Review of "The Mystery of the Genome" (II)
At the end of the previous installment I began examining Sanford's arguments as to why "random mutations are never good". As we saw, most of these ended up being among some of oldest and most discredited creationist arguments around. But he also had a new (at least to me) and more subtle one: that even if there are beneficial mutations they'll turn out to be nearly-neutral. Although it's nice to see that creationists have caught up with Kimura, albeit several decades late, I'm afraid this argument is also invalid.
The "nearly neutral" theory of molecular evolution was developed by Motoo Kimura and Tomoko Ohta in the 1970s. Basically this relies on an old result by Kimura that requires an explanation. Imagine that we have a diploid population fixed for an allele A at the A locus. What is the probability that a new allele a arising by mutation (A -> a) will go to fixation some time in the future? The answer is that it depends on whether selection is acting on it. To make a long story short, there are three (simple) possibilities:
If the a allele is beneficial, then the probability that it will go to fixation depends on the selective advantage it confers. If the fitnesses of each genotype are W(AA) = 1, W(Aa) = 1+s, and W(aa) = 1+2s, then the probability that a will go to fixation is approximately P = 2s. Other fitness functions will change the probabilities, but that doesn't matter for the main point I want to make.
If the a allele is deleterious, then the probability that it will go to fixation depends on the selective disadvantage it confers. The formulas are more complicated and need not detain us for the main point I want to make. What Kimura and others have pointed out is that if the population size N and/or the selective advantage s of an allele are too small, then a beneficial allele (i.e., one with a positive value of s in the above expressions) will behave as if it were neutral. Such an effectively neutral allele will not be under the action of natural selection, but will fluctuate under genetic drift. A quick manipulation of the probabilities given above shows that if the selective advantage s of a beneficial allele is equal to or less than 1/(4N), then the allele is effectively neutral. A similar point can be made for a weakly deleterious allele.
Sanford's main point then is that there are likely to be very few truly beneficial mutations in humans because of this effect. Although this decades-old argument is generally correct for humans, it is misleading for two reasons. First, it neglects to mention that this near-neutrality effect is especially acute in large mammals like humans because of their historically low population sizes. However, most creatures on earth are not subject to this problem to anything near the same extent. How do we know this? There are many lines of evidence, such as the evolution of codon-usage bias. I won't take the time to explain this in full here, but suffice it to say that it can only evolve if selection is able to act on very weakly beneficial mutations. Briefly, we expect to see strong codon bias in species that have large populations. Predictably we find little or no codon bias in humans or mice (in concordance with Sanford's point), but it is present in nematodes (Caenorhabditis elegans and, more strongly, in C. briggsae), cress Arabidopsis thaliana, fruitflies Drosophila melanogaster, and is very strong in microorganisms like E. coli and yeast Saccharomyces cereviseae. Second, Sanford handwaves about the ratio of beneficial mutations to deleterious mutations, when in fact there are no good direct estimates of this number for humans. Direct estimates in other organisms are not abundant either, because it is technically difficult to do so, but there are some for which the picture is not as apocalyptic as Sanford suggests. For example, Sanjuan, Moya & Elena (2004) found that "the proportion of beneficial mutations was unexpectedly high" in the vesicular stomatitis virus. I also know of at least one other study (as yet unpublished, so I cannot say anything else about it) which found that the ratio of beneficial to deleterious mutations in a famous microbe is much higher than previously thought.
Which brings us to the main problem with Sanford's argument. Let's imagine that what he has said in Chapter 2 is right and that there is no evidence for the operation of positive selection (selection for beneficial mutations) in humans. This is precisely where Sanford's argument fails. In fact the opposite is the case: we have strong and abundant evidence that positive selection has occurred in the human evolutionary lineage. To Sanford's embarrassment , there has actually been a steady stream of papers demonstrating positive selection in the last few years, such as, Johnson et al. (2001), Sabeti et al. (2002), Nielsen et al. (2005), Chimpanzee Sequencing and Analysis Consortium (2005), and Voigt et al. (2006). To understand how these estimates work I would recommend evolgen's 7-part series of posts explaining how natural selection can be detected using molecular data (the last one is a good place to start). Only someone completely ignorant in the human population genetics literature could possibly claim that beneficial mutations don't exist in humans.
Since this is one of the central arguments in Sanford's book, I doubt that there is anything else worth discussing. However, I'll check the other chapters and will let you know if this is not the case.
The "nearly neutral" theory of molecular evolution was developed by Motoo Kimura and Tomoko Ohta in the 1970s. Basically this relies on an old result by Kimura that requires an explanation. Imagine that we have a diploid population fixed for an allele A at the A locus. What is the probability that a new allele a arising by mutation (A -> a) will go to fixation some time in the future? The answer is that it depends on whether selection is acting on it. To make a long story short, there are three (simple) possibilities:
- If the a allele is neutral, that is, the fitnesses of the three genotypes are the same W(AA) = W(Aa) = W(aa), then the probability of fixation of a is P = 1/(2N), where N is the size of the population (number of individuals)
Sanford's main point then is that there are likely to be very few truly beneficial mutations in humans because of this effect. Although this decades-old argument is generally correct for humans, it is misleading for two reasons. First, it neglects to mention that this near-neutrality effect is especially acute in large mammals like humans because of their historically low population sizes. However, most creatures on earth are not subject to this problem to anything near the same extent. How do we know this? There are many lines of evidence, such as the evolution of codon-usage bias. I won't take the time to explain this in full here, but suffice it to say that it can only evolve if selection is able to act on very weakly beneficial mutations. Briefly, we expect to see strong codon bias in species that have large populations. Predictably we find little or no codon bias in humans or mice (in concordance with Sanford's point), but it is present in nematodes (Caenorhabditis elegans and, more strongly, in C. briggsae), cress Arabidopsis thaliana, fruitflies Drosophila melanogaster, and is very strong in microorganisms like E. coli and yeast Saccharomyces cereviseae. Second, Sanford handwaves about the ratio of beneficial mutations to deleterious mutations, when in fact there are no good direct estimates of this number for humans. Direct estimates in other organisms are not abundant either, because it is technically difficult to do so, but there are some for which the picture is not as apocalyptic as Sanford suggests. For example, Sanjuan, Moya & Elena (2004) found that "the proportion of beneficial mutations was unexpectedly high" in the vesicular stomatitis virus. I also know of at least one other study (as yet unpublished, so I cannot say anything else about it) which found that the ratio of beneficial to deleterious mutations in a famous microbe is much higher than previously thought.
Which brings us to the main problem with Sanford's argument. Let's imagine that what he has said in Chapter 2 is right and that there is no evidence for the operation of positive selection (selection for beneficial mutations) in humans. This is precisely where Sanford's argument fails. In fact the opposite is the case: we have strong and abundant evidence that positive selection has occurred in the human evolutionary lineage. To Sanford's embarrassment , there has actually been a steady stream of papers demonstrating positive selection in the last few years, such as, Johnson et al. (2001), Sabeti et al. (2002), Nielsen et al. (2005), Chimpanzee Sequencing and Analysis Consortium (2005), and Voigt et al. (2006). To understand how these estimates work I would recommend evolgen's 7-part series of posts explaining how natural selection can be detected using molecular data (the last one is a good place to start). Only someone completely ignorant in the human population genetics literature could possibly claim that beneficial mutations don't exist in humans.
Since this is one of the central arguments in Sanford's book, I doubt that there is anything else worth discussing. However, I'll check the other chapters and will let you know if this is not the case.
posted by Ricardo Azevedo at 10/10/2006 09:53:00 AM
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