natural selection

I had read this paper by Ruiz-Pesini et al. (2004) before, but the particular combination of factors it suggests came together for me in a new way recently:

Effects of Purifying and Adaptive Selection on Regional Variation in Human mtDNA

A phylogenetic analysis of 1125 global human mitochondrial DNA (mtDNA) sequences permitted positioning of all nucleotide substitutions according to their order of occurrence. The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.

Here are the final two paragraphs of the paper:

This combination of the increased predilection to energy deficiency diseases, but protection from neurodegenerative diseases and aging is consistent with the expectations for mtDNA coupling efficiency mutations. Uncoupling mutations would reduce ATP production, increasing the probability of energetic failure. However, they would also decrease mitochondrial ROS production by increasing the oxidation of the electron transport chain, thus reducing oxidative damage and apoptosis. This could decrease neuronal and other cell loss, thus increasing longevity.

Our observations support the hypothesis that certain ancient mtDNA variants permitted humans to adapt to colder climates, resulting in the regional enrichment of specific mtDNA lineages (haplogroups). Today these same variants result in differences in energy metabolism and altered mitochondrial oxidative damage, thus affecting health and longevity. Therefore, to understand individual predisposition to modern diseases, we must also understand our genetic past, the goal of the new discipline of evolutionary medicine (Ruiz-Pesini et al. 2004:226).

So in other words, populations in northern latitudes today are enriched for a number of mtDNA haplogroups that are likely adaptive to cold. Today, these haplogroups (as a class) are largely protective against degenerative diseases of aging, possibly because they reduce oxygen free radical production. But they are also more susceptible to disorders of energy metabolism, because they reduce ATP production.

Needless to say, this says some interesting things about the relationship of longevity and energy metabolism in recent human populations.

But at the moment, I'm thinking about Neandertals. They lived in a cold place, but their lifestyle suggests that energy metabolism was at a premium. At the same time, they had a much shorter maximum lifespan than living people. According to the model of mtDNA mutations outlined by Ruiz-Pesini et al. (2004), this would be a very odd combination: cold adaptation today is linked to longevity and lower energy metabolism; Neandertals required high metabolism but had lower longevity.

Those functional considerations alone suggest that Neandertals needed a highly specialized mtDNA type that would have been unlike those of living people.

But additionally, the increase in longevity and difference in lifestyle apparent in later Upper Paleolithic people gives a clear reason for the replacement of the Neandertal mtDNA type. These people lived longer, and they had markedly less energy expenditure than Neandertals did. Their dietary and cultural adaptations would have been much more similar to recent arctic peoples (and indeed, might well have been completely identical to the ancestors of recent arctic peoples).

Would this have been an exceptional event? I don't really think so, because Ruiz-Pesini et al. (2004) outline how similar cold-adaptive mutations occurred in different macrohaplogroups that today are all present at higher latitudes. The occurrence of potentially adaptive mtDNA mutations appears to have been quite a common event throughout human prehistory, because today's haplogroups appear to be separated by many mutations that are adaptive in different contexts.

The situation is reviewed in two papers by Douglas C. Wallace (2005a, 2005b). The thing that surprised me about these two reviews is that they embrace a positive selection hypothesis for mtDNA migration out of Africa. Consider:

This mtDNA history is remarkable for the striking discontinuities that exist in mtDNA diversity between climatic zones. Of the extensive mtDNA variation present in Africa only two mtDNA lineages (M and N) succeeded in colonizing all of Eurasia. Of the plethora of Asian mtDNA types that subsequently accumulated, only three haplogroups (A, C, and D) and much later G came to occupy the extreme northeastern Chukotka Peninsula of Siberia. This strikingly correlation between mtDNA lineages and latitude and climate led to the hypothesis that mutations in certain mtDNAs that decreased the coupling efficiency increased mitochondrial heat production and permitted people to survive the cold of the more northern latitudes (Ruiz-Pesini et al., 2004) (Wallace 2005a:173).

This passage is followed by a section to support it, of which I find several parts very suggestive (my emphasis):

This hypothesis is supported by the fact that missense mutations in mtDNA protein genes show regional specificity. Missense mutations are prevalent in the ATP6 gene in the arctic, in the cytb gene in Europe, and in the COI gene in Africa. Mutations in different ND genes also show regional correlation (Mishmar et al., 2003). Moreover, many of the ancient missense mutations change amino acids that are as highly evolutionarily conserved as are most known pathogenic mutations, yet have been retained in the human population for tens of thousands of years. Hence, they could not be pathogenic in the environment in which they reside, but rather must be adaptive and thus beneficial. Furthermore, an analysis of the missense mutations in cytb of complex III, for which the crystal structure is known, revealed that many of these missense mutations affected CoQ binding sites which would alter the Q-cycle, proton pumping, and thus OXPHOS coupling (Ruiz-Pesini et al., 2004).

Finally, when European mtDNA haplogroups were correlated with longevity and predisposition to Alzheimer Disease (AD) and Parkinson Disease (PD), it was found that mtDNAs harboring uncoupling variants were enriched in the elderly and deficient in AD and PD patients. This led to the conclusion that the uncoupling mutations must enhance the flow of electrons through the ETC keeping the ETC carriers oxidized. This, in turn, reduces the spurious transfer of electrons to O2 thus minimizing ROS production and reducing mitochondrial and cellular damage.

These same uncoupling mutations would also reduce the efficiency of ATP generation which could then exacerbate ATP deficiencies resulting from milder mtDNA mutations. This could account for the predilection of patients with Leber's Hereditary Optic Neuropathy (LHON) that harbor the milder mtDNA mutations to also have haplogroup J mtDNAs which harbor either the np 14798 or np 15257 cytb missense mutations. Thus ancient adaptive mtDNA variants are affecting individual predisposition to degenerative diseases and aging today.

This last one also would apply to milder slightly deleterious mutations of nuclear genomic loci that contribute to mitochondrial metabolism. One might even conclude that today's mitochondrial degenerative disorders may in part be a legacy of ancient adaptive mtDNA variants that no longer exist.

Now, if we seriously accept the hypothesis that human mtDNA variation is regionally adaptive, then we have to conclude that a lot of literature that assumes mtDNA neutrality is just wrong. For example:

1. If mtDNA is neutral, then the dates of mtDNA lineage divergences may tell us about the initial migrations of some human populations. If mtDNA is adaptive to different regions, then the dates of lineage divergences tell us about the times that adaptive mutations occurred.
2. If mtDNA is neutral, then it is surprising that archaic mtDNA variants are gone. If mtDNA is selected, then this is not at all surprising: the current global mtDNA variation is simply the product of the last globally adaptive mutation.
3. If mtDNA is neutral, then it is reasonable to explain the lack of ancestral haplogroup L outside of Africa as the consequence of an out-of-Africa population bottleneck. But if mtDNA is selected, this distribution is explained as Wallace (2005b:376) suggests: many mtDNA lineages may have entered Eurasia, but only a few survived local selection.

Is it possible that there have been no globally adaptive mutations? If the present pattern of variation is fine-tuned to climate and diet, it seems very unlikely that the massive life history, brain, and energetic changes during Pleistocene human evolution had no effect whatsoever.

The present distribution of adaptive mtDNA variants suggests a scenario for the replacement of Neandertal mtDNA. Variants of human mtDNA that appear to be adaptive in Eurasia, and particularly in the northern parts of Eurasia, evolved recently upon an African background. The present variation of human mtDNA is comparatively recent, but it is ancient enough that some of today's variants were segregating within Africa over 100,000 years ago, and the haplogroup M dispersal from Africa appears to have occurred between 60 and 70 thousand years ago. Ultimately these gave rise to European haplogroups H, T, U, V, W, X, I, J, and K (Wallace 2005b), in the time period between 50,000 and 9,000 years ago.

We know that these variants were superior to indigenous European mtDNA variants because the Neandertal mtDNA is gone today. Yet, we must suspect that the Neandertal mtDNA would have been very well adapted to their cold climate and high energetic requirements. The advantages of the incoming African-derived mtDNA variants were great, but they would not have been free of disadvantages -- especially with respect to either cold (which has historically restricted non-European mtDNA haplogroups to the south) or energy metabolism (which currently restricts European mtDNA haplogroups to the north).

Thus, the replacement of Neandertal mtDNA could occur only upon the abandonment of Neandertal lifeways. Only a reduction in energy expenditure and exposure to cold could allow the spread of the African-derived mtDNA variants. Both these changes could be accomplished by a cultural transition, which additionally could increase dietary supply and thereby change selective constraints on energy efficiency.

In this context, it is very significant that the latest Neandertals adopted Upper Paleolithic tool industries and other cultural elements usually associated with modern humans. This cultural transition may have decreased the selective advantages of endogenous European mtDNA variants and allowed the substitution of newer European variants of African derivation. In other words, it may have been the very process of adopting new cultural and demographic patterns that resulted in the selection against old Neandertal mtDNA, even within the European Neandertal population.

So far, I have said nothing of what benefit the African-derived mtDNA variants may have provided. It seems likely that it was not related to cold (considering the Neandertals had plenty of time to become cold-adapted), energy (considering that the Neandertals appear to have had higher total energy expenditure than later people), or diet (since Upper Paleolithic people had broadly similar (if slightly different) diets to Neandertals).

Instead, I would propose that the advantage of the African-derived mtDNA variants was in the one area (out of mtDNA-associated factors) where Neandertals and later humans significantly differ: longevity. It is not at all obvious that living longer is a better adaptation for humans as compared to the shorter lifespan of Neandertals. As a very recent adaptive change, it may have required fairly exceptional demographic conditions, such as large population sizes, a reliance on extensive trade networks, or other behavioral attributes of recent people. Only in such a cultural context can the survival of older individuals provide a fitness advantage to their younger kin.

I do not think that the mtDNA change was the most important one; it probably followed many other genomic changes in favor of longevity. This would be similar to the effect of mtDNA variants in the face of climate or dietary differences today: no population was likely restricted from inhabiting the arctic by the lack of favorable mtDNA variants, but the fast mutation rate of mtDNA ensured that populations living in the arctic quickly gained new adaptive variants for their cold climates. Likewise, other genetic changes that led to a longer lifespan would quickly have led to mtDNA variants adaptive to the new demographic reality. The global human mtDNA variability likely reflects such trailing adaptive mutations. This might imply that the transition to greater longevity or other aspects of modern human life history would have been accompanied by not one, but multiple adaptive sweeps of global mtDNA variation.

References:

Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace DC. 2004. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science 303:223-226. Full text (subscription)

Wallace DC. 2005a. The mitochondrial genome in human adaptive radiation and disease: On the road to therapeutics and performance enhancement. Gene 354:169-180. Full text (subscription)

Wallace DC. 2005b. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet (Online before print)

Here's an interesting thought:

Background

In mammals, contrary to what is usually assumed, recent evidence suggests that synonymous mutations may not be selectively neutral. This position has proven contentious, not least because of the absence of a viable mechanism. Here we test whether synonymous mutations might be under selection owing to their effects on the thermodynamic stability of mRNA, mediated by changes in secondary structure.

Results

We provide numerous lines of evidence that are all consistent with the above hypothesis. Most notably, by simulating evolution and reallocating the substitutions observed in the mouse lineage, we show that the location of synonymous mutations is non-random with respect to stability. Importantly, the preference for cytosine at 4-fold degenerate sites, diagnostic of selection, can be explained by its effect on mRNA stability. Likewise, by interchanging synonymous codons, we find naturally occurring mRNAs to be more stable than simulant transcripts. Housekeeping genes, whose proteins are under strong purifying selection, are also under the greatest pressure to maintain stability.

Conclusion

Taken together, our results provide evidence that, in mammals, synonymous sites do not evolve neutrally, at least in part owing to selection on mRNA stability. This has implications for the application of synonymous divergence in estimating the mutation rate.

That's the abstract of a study (free text online) in Genome Biology by J. V. Chamary and Laurence D. Hurst.

What is the net effect of such selection? The short answer is nobody has any idea. Consider:

The substitution rate at synonymous sites in exons is often used as a measure of the mutation rate [8,9]; however, this assumes neutral evolution of synonymous mutations [1,2]. By providing a parsimonious mechanism by which selection could act on synonymous sites, we can ignore the objection that prior evidence is indirect. Nevertheless, it is presently unclear to what degree synonymous mutations are favored or opposed by selection due to their effects on mRNA stability. Without being able to quantify the latter, as well as the net effect of other biases (for example, splice-associated), it will not be possible to directly estimate the extent to which use of the synonymous substitution rate leads to underestimates of the mutation rate and the mutational load.

And:

Indeed, it is quite possible that there exist no preferred codon within a gene while at the same time synonymous mutations are under selection. More generally, a complex set of trade-offs between different forms of selection and mutational biases may render interpretation of patterns of codon usage very difficult.

It seems possible to me that selection on mRNA stability may allow certain kinds of fine-tuning changes, analogous to selection on promotors or inhibitors. If the half-life of an mRNA within a cell could be decreased slightly, it might well have an adaptive (or conversely maladaptive) result. Would it make enough difference to be selected? Maybe not in most cases, but in some cases it might well do so. And Charmary and Hurst are able to show that genes subject to strong purifying selection appear to have greater constraint on mRNA stability -- in my view the most persuasive of their arguments for the effect.

It also occurs to me that selection on mRNA structural stability would also be a consideration for the origin of the genetic code. Certain patterns of redundancy in silent sites would potentially be targets of selection, for long-lasting or shorter-lasting RNA codons as options for the same amino acid.

It just goes to show how many real unknowns we still face when looking at molecular evolution. If synonymous mutations aren't really neutral, what will we discover next?

References:

Chamary JV and Hurst LD. 2005. Evidence for selection on synoymous mutations affecting stability of mRNA secondary structure in mammals. Genome Biol 6:R75. Free full text online

Williamson et al. (2005) present a new mathematical method for deriving information about population size change and selection from the allele frequency spectrum of variation taken at multiple genetic loci. Their method depends on separating sites that are selected from those that are neutral, and thereby isolating the effects of demography from those of selection. They then apply their technique to human genetic data to derive estimates of the average selection on selected sites, and the timing and magnitude of population size change from nonselected sites.

Oh, if it were really so easy.

Selection

To be fair, the paper states a major concern with accurately identifying selection in the context of species like humans and Drosophila that have experienced recent population growth. In other words, the main interest is not in deriving evidence about human prehistory, but instead about making sure that estimates of selection are not biased by population growth.

With respect to selection, their major conclusion is as follows:

We find evidence that negative selection on nonsynonymous mutations is widespread, which implies that deleterious mutations make up a significant proportion of standing nonsynonymous variation. Exactly how this genetic variation contributes to phenotypic variation is a matter of considerable debate, especially for medically interesting phenotypes such as multifactorial genetic disease. Because deleterious mutations, by definition, have phenotypic effects, and because of the widespread nature of negative selection on nonsynonymous mutations, it seems likely that negatively selected, generally rare nonsynonymous SNPs have some negative impact on human health. If there is a general relationship between nonsynonymous polymorphism and human genetic disease, then our genomic estimates of the fitness effects of different types of mutations contain prior information about the likelihood that a mutation contributes to disease. It may be possible to use this information to aid in identifying SNPs that cause disease. Other studies have suggested this approach (e.g., Livingston et al. 2004), but it was unclear which of the many measures of exchangeability to use. We feel that the relative fitness of different amino acid changes is the best way to evaluate exchangeability, and we have done that here by using a model that includes demography and selection (Williamson et al. 2005:7887).

Readers may note that other studies have found evidence for a very high proportion of positive selection across the human genome (discussed in this post). The test applied in the current paper is not well suited to detecting evidence of positive selection, particularly if it is widespread, because it depends on the difference in frequency spectra between "selected" and "neutral" sites. Why the scare quotes? Because although noncoding sites or synonymous SNPs may well be neutral in the literal functional sense of not being targets of selection, it is impossible to verify that they are unlinked to selected sites. For the purposes of detecting negative (purifying) selection, this is not such a problem, because linkage will affect nearby sites only weakly (although this weak effect, called "background selection," may well influence the average level of variation in Drosophila).

In any event, even if positive selection has been very common across the genome, most sites that have been subject to positive selection should have been fixed long ago. Only a few should still be under selection now, and these are predominantly very recent mutations.

Consider the following scenario. The study considered 301 human genes. According to common knowledge, repeated here, positive selection leads to a relative excess of high-frequency alleles, compared to the predictions of neutrality (which predicts that there should be very few high-frequency alleles). But these high-frequency variants represent only a small proportion of the total number of genes currently under positive selection, since an allele being driven to fixation passes through every intermediate frequency, not merely the high ones. To detect evidence for positive selection, this study would have to find dozens of high-frequency variants in excess of neutral theory, representing scores of selected genes. But suppose instead that only one positively selected gene actually was in the sample. If so, then out of the human genome of approximately 20,000 genes, we might expect to find 60 or 70 genes currently under positive selection. In our fictive scenario it would be rash to extrapolate from a sample of 1, but in fact there are good reasons to think the true number is much higher. One such gene might take 1000 generations to transit from its appearance to fixation. There have been 100,000 generations in the 2 million years since the origin of our genus, and at least 300,000 since our divergence from chimpanzees. In other words, the complete transformation of the human genome by positive selection, altering thousands of genes -- or even all of them, multiple times -- would be far from detectable by this test.

But remarkably, this test does find evidence for positive selection -- in noncoding substitutions! The authors put it less sensationally: "Interestingly, we find marginal evidence for weak positive selection on noncoding indel polymorphisms" (7885). I have no explanation for it. But if there actually is a statistically detectable excess of high-frequency variants for these polymorphisms, it may reflect selection at linked sites, or issues with the composition of the sample. If the level of positive selection is detectable, it is another strong evidence of the power of such selection over the long timespan of human evolution.

In contrast to positive selection, even very strong purifying selection may leave low-frequency variants within the population for a long time. These variants are picked up within samples in large numbers. Low frequency variants are predicted to make up most genetic variation under neutrality, so the proportion of such variants is always a substantial part of the sample. High numbers make for powerful tests. For the human data examined in this study, the nonsynonymous coding sites have a higher proportion of low-frequency variants than do the noncoding, synonymous sites. Thus, they provide strong evidence of negative (purifying) selection.

Human demography

So the results of the method applied to selection are mixed. It detects the weak force of purifying selection strongly; it detects the strong force of positive selection weakly. But as the authors perceptively note, the inference of demographic history and the inference of selection are not independent of each other. Therefore, the inferences about demography are in part subject to the weaknesses in detecting the effects of past selection. This study shares this problem with all previous work that has attempted to estimate past human population size from genetic evidence.

How can selection affect interpretations of demography? Here's one way: Positive selection occurs rapidly relative to rate of recombination between sites. This means that a selective sweep may affect a relatively large section of a chromosome, including many "neutral" sites. This is the principle behind John Gillespie's (2002) pseudohitchhiking, or "genetic draft" model of neutral evolution. In a nutshell, if positive selection has been common, there is no reason to think that genetic variation at noncoding sites provides any indication of demographic parameters. The current study (by Williamson et al. 2005) assumes that positive selection has not had such an effect, nor has any other force significantly affected the variation of neutral sites.

These are the kinds of influences that have been suggested to result in the large difference between census population sizes (the number of individuals within living species) and estimates of effective population sizes (measures of the rate of genetic drift) in nature. In humans and in most other animal species, the rate of genetic drift on neutral sites appears to have been much stronger than the census population sizes of those species would predict. This is a systematic difference that leads species to have much lower genetic variation than would be expected if they evolved under genetic drift alone. At present, the relative importance of selection and demographic factors in leading to this systematic difference is unknown. I suspect that selection has been strongly important in this difference, others argue that demographic factors have been the most important.

In most previous genetic work, the effective population size (denoted as N_e) is around 10,000 individuals. Some scientists have suggested that the human population actually was once that small -- that only a few tens of thousands of people once comprised the entirety of humanity. If this were true, then the human population must have expanded in size massively sometime in the recent past. The evidence for a recent change in the mitochondrial DNA molecule was once suggested to be evidence for this change in population size, which was inferred to have occurred during the Late Pleistocene, perhaps 50,000 years ago. From these estimates comes the scenario of an expansion from a single small African population beginning after 100,000 years ago, reaching Europe and the Far East by 30,000 - 50,000 years ago.

Recently, it has become clear that a single massive expansion of a global human population cannot explain the pattern of genetic variation in living people. Simply put, the pattern of the 16,000 base pairs of the mtDNA molecule is not replicated by the 3 billion base pairs of the nuclear genome.

To be sure, some genes do show a pattern of recent ancestry and apparent expansion. The FoxP2 gene, for example, has a recent common ancestor for living people (within the past 200,000 years), and shows strong signs that it has not evolved neutrally. If all other genes looked like this, it would be strong evidence of massive population growth.

But most genes do emphatically not look like this. This has been understood for several years, following reviews by Molly Przeworski and colleagues (2000), Jeff Wall (2000), and even my own dissertation (Hawks 1999). Many genes show no excess of rare variants, most show only a slight excess. The average gene shows no sign whatsoever of a massive population expansion during the Late Pleistocene. This has been concluded most powerfully by recent genome-wide studies of SNP variation by Marth and colleagues (2003; 2004; reviewed previously in this post).

Where does the current paper (Williamson et al. 2005) come in? Summarizing evidence from over 300 genes, this study does find evidence of a population expansion. Yes indeed -- a population expansion that happened 18,000 years ago! This expansion took the human population from a previous size of around 8000 individuals to a current size of around 50,000 individuals.

Of course these estimates are far from realistic in anthropological terms. If anything, 18,000 years ago much of the human population should have been contracting rather than expanding. The idea that the human population could have been as amll as 8000 individuals (or very generously 100,000 individuals) during the LGM is simply ridiculous. By that time, the certain ancestors of living people were present from the western tip of Iberia to the edge of (or possibly well into) Beringia. If a genetic estimate cannot gauge a population that must have numbered several millions of people, it is time to stop talking about genetic estimates.

To be fair, the demographic conclusions of the paper are phrased cautiously:

Therefore, although we find it striking that the time of population growth (18,200 years B.P.) roughly corresponds with events in human history that may have induced population growth, such as the end of the last ice age and the origin of agriculture, we feel that our demographic inferences should be interpreted cautiously until the full range of plausible demographic models has been explored in one coherent framework (7887).

At the same time, this apparently cautious discussion raises the more critical problem of a complete lack of communication or citation from any anthropologist. Hmm, I guess the last glacial maximum does roughly correspond to the "end of the last ice age and the origin of agriculture," in the usual manner of genetics confidence intervals. That is to say, it is only twice as old as either, so it might as well be the same.

Speaking of confidence intervals, again in this paper there are none. No confidence intervals on the demographic estimates, no confidence intervals in the supporting text, no figure showing the likelihood surface, none, nothing, nada.

What remains?

In a sense, the bone I am picking is different from that pursued by Williamson et al. (2005). What I care about is evidence for ancient demography. What they care about is better quantifying selection. I think that their paper is incomplete on their own terms, because of the problem quantifying positive selection, but that it is a credible theoretical effort. In particular, the insights about the frequency of genetic disorders based on their findings are a likely contribution to the future study of genetic variation in coding gene regions.

But the inclusion of demography in this study confuses much more than it clarifies from the perspective of the anthropologist. Its estimates of demographic changes are clearly false, and the lack of detail about confidence intervals makes them impossible to evaluate. In the face of this fatal problem, it is fair to wonder whether the apparent insights about purifying selection have any value.

The main importance of the data from these many genes is what they do not show. They do not show an expansion of many orders of magnitude. They do not show a current effective size that is anywhere near the current human population size (or a size sufficient to settle any large part of the world). They do not show evidence for expansion coincident with an "out of Africa" movement of people, over 50,000 years ago.

Instead, the conclusion is concordant with the discussion of Eswaran and colleagues (2005:3):

Thus, the nuclear data do not consistently signal expansion, and when they do, the signal is of a mild expansion, perhaps reflecting only post-Pleistocene population growth associated with the spread of agriculture.

The summary of current work is that we can completely exclude the hypothesis that "neutral" genetic variation in humans is explained entirely by past human population size. It simply cannot be true, because if it were, there should be strong signs of expansion that we do not in fact observe.

On the other hand, perhaps genetic data may tell us something about past human population size, even if population size is not the only explanation for genetic variation. We might expect that some demographic changes may have influenced genetic variation in distinctive ways that could be separated from the effects of selection. If so, then the results of the current paper may be relevant. If natural selection -- especially purifying selection -- explains most rare alleles at nonsynonymous coding sites, then perhaps the residue of rare alleles at synonymous or noncoding sites is a sign of recent changes in demographic patterns?

This possibility is suggestive, but it appears at present to be fairly far from the data. If unknown factors (which may include selection) have altered "neutral" genetic variation by an order of magnitude or more from their neutral predictions, then it is hard to believe that a relatively small change in population size will be accurately measured by any genetic observations.

References:

Eswaran V, Harpending HC, and Rogers AR. 2005. Genomics refutes an exclusively African origin of humans. J Hum Evol Online advance before print.

Gillespie JH. 2000. Genetic drift in an infinite population: the pseudohitchhiking model. Genetics 155:909-919.

Williamson SH, Hernandez R, Fledel-Alon A, Zhu L, Nielsen R, and Bustamante CD. 2005. Simultaneous inference of selection and population growth from patterns of variation in the human genome. Proc Nat Acad Sci USA 102:7882-7887. PNAS online

Orr (2005) considers the likelihood of the same mutants being fixed in two populations as a function of parallel selection, compared to drift. The model used is a very simple one, basically involving a single locus in each population with a limited number of advantageous mutants that may be presented to both populations.

The argument for the idea that beneficial mutations are limited is probably right:

Throughout this analysis, I make a major assumption: the number of beneficial mutations is small. This will almost certainly be true for two reasons. First, environments are autocorrelated through time, making it unlike [sic] that a previously highly fit wild-type allele would suddenly plummet in relative fitness; second, random changes in a functional protein are much more likely to worsen than to improve protein function (216).

The result of the paper is that parallel evolution is likely under such circumstances. This is not especially surprising, and the innovative aspects of the paper are the demonstration that this is true under many models of the distribution of fitnesses of mutations. The equations in the paper are derived from extreme value theory, with the basic theme being that the fittest possible new mutations are also the rarest, so these will preferentially be incorporated into populations.

Does this study apply to natural populations? Even most closely related populations typically differ in ecology in some respects, so it is hard to say that the model where mutations have the same fitness characteristics in two different populations is always relevant. Likewise, over the long term it is likely that a natural population will be as near to an optimum allele as is practicable. That is to say, the argument above that wild-type alleles are unlikely to plummet in relative fitness, carried to its logical extreme, would predict that any natural population of substantial size would already have had the opportunity to explore all the adaptive space available to it by recurring mutations.

Only in fairly unusual circumstances will populations be limited from achieving higher fitness (for any single gene) because mutations don't occur often enough. Instead, they will be limited by the fact that the mutations that do occur are never more adaptive than the current wild-type. The unusual circumstances would include cases in which the adaptive landscape really is complex; for example, where the phenotypic characters influenced by the gene are themselves subject to complex patterns of stabilizing selection. Here, the possibility for stepped advantages among many genes creates the opportunity for a progression of mutations. That is to say, many genes that interact with each other are all highly optimized and adaptive mutations at each of them are incredibly rare. But when an adaptive mutation occurs at one of these genes, it may shift the interaction in ways that make a new (perhaps recurring and previously neutral or deleterious) mutation at one or more of the other genes more likely to be adaptive. In this way, a highly polygenic trait might be mutation-limited in its evolution, while no individual gene can be said to be mutation-limited.

References:

Orr HA. 2005. The probability of parallel evolution. Evolution 59(1):216-220.