To: All Msg #69, Nov2992 06:39AM Subject: Probability of good, neutral and bad mutations.

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From: L.A. Moran To: All Msg #69, Nov-29-92 06:39AM Subject: Probability of good, neutral and bad mutations. Organization: UTCS Public Access From: (L.A. Moran) Message-ID: Newsgroups: The original question (from David Rice?) was, "What is the probability of a "random" mutation being benificial to an organism?" Mark Isaak asks, "Let's now extend the question a little. What is the ratio of good and bad mutations to neutral mutations? I think this is a more interesting question because neutral mutations won't necessarily stay neutral as the environment changes. For a population with a large variety of neutral mutations, when the environment changes, some individuals may very well already have acquired a "good" mutation needed to deal with the change. (Of course, many more won't be able to deal with the change, but they'll die off and leave the picture eventually.)" Let's consider a gene that has a coding region of 1800 base pairs. The protein that it encodes contains 600 amino acids (recall that a codon consists of three nucleotides). This is an average sized protein. If we examine homologous proteins from many organisms we would typically find that about one third of the amino acid sequence is highly conserved (ie. invariant); about one third is moderately conserved; and the remaining third is poorly conserved. Let's use these estimates to calculate allowable mutations. Consider the conserved region. It appears that any mutation in this sequence that results in an altered amino acid is harmful. That is why we don't see such changes preserved in modern living organisms. However, some nucleotide substitutions ("mutations") are possible because they do not alter the sense of a codon. For example, several different nucleotides can occupy the third position of a codon without altering the amino acid encoded. For a rough estimate of the probabilities of good, bad and neutral mutations let's assume that the first two nucleotides of each codon in the conserved region are invariant and that the third position can vary. There are 600 nucleotides in the conserved region and each one can be mutated to three other possibilities. Thus there are 1800 possible "mutants" if one counts single nucleotide substitutions. Of these 1200 are "bad" because they will alter the encoded amino acid. But many of the remaining 600 possible mutations are also "bad" because they result in a new codon or because they result in an unusual codon that is not used efficiently. As a rough estimate let's assume that half of them are neutral and half are bad. In summary, for the conserved region we have 1500 bad possibilities and 300 neutral possibilities. Comparing with the moderately and poorly conserved regions; nucleotides mutations bad neutral ----------- --------- --- ------- invariant (conserved) 400 1200 1200 0 variable (conserved) 200 600 300 300 invariant (moderate) 300 900 900 0 variable (moderate) 300 900 450 450 invariant (poorly) 200 600 600 0 variable (poorly) 400 1200 600 600 ----- ----- totals 4050 1350 For the entire gene we have 4050 bad mutations and 1350 neutral mutations. Some of the neutral mutations will be slightly benificial and some will be slightly harmful but the effect on fitness is too small to make much of a different. Some of the mutations will be "good" because they result in changes that correct the accumulation of slightly harmful mutations (by genetic drift). It is difficult to guess the number of potentially "good" mutations in a gene found in a living organism. I think that there may be about 50 possibilities for a gene of average size that is moderately conserved. This gives 1% good mutations, 24% neutral mutations, and 75% bad mutations for the codong region of a typical gene. Laurence A. Moran (Larry)


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