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Part three (maybe the last).

Jaimehlers has contradicted me here and in another thread, when I claimed most mutations are harmful.  Quite rightly, Jaimehlers has asked me to support my statements.

Theoretical is fine.
Actually, let me ask you a question.  How high do you think the rate of lethal mutations is?  A ballpark estimate is fine.

Rather than me doing a mildly educated guess, here is some evidence from greater experts than I'll ever be:

One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral. Hiroshi Akashi more recently proposed a bimodal model for DFE, with modes centered around highly deleterious and neutral mutations. Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the distribution of fitness effects of random mutations in vesicular stomatitis virus. Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral.

Because more DNA changes are harmful than are beneficial, negative selection plays an important role in maintaining the long-term stability of biological structures by removing deleterious mutations. Thus, negative selection is sometimes also called purifying selection or background selection.

A paper involving human genetics quotes:
The difference in the number of rare vs. common alleles was used to estimate that 79–85% of amino acid-altering mutations are deleterious (Kimura 1983).
(I did not look into the original Kimura reference – busy travelling with slow limited internet access – happy to get into that when I’m back home with proper internet next week.)
One study on the comparison of genes between different species of Drosophila suggests that if a mutation does change a protein, this will probably be harmful, with an estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial

And the reference for the wiki quote above says:
Our analysis suggests that approximately 95% of all nonsynonymous mutations that could contribute to polymorphism or divergence are deleterious, and that the average proportion of deleterious amino acid polymorphisms in samples is approximately 70%.

So the findings in different species and study methodologies confirm what I’m saying about most mutations being harmful.  Of course many factors impact these studies and not all results can be perfectly adjusted for them. Dominant lethals, by their lethal nature, just don’t present themselves for study.   Recessive lethals get purged in bottlenecks or bouts of local inbreeding. Some deleterious mutations can “surf” to higher frequencies on local waves of fecundity. Some are held in relatively stable polymorphisms by competing pressures e.g. the famous sickle cell anaemia example you quoted.

But the key to understanding the problem of damage caused by point mutations is that many genes make proteins (or regulate them). Proteins are not genetic information – they are 3D products that need to operate in a 3D molecular environment in which they’ve already adapted over many generations through natural selection. So structural proteins are quite sensitive to amino acid substitutions that alter their 3D structure, and in enzymes the 3D structure is particularly critical to catalytic function.  It’s easier to stuff up the optimised 3D fit of folded proteins than it is to have changes with no effect or enhancements.  But negative selection works steadily to cleanse the problems .

Furthermore, mutating an amino acid to a residue with significantly different properties could affect the folding and/or activity of the protein. There is therefore usually strong selective pressure to remove such mutations quickly from a population.

All of this is before we get into more serious forms of mutation such as insertions, deletions, and (depending on your definition of “mutation”) chromosomal aberrations.

Jaimehlers, are you content with this, or do you need further clarification?
Changed Change Reason Date
Dante good discussion October 31, 2013, 09:17:58 AM
wheels5894 Great post without of info October 31, 2013, 09:17:29 AM