Re: Haldane's dilemma

AdrianTeo@mailhost.net
Thu, 01 May 1997 09:56:59 -0700

David Campbell wrote:
>
> >> Adrian wrote:
> >> >> [most previous material sniped]
> [me]
> >> Much of the genome does not code for anything actually used by the cell
> >> and, so far as we know, could vary freely (spacers, exons, pseudogenes,
> >> etc.). Also, the estimate of harmful to neutral mutations of Kimura sounds
> >> high relative to the results of mutational studies. A recent (this year)
> >> Nature (sorry for the vague reference, but it's as much as I remember)
> >> reviewed a paper that found most mutations had little effect on efficiency
> >> of the studied proteins.
> [A]
> >I am sorry, but I don't get your point. If most mutations have little
> >effects, then aren't they neutral?
>
> Yes, that's my point. If most mutations are about neutral, then the rate
> of mutation (as measured by comparing DNA of two species) may be quite high
> and may readily explain the observed level of difference.

I checked and found that this is basically Kimura's argument. Most
evolutionary change at the level of genetics is from substitution of
neutral mutations.

However, Haldane calculated that the minimum possible cost of
substitution under any condition to be:

cost= ln(1/P0), where P0 is the freq of the trait at the start of
substitution.

The selective value of the trait is irrelevant to the cost, as the
formula shows. This simply means that even neutral substitutions impose
a cost. It doesn't solve Haldane's problem.

> >> In animals, genome duplications seem to have been quite
> >> rare, but gene duplication is not all that unusual. Several common genetic
> >> diseases (e.g. Down's syndrome) represent duplication of sizable portions
> >> to entire chromosomes; duplication on the scale of genes would rarely be
> >> noticable unless it were looked for.
> >
> >I still don't see how this addresses the problem of getting around the
> >limit imposed by cost of substitution. Perhaps you can elaborate.
> >
> I think these data suggest that the average cost of substitution is quite
> low because of the many neutral mutations that are possible.

The formula above shows that it is not true. Neutral mutations tend to
have a much higher cost than the minimum given by the formula. Kimura
(1983, pg35) suggested that on average, a single neutral substitution
requires 4N generations to reach fixation (where N is the effective pop
size). That excludes the time for unsuccessful attempts.

And to make matters worse, they offer no selective advantage.

> Additionally,
> many mutations have little or no physiological effect but establish
> reproductive isolation. A classic example are mouse populations from
> different valleys in Italy. Many of these isolated populations have unique
> chromosomal rearrangements (fusion or separation) that make successful
> meiosis unlikely in a cross with the normal strain.
> Punctuated patterns of evolution suggest that major changes often occur
> rapidly and locally, making the "average" inadequate to characterize the
> whole pattern.

Smaller isolated sub-populations still incur the cost of substitution.
It is inevitable that to get from few to many, a cost has to be paid.

Also, in small pop, differential survival is less effective, and random
processes have greater effects. While change can be faster in small pop,
the effects are even more likely to be harmful.