more than enough variation out there for selection to work on.

Also, I usually make the point that even mutations that bestow a very small selective advantage can be picked up by selection very efficiently. For instance, it can be mathematically demonstrated that a new mutation with selective advantage of 1% (that is, its carriers make only 1% more progeny than the average in the population - basically nothing, especially in low progeny organisms like ourselves) is actually destined to completely take over the population in 2% of the cases in which it appears, and it will do so in just a couple of thousands generations. That never fails to impress me (though it doesn't always impress my interlocutors, I'm afraid! ).

Dr. Evil

One good point to make is that many mutations that seem harmful in humans actually confer a reproductive advantage. Remember, mutation doesn't give a damn about individuals as long as it has an overall positive effect on the population. So with that in mind:

A heterozygous mutation in the cystic fibrosis chloride channel confers a resistance to cholera (Fontelo P., Protection against cholera. Science. 1995 Jan 27;267(5197):440 and Gabriel SE, Brigman KN, Koller BH, Boucher RC, Stutts MJ. Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science. 1994 Oct 7;266(5182):107-9.) in the homozygous state it is deadly but because of the recessive nature of the gene there will be more heterozygotes (carriers with cholera resistance) than homozygotes inferring a selective advantage to individuals with the gene (you can deduce this using Hardy-Weinberg equation). Its also interesting that the cftr mutation occurs most predominantely in populations where cholera outbreaks are more frequent.

Another example of heterozygote advantage is with sickle cell trait, which confers malaria resistance. Once again it occurs in areas with high rates of malarial infection sooo, individuals that are heterozygous have a selective reproductive advantage (Aidoo M et al., Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 2002 Apr 13;359(9314):1311-2. There is a lot written about this subject).

There are other examples of this if you are interested in doing a little research. Heriditary persistance of fetal hemoglogin is a mutation that confers malarial resitance with very few side effects. Also Glucose-6-phosphate dehydrogenase deficiency is another mutation to investigate in conferring malaria resitance. Its usually not to terrible as long as you don't eat fava beans

RufusAtticus

The interesting thing is that the most successful treatment of sickle-cell anemia (hydroxyurea) works by turning the fetal hemoglobin genes back on.

ps418

Interesting refs Dr Evil. There are at least two other examples I can think of of genes that confer resistance to infectious agents. The CCR5 delta32 allele also confers resistance in HIV. Heterozygotes show ~30% slower progression from infection to AIDS and infection to death, and are homozygotes are almost completely immune to HIV infection, and there are no known deleterious effects in either hetero- or homozygotes. The 'null allele' of the Duffy antigen receptor for chemokines (DARC) confers complete resistance to infection by Plasmodium vivax, and also is not associated with any deleterious effects. Plus, the fact that this alleles is nearly fixed in Africa but nearly absent elsewhere shows that it has been under very strong positive selection. Check out this thread for refs. There's also a recent report of a common susceptibility/resistance allele (FUT2 gene) for Norwalk virus infection in Nature Medicine, although I guess this wouldnt be a great example since mortality associated with NWV is insignficant.

Lindesmith, Human susceptibility and resistance to Norwalk virus infection. Nature Medicine May 2003 Volume 9 Number 5 pp 548 - 553.



Patrick

Dr. Evil

If you want to stay out of the arena of diseases you could do a search about genetic traits in athelets. I've heard about a study in which they took muscle biopsies of athletes and examined them for different characteristics that seperate them from mere mortals like ourselves (I was told that one of the subjects was Lance Armstrong and that his muscle profile had some interesting characteristics). I haven't seen this with my own eyes so take it with a grain of salt.

The CCR5 delta32 allele and HIV resistance brings me back to the days of my Biology of AIDS seminar I took while an undergrad. The class was set up in a manner that half the class was supposed to argue the classical approach to HIV infection while the other half argued the Duesberg model of AIDS, it was quite fun actually. At the time it was known that HIV infection in Africa was less fatal than in the West and some individuals seemed to suffer no mal-effects from the virus. I was selected to argue the Duesbergian model stating that this fact suggested HIV was a harmless passenger virus and that the treatments we used in the west to combat HIV were the actual culprits in the onset of AIDS. Needless to say it was a hopeless arguement, but I had a lot of fun speculating and propsing alternative hypotheses to the class.

Advocatus Diaboli

Hmmm. I was under the impression that immunity to HIV came from a deletion. Live and learn.