Tuesday, March 04, 2014

Explaining why of Mutation


     Time to time, I have been receiving queries related to subject. The questions have sometimes lead to me to think deep into matters and sometimes go deep down into papers. Whatever said, it is interesting. It seems certain questions are repeated by many people. So I thought, the question needs to be addressed with my thoughts and opinion in a broader open space. That should avoid some people the trouble of framing questions for me. I have rephrased the question so as to get the readers what is being asked for

      The common question is about mutation. Mutation is an important aspect of evolution. Evolution, lets 2 organism compete (for whatever survival purpose). If mutation wasn't there on first place then that should have still kept 2 different species on equilibrium. So why haven't there been an example of no mutation in the first place. In ASM blog (Link), a question was asked. Given that most mutations are deleterious, why does the mutation rate not evolve to zero?

     The most common answer is "Mutation causes evolution, which sustains the need for genes to pass on, and hence mutation cannot be zero". Lets design a thought experiment. If I artificially grow a bacteria in a medium for long generations (say some 10000 generations), without any hinderance, we wil get a population that has no selective factor. So over generations, theoretically speaking mutation is leading to more wastage, thus mutation rate should decline. This is called as "General reduction principle". Such an experiment has been done (Link). The result was that mutation rate didnt decline, instead has increased by about 2 orders. The explanation is very simple. To start with, there was a mutation rate (however small that be), which created random mutants which has better properties (However slight edge that maybe) which fuelled competiton thus not allowing other members to reduce the mutation rate. This phenomenon is known as "Mutator hitchhiking hypothesis". My simple point is this, Mutation already exists at a certain level, which cannot be brought down, since there are cheaters in the field.

Fig 1: Mutation fuelling itself.
     A seemingly subsequent question is how did mutation come into existence in first place. There is no clear evidence to support thge idea, but anyways idesigned one more thought experiment. Lets say I have 2 bacterial strains (X and Y) with zero mutation rate. Inoculating X and Y into a nutrient rich medium, the DNA polymerase begins to transcribe to make new copies. Polymerase of X increases the speed of incorporation of nucleotides, but Y is steady. In no time, X would be in larger quantities than Y (advantage). This selects for increasing polymerase speed till a limit is pushed where the excessive speed of incorporation leads to first mutation. The genetics can sacrifice the change in 1 base for the cost of achieving more copy numbers, and the concept of mutation is born. Once mutation has entered the scene, mutation fuels itself. Of course such an experimet can never be conducted (For many reasons, including we never have two strains of organism that has zero mutation to start with). Please note, one of the main reasons of mutation is mis-incorporation of bases due to excessive polymerase speed of work.

      Now coming to a major question. Given that most mutations are deleterious, why does the mutation rate not evolve to zero? One more thought experiment (ok, this is the last). 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.

Fig 2: Mutation leading to Antibiotic resistance.
  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.

     I hope that clarifies the question of why mutation is important and we can never have a zero mutation scenario.

Paul D. Sniegowski, Philip J. Gerrish, & & Richard E. Lensk (1997). Evolution of high mutation rates in experimental populations of E. coli. Nature, 387 (12), 703-705.  PMID: 9192894.

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