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In a recent post, Professor Larry Moran accused me of shifting the goalposts, in order to avoid a discussion about whether evolution could account for the fixation of 22.4 million mutations in the human lineage, since we broke away from the chimps, five million years ago. Not being one to run away from a controversy, I’ve decided to make this question the topic of today’s post.
I’d like to begin by defining the neutral theory of evolution:
“This neutral theory claims that the overwhelming majority of evolutionary changes at the molecular level are not caused by selection acting on advantageous mutants, but by random fixation of selectively neutral or very nearly neutral mutants through the cumulative effect of sampling drift (due to finite population number) under continued input of new mutations.”
(Motoo Kimura, “The neutral theory of molecular evolution: A review of recent evidence,” Japanese Journal of Genetics 66, 367–386 (1991)).
And here’s a handy definition of the term “genetic fixation”:
1. the increase of the frequency of a gene by genetic drift until no other allele is preserved in a specific finite population.
(Stedman’s Medical Dictionary. Copyright 2006 Lippincott Williams & Wilkins.)
“Evidence, please!”
In a previous post, I asked for some experimental evidence to back up Professor Moran’s claim that 22.4 million nearly neutral alleles could have become fixed in the human genome during the last five million years. Were there any other organisms – bacteria, for instance – exhibiting the fixation rate predicted by evolutionary theory for neutral alleles?
Professor Moran kindly provided an example, in his response to my post:
Fortunately for Torley, there are a number of papers that answer his question. The one that I talk about in class is from Richard Lenski’s long-term evolution experiment. Recall that mutation rates are about 10^-10 per generation. If the fixation rate of neutral alleles was equal to the mutation rate then (as predicted by population genetics) then this should be observable in the experiment run by Lenski (now 60,000 generations).
The result is just what you expect. The total number of neutral allele fixations is 35 in the bacterial cultures and this correspond to a mutation rate of 0.9 × 10^-10 or only slightly lower than what is predicted. There are lots of references in the paper and lots of other papers in the literature.
Wielgoss, S., Barrick, J. E., Tenaillon, O., Cruveiller, S., Chane-Woon-Ming, B., Médigue, C., Lenski, R. E. and D. Schneider (2011) Mutation rate inferred from synonymous substitutions in a long-term evolution experiment with Escherichia coli. G3: Genes, Genomes, Genetics 1, 183-186. [doi: 10.1534/g3.111.000406]
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The 12 evolving E. coli populations in Richard Lenski’s long term evolution experiment, on June 25, 2008. Image courtesy of Wikipedia.
Initially, I was very impressed with Lenski’s paper, and I was inclined to think that Professor Moran had proved his point. Scientia locuta est, causa finita est. Or so I thought.
A skeptical biochemist
It was then that I was contacted by a scientist who wrote to me, arguing that the fixation of 22.4 million mutations in the human lineage during the last five million years by a combination of selection and genetic drift was impossible and nonsensical for any population of organisms, especially when we consider the pattern of fixation. Strong words! Who was this mysterious scientist? Readers might be surprised to learn that he’s a biochemist with a very impressive track record named Branko Kozulic, whom I introduced to readers in a previous post, titled, The Edge of Evolution? A short summary of his career achievements is available here. Dr. Kozulic also serves on the editorial board of the Intelligent Design journal Bio-Complexity.
By now I was intrigued. Here was a prominent biochemist disagreeing with the arguments of another prominent biochemist! (Larry Moran is a Professor of Biochemistry at the University of Toronto.) Who was right? I decided to investigate the matter further.
There are three different mutation rates
Dr. Kozulic pointed out that we need to distinguish between three different mutation rates:
(a) the number of mutations per base pair per generation, which is indeed roughly constant across all organisms; and
(b) the number of mutations per individual per generation, which varies widely between different kinds of organisms, for reasons that I’ll discuss below; and
(c) the total number of mutations entering the population per generation, which is equal to “the number of gametes produced each generation, 2N, times the probability of a mutation in any one of them, u.” (John Gillespie, Population Genetics: A Concise Guide, Johns Hopkins University Press, 2004, pp. 32-33.)
Professor Moran does make this distinction in some of his posts – for example, this one, where he states that there is “one mutation in every 10 billion base pairs that are replicated,” and then goes on to say that there are “133 new mutations in every zygote.”
Which mutation rate is the fixation rate equal to?
In the passage cited above, Professor Moran referred to Lenski’s long term evolution experiment:
If the fixation rate of neutral alleles was equal to the mutation rate then (as predicted by population genetics) then this should be observable in the experiment run by Lenski (now 60,000 generations).
Did you notice the reference to “the mutation rate”? As we saw above, there are three mutation rates. In chapter two of his book, Population Genetics: A Concise Guide (Johns Hopkins University Press, Baltimore, second edition, 2004), which I’ve been recently perusing, evolutionary biologist John Gillespie repeatedly refers to the mutation rate for a given locus. And in population genetics, altering the numerical relationship between the mutation rate and the (effective) population size can lead to dramatically different results. For example Gillespie, in the textbook referred to above, writes:
If 1/u << N, the time scale of mutation is much less than drift, leading to a population with many unique alleles. If N << 1/u, the time scale of drift is shorter, leading to a population devoid of variation. (2004, p. 31)
Professor Moran is kindly requested to state whether he agrees with this statement, and if not, to provide some references to support his views.
Fixation in human beings: five orders of magnitude faster than in Lenski’s bacteria!
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In the passage cited above, Professor Moran referred to Lenski’s results with E. coli bacteria: a mere 35 fixations after 60,000 generations. That’s about 0.0006 fixation events per generation, for the population as a whole.
By contrast, the fixation rate which Professor Moran claims for human beings (130 per generation) was 200,000 times faster than the rate which Lenski observed for his bacteria. That’s a difference of over five orders of magnitude! This difference in fixation rates requires an explanation. Do we agree on this point, Professor Moran?
Finding the cause that explains the pattern
Now, clearly something was responsible for producing the 22.4 million neutral alleles that distinguish the human lineage from that of chimpanzees. Nobody disputes that. What Dr. Kozulic rejects is the idea that all these mutations could have been fixed by any undirected process (e.g. random mutations plus natural selection, or plus genetic drift), within the time available, especially when we consider the pattern of fixed mutations.
I’d now invite readers to have a look at an article by Rasmus Nielsen et al., titled, A Scan for Positively Selected Genes in the Genomes of Humans and Chimpanzees (PLoS Biology, 3(6): e170. doi:10.1371/journal.pbio.0030170, published May 3, 2005). In particular, I’d like readers to check out Figure 1, showing the distributions of nonsynonymous and synonymous nucleotide differences among genes, for the chimpanzee sequence.
What the figure shows is that multiple mutations (up to 21) have become fixed in thousands of different proteins, within the relatively short span of five million years.
In short: it is the pattern of fixation which neither the theory of neutral evolution nor the neo-Darwinian theory of natural selection, nor any combination of the two, can adequately explain. Until Professor Moran comes up with an explanation of his own, and some research to back it up, the ball is squarely in his court.
Over to you, Professor Moran.