Moselio Schaechter

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November 10, 2011

Talmudic Question #81

Given that most mutations are deleterious, why does the mutation rate not evolve to zero?


I have a thought experiment. Say, I have a bacteria that produces a mutation once in every 1 generation (practically mutation rate is calculated per base incorporation. This is just for making calculations easy). That means when the cell divides there is a mutant and a normal. And lets say the mutant is not fit for survival. The mutation is deleterious. The unmutated cell survives and replicates. Lets say this happens a million times. The cell has actually lost a million cells and by chance one mutation is good, which leads to appearance of a variation. The variation being a good one can compete with the normal type when there is a selective pressure. If there is no selective pressure, the mutation being non lethal still survives and replicates, the number being less than the normal.

Overtime (after billions of replication rounds, I have a heterogenous population. There is more than 99% of normal type, and 1% of different variants and during the process lost a billion cells in trying to be different. To this if I add an antibiotic, the mutant (which maybe less than 0.01%) survives which can now proliferate. If I had a zero mutation rate, everything would have been killed in one boom. Eventhough in the process I lost billions of cells (deleterious mutation), the remaning 0.01% of cells will carry the gene pool. Without mutation whole gene pool is lost. Given the fact that cells are exposed to all kinds of challenges, mutation provides a means to escape total anhilation even though there is significant loss (This is in contrast with total loss by trying to save more cells). This is clearly advantageous.

A good example is a particular BRCA1 germ line mutation, leading to hereditary breast cancer, with a high prevalence in Ashkanazi women. This mutation apparently arose in a person at least two thousand years ago. One possible explanation for its evolutionary persistence, involves that tumors could develop after reproduction...

To get anywhere with this question, we have to presuppose some other methods of adaptation that don't involve actual mutations, because no environment is static. Just because one population tries to do without doesn't mean all the others do. Viruses, in particular, depend more on their mutations for continued viability than cells, pathogenic bacteria more than eukaryotes, and microbes more than us. The viruses will continue mutating no matter what we achieve.

So, here we are, bobbing about in a seething cauldron of mutating viruses with our exons and memes and vaccines and recombinant gene therapy. The Joneses, next cauldron over, have all that and mutations besides. Eventually the viruses cough up a mutation our civilized library of adaptability cannot best.

Soon only Joneses bob about in our cauldron.

I could imagine that human genome is now close to zero mutation rate (taking about 5000 - 10,000 years as our 'infinitesimal' time interval); something else is afoot: very fast growth and mutations of "memes". This is something akin to the fast evolution of RNA/DNA by horizintal gene tranfer just before the time of LUCA (if there was one).

Changing environment?

Does anyone have a link to a study showing that most mutations (in bacteria/archaea) are deleterious? (Asiide from quoting Murphy's Law).

Who said their mostly deleterious? Roughly a 1/3 are fixed by wobble base/degeneracy*, and a number of others would be expected to be neutral or nearly so due to the strong error correction inherent in the standard genetic code. I think the mutations we notice are certainly more likely to be deleterious. But what's science without a little sample bias?

In the context of nearly neutral evolution, accumulation of these mild mutations allows for an eventual leaps in protein function when only a single residue is changed, that one change likely being deleterious if taken alone or in a different order.

* Interestingly, most of the GC-content differences between microbes can be found in changes to the 3rd codon base, a fact that's been rediscovered a number of times. Also, twofold degenerate sites reflect the higher likelyhood of transition over transversion mutations.

Because some aren't.

Any mechanism that might keep the mutation rate low would be subjected to deleterious mutations...

Hmmm... Really interesting question!

Problem is: it cannot evolve to zero unless it is not zero. If mutation rate slows down to near zero, evolution will also slow down, and the probability of a "beneficial" mutation of "no mutation" will be astronomically low.

It reminds me of that story dating back to the time when everybody's wishes came true... until... until one man's wish was: "I wish that nobody's wish comes true!"

Zero mutation rate means no variation and thus the halt of evolution through the loss of environmental adaptability. This decreases the fitness of an organism that achieves this state versus one that allows a some mutations, even if most of these would be deleterious.
This is of course assuming the organism inhabits an ever changing environment. If the environment changes enough, an "immutable" organism would then be doomed to extinction.

In earth or earth-like environments, where evolution is the base for all life - there cannot be such thing as evolution to zero mutation rate. If such mistake happens than the unfortunate species will parish. Mutation rate evolve to zero is "Point Counter Point".

Is there a level of noise that is unavoidable during replication? Would unlimited energy and proof-reading be able to reduce the mutation rate to zero?

A mutation rate of zero can be good for an individual organism, but deleterious to a population because of selective pressures. Hence good for population, bad for individual, and evolution/selection works on populations.

Nice one! I would love to hear John Roth hold forth on this topic! All I can modestly add is that I don't know about "most" mutations being deleterious...I mean, it sounds that way. But then I am wondering what percentage of base substitutions are silent due to codon degeneracy---for at least some classes of mutational changes?

It also reminds me of the "no proofreading" problem with RNA polymerases. RNA viruses using that enzyme for replication are extremely prone to mutation, and make many defective progeny (do we have a number for that?). Yet the "lottery winners" have their shot, as well.

Because error-checking and correcting the DNA takes energy, organisms have a limited amount of energy, and thus at some point the cost of error-checking outweighs the benefits.

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