recent selection

Alon Keinan and David Reich [1] have tested an obvious prediction of the hypothesis that recent selection has had a major effect on variation across the genome, and in doing so have provided some strong support for our hypothesis of a recent acceleration.

A new mutation that increases rapidly under positive selection will carry with it a lot of nearby variants that are physically linked to it. The region of this "genetic hitchhiking" will depend on the local rate of recombination -- the lower the recombination rate, the longer the extent of the hitchhiking region.

Meanwhile, a new mutation takes a while, sometimes many thousands of years, to spread widely beyond its population of origin. We can measure population differences for a single locus as F_ST. The F_ST attained by a new selected variant depends on what frequency it has reached in different populations. For many selected alleles, they have not yet attained high frequencies anywhere, and so F_ST is low. But for a few, the selected variant has reached a high frequency in a few populations, but remains rare elsewhere. These are recognizable as high F_ST loci.

What is true of the selected allele itself will also be true, to a lesser extent, of the linked haplotype that is hitchhiking along with it. And so, if selection has been sufficiently common in recent human history, there should be a relationship between the local rate of recombination and measures of population differentiation like F_ST.

Which is exactly what Keinan and Reich found.

Further, they found that this relationship is true of regions of the genome that contain a lot of coding loci, and much less true of gene-poor regions:

We cannot envision any demographic or mechanistic explanation that would produce a correlation between recombination rate and allele frequency differentiation as observed and we hypothesize that our observations reflect a history of natural selection. Natural selection is usually expected to increase population differentiation at linked neutral sites, an effect that is expected to extend over longer physical distances in regions of lower recombination rate. A prediction of an explanation based on natural selection is that the effect would be more marked in regions that are more likely to be influenced by selection, such as genes.

The observed F_ST in these categories is not super-high -- we're not looking predominantly at genes for which more than 20 percent of the variation is the between-population component. Therefore, the comparison can encompass quite a bit more of the selected variation in the genome, instead of the extremely stringent cutoffs required to identify an individual candidate gene. It's a bit like getting a measure of wind speed as opposed to looking at the few highest-flying kites.

Perhaps the most interesting aspect of the study is that they compared the Phase 3 HapMap samples, which include some pairs of nearby populations. They found that the apparent effect of selection on population differentiation was much higher for those nearby pairs of populations:

In addition to qualitatively replicating our findings, analysis of HapMap 3 data allows us to generalize them to additional populations. A striking result is that the relationship between FST and recombination rate is stronger for FST between pairs of closely-related populations, whether within or outside Africa: FST between a West African sample and Maasai (of mixed West African and East African ancestry [57]) decreases by an average of 6% for every 1 cM/Mb (Figure 4D), FST between Italians and individuals of North-Western European ancestry decreases by 10% for every cM/Mb (Figure 4E), and FST between Japanese and individuals of Chinese ancestry decreases by 4% (Figure 4E). In view of the large effective population size in recent human history since each of these pairs of populations have split, these observations support the possibility that the different patterns observed between different pairs of populations are due to natural selection operating more efficiently in the context of larger population sizes.

That's a direct sign, in other words, of the recent acceleration of positive selection in human populations. There are a lot more genes that are geographically circumscribed and low in frequency affecting F_ST at a more localized level, and fewer affecting major allele frequencies between continental regions. It's a neat comparison, and it helps to answer the comment that selection is somehow "weak", or insignificantly different from drift, because the new selected alleles haven't spread very far. The point is, most of them are so new that they haven't had time to disperse widely and reach appreciable frequencies very far from their origins.

UPDATE (2010-03-28): A reader pointed out an error in the post; I had written "lower" recombination rate at one point that should have been "higher". I have corrected the text.

References

Time has a story about Stephen Stearns and colleagues' work characterizing ongoing selection using the Framingham Heart Study sample:

If these trends were to continue with no cultural changes in the town for the next 10 generations, by 2409 the average Framingham woman would be 2 cm (0.8 in) shorter, 1 kg (2.2 lb.) heavier, have a healthier heart, have her first child five months earlier and enter menopause 10 months later than a woman today, the study found. "That rate of evolution is slow but pretty similar to what we see in other plants and animals. Humans don't seem to be any exception," Stearns says.

I haven't had a chance to see the new study yet, and I'll do a little review when I get it. Jerry Coyne has some more information based on a preprint.

My students have heard me say many times that it would take a sample of thousands of people to test the hypothesis of neutrality within today's population. Well, Framingham is one such sample, and it's not surprising that some things would be found significantly to affect fitness.

The Time article mentions our work on recent evolution in a very positive way. Of course, the Framingham sample isn't suitable for testing what has been going on during the last 40,000 years; it is about mass selection on phenotypes in the present American population. That will involve mostly selection on standing variants, things that are already common in the population. Some of those may be things that were increasing in the past, others not -- some may even be reversals in direction compared to pre-industrial times. And there's no predicting how they might change in the future, as we continue to change our environment out from under ourselves.

I've seen a few comments that we shouldn't trust the sample because it's unrepresentative, too small, etc. I think people may be overlooking the fact that the Framingham Heart Study is bigger than the census sizes of many species in nature. You can detect selection on phenotypes in this sample, and they surely know the heritabilities of many of them. But I'll have to see the paper.

François Balloux (2009) has a polemic in the online access area of Heredity presenting references about mtDNA selection, and arguing that the use of this single genetic marker is no longer warranted without support from other loci.

Yay! I've been saying that both here, and in peer-reviewed articles, for several years. I think serious workers know that one gene is not enough; two genes (mtDNA and Y chromosome, for example) aren't enough -- we have to integrate information across every possible source, genetic, skeletal, and anthropological, to really test hypotheses about the past.

Still, an industry of mtDNA sequencing has grown up, reviewing each others' grants and papers, and shutting down any discussion of adaptive changes. Balloux's commentary addresses this problem -- I'm going to quote the same paragraph as Dienekes:

Let us assume I gave a seminar. I would tell the audience about my latest results on the population history of the pigmy shrew. My findings would be based on a stretch of DNA comprising several metabolic genes, showing no signs of genetic recombination. Armed with sequences from a large number of individuals sampled over a broad geographical area, I would make some inference on the colonization routes and times. To make life easier, I would restrict my analysis to the mutations I liked best, with nice names having been given to related sequences, rather than relying on dull mathematical quantities. As I reach one of the key conclusions of the lecture, which would go as follows: 'It is obvious from the distribution of haplotypes Amanda, Eugenie* and Hector_2 that the Outer Hebrides were colonised about 50,000 years ago, this was followed by considerable population fluctuations, a bottleneck during the last Ice Age, a swift recovery and a dramatic recent expansion over the last 200 years and...'. Imagine that, at that climactic stage I was interrupted by someone in the audience. The impertinent would say, 'Sir, can I just ask you whether this confidence in your conclusions may not be misplaced; your analysis is based on a single genetic marker, which comprises genes with a central role in metabolism and is thus likely to have been affected by natural selection'. An awkward silence may ensue, as I would find it difficult to dismiss this criticism easily.

Well, let me tell you, I've been in dozens of audiences, and have raised that exact point. Here is a sample of the bogus responses I've gotten to this question:

Bogus answer 1: There are no functional differences between humans and chimpanzees in the mtDNA, so it can't have been selected during human evolution. False, false false!

Bogus answer 2: Metabolic processes are highly conserved, and humans couldn't have changed much. Hello? Have you noticed that your breakfast didn't exist in the Paleolithic?

Bogus answer 3: But the pattern of variation can be equally explained by a bottleneck. Some aspects can, others can't so easily.

Bogus answer 4: We examined only noncoding parts of the mtDNA, so there could be no selection. Yes, believe it or not, this is the most common response. I guess they don't teach people about linkage anymore.

Bogus answer 5: There's little or no evidence of selection on any gene in recent human evolution. Human evolution may have stopped entirely. Oh, lord. Yes, I've gotten this one many times.

There have been others over the years. Yet mtDNA is a big business -- people seem to be worried that the slightest criticism will bring down the whole thing like a house of cards. That's not true, even if mtDNA has sometimes been selected during human prehistory or history, that doesn't mean it isn't a useful marker for many purposes. But many seem more comfortable avoiding the issue entirely.

I think that taking the hypothesis of selection seriously would improve most of the work in this field. The possibility of selection doesn't eliminate demographic interpretation -- for example, the high ancient African mtDNA variation allows us to test hypotheses about African demography before 50,000 years ago, and there the data appear to reject the hypothesis of selection, at least after around 150,000 years ago. Gene genealogies don't allow us to see the whole past, just the time and forces that they experienced. If we ignore one of the major forces, we are reducing our knowledge.

There is an obvious problem testing the hypothesis of selection with mtDNA. When we consider any one single locus, it's always possible to find some demographic scenario that yields exactly the same predictions as selection. It's just a mathematical necessity -- selection is fundamentally a demographic phenomenon, and the increase in frequency of selected alleles looks similar to exponential growth of a small population.

So what can we do? Fortunately we have lots of options. We can test the proposed demographic hypotheses against the historical record. When we make observations that show that people 1000 years ago had very different frequencies of common haplotypes, well, we know it was selection. There hasn't been any genetically significant bottleneck in the last 1000 years! When we see small Neolithic population samples dominated by haplotypes that are very rare today, again, no historically possible bottleneck could have caused that.

Balloux with his colleagues (2009) has shown that one aspect of mtDNA patterning -- the association of haplogroup diversity with geography -- is very unlikely to have arisen by genetic drift. Here's part of their abstract:

We show that populations living in colder environments have lower mitochondrial diversity and that the genetic differentiation between pairs of populations correlates with difference in temperature. These associations were unique to mtDNA; we could not find a similar pattern in any other genetic marker. We were able to identify two correlated non-synonymous point mutations in the ND3 and ATP6 genes characterized by a clear association with temperature, which appear to be plausible targets of natural selection producing the association with climate. The same mutations have been previously shown to be associated with variation in mitochondrial pH and calcium dynamics. Our results indicate that natural selection mediated by climate has contributed to shape the current distribution of mtDNA sequences in humans.

They took a dual approach to testing the hypothesis of selection. First, they modeled the evolution of haplotype diversity under neutrality, and showed that the empirical distribution lies significantly outside that range of results. But even so, we might imagine some bottleneck scenario that would cause low diversity in high-latitude peoples, and this would be difficult to refute historically because many of those populations have poor historical documentation. But demography should have similar effects on other genes, and they were able to show that the rest of the genome doesn't share the mtDNA pattern.

It's really not that hard to test demographic hypotheses, using comparative genomics and anthropological knowledge. That's what anthropological genetics should be doing more and more. There was a time when obtaining a reasonable sample of mtDNA was an accomplishment, and comparing that sample to other genes was not feasible. But that time is past, and hopefully the review process -- journals and grants -- will start demanding some integration of mtDNA phylogeography with results from the rest of the genome.

Back to Balloux's conclusion:

Exploiting these new resources of autosomal variation will present significant challenges, but it will not help overcoming them if a large fraction of the community of human population biologists persists in sticking to mtDNA as the marker of choice.

Mitochondrial DNA isn't the tip of the iceberg -- it's an ice cube on top of the tip of the iceberg.

Related:

"Mitochondrial DNA selection review"

"Mitochondrial DNA and sperm"

"mtDNA selection in Iceland?"

"Complete Neandertal mitochondrial sequence, and selection on human (not Neandertal) mtDNA"

"Did Neandertals need better mitochondria?"

"Has the dam broken on mtDNA selection?"

Mitochondrial DNA adaptations in living human populations"

OK, that's enough related posts. But you can find a whole lot more by searching the topic!

References:

Balloux F. 2009. Mitochondrial phylogeography: The worm in the fruit of the mitochondrial DNA tree. Heredity (advance online): doi:10.1038/hdy.2009.122

Balloux F, Lawson Handley L-J, Jombart T, Liu H, Manica A. 2009. Climate shaped the worldwide distribution of human mitochondrial DNA sequence variation. Proc Roy Soc Lond B 276:3447-3455. doi:10.1098/rspb.2009.0752