- Synopsis:A Prezi showing the results and methods for our poster at the AAPA meetings, April 2012.
I just want to note this study by Mark Christie and colleagues  because it is such a clear demonstration of powerful selection working on standing variants in association with domestication. Rachel Newer has a good description of the study in the New York Times Green blog. Here's the study's abstract:
We used a multigenerational pedigree analysis to demonstrate that domestication selection can explain the precipitous decline in fitness observed in hatchery steelhead released into the Hood River in Oregon. After returning from the ocean, wild-born and first-generation hatchery fish were used as broodstock in the hatchery, and their offspring were released into the wild as smolts. First-generation hatchery fish had nearly double the lifetime reproductive success (measured as the number of returning adult offspring) when spawned in captivity compared with wild fish spawned under identical conditions, which is a clear demonstration of adaptation to captivity. We also documented a tradeoff among the wild-born broodstock: Those with the greatest fitness in a captive environment produced offspring that performed the worst in the wild. Specifically, captive-born individuals with five (the median) or more returning siblings (i.e., offspring of successful broodstock) averaged 0.62 returning offspring in the wild, whereas captive-born individuals with less than five siblings averaged 2.05 returning offspring in the wild. These results demonstrate that a single generation in captivity can result in a substantial response to selection on traits that are beneficial in captivity but severely maladaptive in the wild.
We have few cases of new or recent domestication, so this kind of experiment is hard to do in other contexts. Also, in this case the selection is "natural-looking", imposed by the captive environment in some way, instead of directly applied by culling undesirable individuals. In most cases of mammal domestication, the wild relatives are either now vanishingly rare, or have been potentially influenced by introgression from the domesticated population. But I think it's reasonable to hypothesize that the additive variation in behavioral traits in wild populations is large enough to have allowed early mammalian domesticates like dogs and horses to adapt to captivity almost as fast as the salmon. Notice that the key element here is high reproduction in captivity, and in the salmon that trait covaries negatively with success in the wild.
Domestication may not have been a "hump" that humans brought wild animal populations over; it may have been a valley that trapped once-wild animals into dependence on humans.
- . Genetic adaptation to captivity can occur in a single generation. Proceedings of the National Academy of Sciences of the United States of America. 2011 .
My graduate student Marc Kissel and I are putting on a poster today at the AAPA meetings. Marc has prepared a nice PDF of the poster and we're putting it here for people to have access after and beyond the meeting. Thanks to the magic of QR codes, we're able to direct people to this page from the poster itself, so welcome!
It's scaled giantly at the moment and I'll work on finding a way to decrease the zoom level. But it will download and display fine on any PDF viewer. Enjoy!
I keep seeing people, who really ought to know better, saying that the new Neandertal genome results show that the gene flow must have been Neandertal men mating with modern human women, and not the other way around.
You see, they're fixated on the idea that the mtDNA showed no signs that the Neandertal clade survived into the present-day population. That result really convinced some people that interbreeding was impossible. They're flummoxed that some of the rest of the genome has significant signs of intermixture. It's like their world is spinning out of control. I'm not naming any names, but if you've followed much of the press around the Neandertal genome, you've probably seen this suggestion.
I don't know why it hasn't occurred to them that the Neandertal mtDNA type was probably lost because of natural selection.
To avoid raising the awful specter of Darwin, they've been talking about weird mating restrictions. Well, I suppose that if you really have to find a way to get Neandertal nuclear genes into us, without bringing mtDNA along, a total lack of Neandertal women contributing genes is formally one way to get that.
I'd just like to see these people explain how exactly we managed not to get any Neandertal Y chromosomes, either.
Is it safe to talk about selection, now?
UPDATE (2010-05-11): A reader writes:
With regard to your latest blog post on lack of neanderthal mitochondrial and Y chromosome DNA in humans: yes, it's possible natural selection had a part. However, given that only a small proportion of our ancestors seem to have been neanderthals at the appropriate time, it strikes me that this is a case where drift could be the correct explanation - despite the fact that I'm usually not a big fan of drift as an explanation.
Much depends on the size of the ancestral population and the pace of population growth in the generations surrounding the pickup of Neandertal genes. Drift is less likely to eliminate alleles in a growing population, but it depends how many copies there were to begin with. The key questions -- where and when the population was growing -- are unlikely to be the same as assumed by the modeling that showed drift couldn't have eliminated the Neandertal mtDNA, as most assumed the location of contact would be Europe and the time would be late.
There were other deficiencies with the modeling, also. Here we've been working on a source-sink model as a possible demographic scenario for Pleistocene humans; that kind of metapopulation dynamic might easily explain allele losses without selection, and becomes more and more credible as we learn the variance of contribution of Neandertal-like alleles across the genome. It's a different world this week than last week.
These are all mathematically tricky answers, clever, but academic unless we have good matches to genome-wide variation. Meanwhile a very simple answer, easy to explain to anyone, lies fallow. Exceedingly curious.
I'd be happy to be proven wrong about the Y chromosome, by the way -- we don't really know that Neandertals didn't have a human-like type, although we do now that today's human population has an exceedingly recent coalescent time. Could be bad estimates of mutation rate. Maybe we'll have more surprises in store.
It is often claimed that ancient genes that were once very adaptable are discarded over time by drift, bottle necks etc. What if an ancient trait were again valuable as climate swings or other environmental opportunites and are now again favorable. My point is that if an organism, especially in a variable climate, that carried this gene would be at a selelctive advantantage if that trait were inherited. The inheritable “trait” being the ability to retain ancient DNA. Also, this trait could be inherited in pieces spread over more than one organism, which are recombined through hybridization with the same results.
The most basic version of this is frequency-dependent polymorphism. Suppose that an allele is useful when rare, and harmful when common. Over the long term, it will never approach fixation, but nor will it become extinct unless the advantages are weak relative to the size of the population.
Now, suppose that the allele is advantageous only some of the time, and otherwise neutral. Now it can drift to fixation. If the times when it is useful are far enough apart, it can drift to loss. But anytime the environment is favorable for the allele, it will get a little boost. The tendency will be toward fixation, biased just to the extent of the strength of selection and duration of the favorable time intervals.
OK, add another element of complexity. The allele is favored during some intervals, and disfavored during others. Motoo Kimura described the dynamics of this scenario; the ultimate fate of the allele depends on the duration of the time intervals, of course, and may lead to an unstable polymorphism, fixation or loss.
You propose a "reserve" mechanism, where the genome holds on to old variants to resurrect them at some later time when they become useful.
Of course, we potentially have such a mechanism now, as we can dig up ancient DNA and experiment with it in vivo. But you suggest that a reserve of ancient genetic material might be adaptive.
I believe the dynamics of such a mechanism would be the same as if the population were merely larger. In that case, drift (and selection against recessives) would be much slower to eliminate alleles that had lost their advantage. So when the environment changed, the population could respond more quickly without waiting for the old variants to reappear by de novo mutations.
Also, a larger population makes it much more likely for mutations to happen.
There's no evidence that a store of ancient genetic variants lie silent in our genomes, but I think you might look at actual gene silencing mechanisms as a parallel to your suggestion. We do retain functional genes within our genomes that we turn off by methylation early in development. The genes either act early in development, are imprinted by maternal or paternal origin, or are turned off in tissues that don't need them. That's a way of maintaining variations for use in some circumstances but not all.
I cannot say enough about Ewens' book, Mathematical Population Genetics. If you can work through it, you can do population genetics. It doesn't cover every au courant topic, but those will change next week anyway. And it's on Kindle now. Which I suppose probably looks pretty good on the DX, assuming the math displays well -- the book's format is just the right size for it.
Anyway, this interview from 2004 was probably conducted around the time the book was released. It covers pretty much the gamut of his career. I have to select some part to quote for you, so I'll select the passage that would be most likely to come out of my own math in my genetics class:
WE: Of course there is a strong possibility that the neutral theory is assumed not because it is appropriate but because the math of that theory is so very simple compared to the math applying for any selective theory.
AP: Can I follow that up? Do you think that that has lead to models of phylogenetic change that is not very well supported by the evidence?
WE: I think that that is quite possible. However, here we enter into another question. In mathematical population genetics theory you know from the very start that you are making big simplifying assumptions. You are in a very different position from a physicist, who might believe that his mathematical models describe reality exactly. No sensible population geneticist would make any claim along those lines. He or she is forced to simplify, because reality is so complicated that you don’t know it in any detail, and even if you did know it and used math describing it faithfully, the analysis would be impossible to carry through. So simplification is unavoidable. I do not know whether the use of the neutral theory is too much of a simplification and has lead us to incorrect and distorted views about the true evolutionary tree, it’s shape and dimensions, but I suspect that there has been quite a significant distortion.
There is much more at the link, some history of association testing, genetic draft, a lot on Ewens sampling theory, and a touch about his work here in Madison.
This is a doofy story running on MSNBC without an author byline: "Shrinking of Scottish sheep tied to warming". Why do I say "doofy"? Take a look at the way it describes natural selection:
The study upends the belief that natural selection is a dominant feature of evolution, noting that climate can trump that card.
"According to classic evolutionary theory," [study author Tim] Coulson added, the sheep "should have been getting bigger, because larger sheep tend to be more likely to survive and reproduce than smaller ones, and offspring tend to resemble their parents."
Yes, and classic evolutionary theory also says that if you stop killing the small ones, the population average is going to get smaller. Duh. A reduction will happen in a single generation as small individuals remain to become adults who would otherwise have been removed. The reduction may continue for a few generations, either by chance, or by changing the environmental component of variance in size. It can go on for many generations if there is a heritable component to size that confers a disadvantage on the largest individuals. Plausibly, larger individuals take longer to develop, there may be advantages to smaller size in females that are no longer opposed as strongly by antagonistic selection for larger size in males, or any number of other possibilities.
Has climate "trumped natural selection"? No. Cold and consequent food scarcity in this case is one cause of selection (killing small lambs). Possibly, one or more causes of stabilizing selection remain in force (maybe longer development time, but there are other possibilities). Or maybe not. Climate change has caused a change in the pattern of selection, by relaxing selection against small individuals who would otherwise have died from food scarcity.
The way the article describes selection is an old-time fallacy -- "survival of the fittest" is recast as "survival of the strongest", where strongest means "biggest". If the small are somehow fail to be eliminated, then natural selection is failing at its work. It's the eugenic fallacy, brought to 21st century climate change. It makes an eye-catching headline -- "Climate Change Overpowers Natural Selection". But it's false.
A more accurate headline would be "Wee Lambs, Once Doomed to Starve, Saved by Climate Change"
I happen to have been reading some of the earlier research on these sheep, so I know that the work is interesting because researchers actually know about the fitness outcomes for individuals across their study duration. The observed fitness outcomes indicate that larger individuals have more offspring within each generation, but the population nevertheless became smaller over time. That comes down to viability of small young individuals and the non-heritable (environmental) component of variance in size, in a fairly complicated way. I'll revisit the paper later to describe the study more fully. I just wanted to point out that this news story gets it totally wrong. Climate change is one of the big causes of the pattern of natural selection, it doesn't magically repeal it.
Elliott Sober's book, The Nature of Selection, discusses the philosophical underpinnings of evolutionary explanation in relation to other sciences. I turn to it once in a while when I need to sharpen a definition, and today ran across this passage (p. 50-51):
The source laws of physical theory have the austere beauty of a desert landscape. Just four types of force are recognized, and some scientists hope to make this list even shorter (Davies 1979). By contrast, the theory of natural selection exhibits the lush foliage of a tropical rain forest. The physical circumstances that can generate fitness differences are many. Perhaps someday these will be regimented and reduced in number. But at present evolutionary theory offers a multiplicity of models suggesting a thousand avenues whereby the morphology, physiology, and behavior of organisms can be related to the environment in such a way that a selection process is set in motion.
I was reading through an excellent review of the recent literature about mtDNA and selection, from Damian Dowling and colleagues (2008). The review focuses on the patterning of evidence for selection in ecological and phylogenetic terms, and to some extent upon the function of mtDNA or the mito-nuclear complex of proteins involved in oxidative metabolism. It includes a long passage covering the significant mismatch between mtDNA variation and effective population sizes across animals (but not mammals). A short section discusses the possibility of adaptive polymorphism maintained by mito-nuclear interactions:
Knowing that deleterious mutations in mtDNA can accumulate within populations because of genetic drift , there certainly seems to be scope for mito-nuclear co-evolution to proceed via a ‘compensatory’ model. Under this model, deleterious mutations accumulate in the mitochondrial genome, with selection then favouring an adaptive response in the nuclear genome to restore any compromised metabolic function . In effect, mtDNA mutations will act as the drivers of adaptive evolution in nuclear genes. This scenario is not unlikely, given that more than 1000 nuclear-encoded proteins, which are essential for metabolism, are transported into the mitochondrion .
Additionally, given that at least some mtDNA polymorphism might have been shaped via positive selection  and , scope might also exist for mito-nuclear co-evolution to proceed via a model in which adaptive mutations in one genome select for a response in the other.
There has been recent interest in the coinheritance of sex chromosomes and mtDNA. Because the sex-determining chromosome is opposite in birds from mammals, a number of natural experiments may be available to examine the role of coevolution for the mtDNA and co-inherited sex chromosomes. Further, a number of studies have identified a substantial cytoplasmic contribution to fitness and lifespan variance in Drosophila, suggesting that adaptive variation in mtDNA may be segregating within populations.
The review discusses the possible importance of the adaptive perspective for aspects of biology ranging from life history and aging to speciation (where fast-evolving mtDNA genes may induce hybrid incompatibilities). And sperm are a surprising focus of research -- mtDNA mutations affect motility, fertility, and the outcome of sperm competition. On that topic, more later.
Dowling DK, Friberg U, Lindell J. 2008. Evolutionary implications of non-neutral mitochondrial genetic variation. Trends Ecol Evol 23:546-554. doi:10.1016/j.tree.2008.05.011
Fed up on hobbit news? Well, I'm going to do my best this week to scoop the science journalists, covering stories in paleoanthropology that ought to get some more attention but might be drowned out by otherwise hobbitrocious stories.
I'll start with a story in which I have a special interest -- a new paper by Jeff Wall, Kirk Lohmueller, and Vincent Plagnol, titled, "Detecting ancient admixture and estimating demographic parameters in multiple human populations."
A couple of years ago, Wall and Plagnol (2006) looked at a sample of genes in the "Environmental Genome Project. At that time, the sample consisted of 135 genes in 12 Yoruba and 22 CEPH individuals. It's not a large sample by today's 3.9-million genotype standards. But the EGP sample has one important thing going for it -- with resequencing data, we have access to a much larger number of mutational differences at very small map distances from each other. Tight linkage between sites means that we can use the genealogical properties of samples to examine much more ancient events. The HapMap gives us a vast number of genotypes from a large sample of individuals, but the density of loci is quite low -- an average of nearly 1000 base pairs between loci. The EGP doesn't sample as many loci, but it gives a denser representation of the variation at each locus. Only this kind of sample is sufficient to test for genetic ancestry of modern human populations in ancient populations of the Middle Pleistocene.
Plagnol and Wall applied a simple admixture model to these data, and found that the complete out-of-Africa replacement model did not adequately explain the variation in the European-derived sample. Instead, they found that a model with 5 percent admixture of some non-African Middle Pleistocene ancestral population was a much better fit for the current diversity of European gene trees. In other words, the low variation of recent humans cannot be explained by a small population in a single ancient population; instead, there must have been several populations, partly isolated from each other, one or more of which gave regionally-specific alleles to modern Europeans. Multiregional evolution fits those observations very well -- this is not one or two introgressive genes, and there is no specific evidence of selection on them (although selection may be responsible).
A number of people picked up on that study in the course of later work. Gregory Cochran and I discussed it in our own 2006 paper about genetic introgression. In late 2005, Dan Garrigan and colleagues had published their own analysis of a pseudogene region on the X chromosome, called RRM2P4. Garrigan reviewed this work together with Mike Hammer (2006) and again with Sarah Kingan (2007). Early last year, I also reviewed the evidence together with Cochran, Henry Harpending and Bruce Lahn (2008).
We and many other people are following up on this research, trying to discover the ancestry of human populations beyond the simple out-of-Africa replacement scenario. In the new study, Wall and colleagues extend their analysis to a more recent release of the EGP, including 222 genes, and adding 24 Chinese individuals to the 12 Yoruba and 22 CEPH individuals. It's a simple paper and relatively short. In a word, they find that their data reject the simple out-of-Africa replacement scenario, and that the genetic variation of coding genes in their sample must be explained in part by long-standing population structure.
It's not proof that the Neandertals, or any other particular group of ancient humans, survived and passed their genes on to more recent people. This is a study of the genes of recent human populations, and it merely concludes that their ancestors could not have lived in a single small population. Maybe every Neandertal became extinct, and present-day Europeans got this genetic variation from somewhere else. But it is logical to figure that non-Afircan populations may have been among the contributors to present non-African peoples -- particularly since the statistical test focuses on region-specific gene frequencies. The study also finds evidence that today's African population has a complex ancestry -- a kind of multiregional scenario playing out inside Africa (or potentially involving gene flow back into Africa from elsewhere).
Testing for admixture
Wall and colleagues reasoned that an allele coming in from an ancient, partially isolated human population would vary in a distinctive pattern. Because of the long history of partial isolation in an ancient subpopulation, they expected that such an allele would come in with multiple mutational differences from the non-introgressive allele. And if it came in from some non-African population, it ought to show relatively strong differences in frequency between populations. So they devised a statistic, mathematically combining FST and a linkage measure -- the idea being to detect alleles that differentiate populations and that are surrounded by large sets of tightly linked polymorphisms.
This kind of pattern might also occur under positive selection. But a new mutation under positive selection would start out weakly linked to nearby polymorphisms, each of which already exists at some substantial frequency in the population. An introgressive allele might be linked to several other unique mutations that happened during the long period of limited gene flow between ancient populations. And a new mutation would not tend to be surrounded by high FST polymorphisms, until it got to be very common in the population -- up above 50 percent. In contrast, an introgressive allele coming into the population with several nearby mutations would generate a cluster of relatively high FST polymorphisms even at low frequencies. It may not be a perfect test for any individual locus -- there's a lot of uncertainty. But applied to more than 200 loci, it should be possible to test the hypothesis that "archaic admixture" is zero.
Wall and colleagues do test that hypothesis, and they are able to refute it strongly for each of the three groups. Living European and Chinese samples refute the out-of-Africa replacement model with p<0.01. The Yoruba sample refutes the hypothesis of panmixia in ancient Africans at p<0.0000001.
The authors also provide a supplementary table with a list of genes that may be candidates for introgression. I didn't see any really obvious genes on the list, but each of them bears some examination. I expect that we will be able to use more detailed analytical techniques to look at the regions around these genes and see what is going on. Or at least, in the next couple of years more and more resequencing data will become available, allowing us to test the same hypotheses with larger samples.
It's worth pointing out that nothing in the approach of Wall and colleagues implies that any of the putative introgression occurred under natural selection. I've argued that introgression may have occurred under selection in ancient humans, but so far few other people have looked at the question with the idea of ancient selection in mind. No doubt we can improve a bit on the methods in the paper if we are willing to make some assumptions about the evolutionary dynamics involved in Late Pleistocene populations.
So what's not to like about this study? After all, here we have what appears to be strong evidence against an exclusive out-of-Africa replacement. It suggests that the ancestry of recent Europeans and Asians owes something to the Middle Pleistocene populations of those regions, and gives an estimate of that contribution consistent with what we know so far about the Neandertal genome.
But I have to approach this study as critically as I would any other piece of population genetics. In this case, there is a clear weakness to their model. The authors tested for significance of a single parameter, which they call "archaic admixture." Consider their Figure 1, a schematic of their population model:
Is "archaic admixture" significantly different than zero? Well, you can see that must depend on the values of no less than six other parameters. When did the European population start growing significantly -- was it after the Last Glacial Maximum? During the Neolithic? The Aurignacian? How about the African population? Was there really a long bottleneck in the ancestry of Europeans?
The reason why I'm so critical of population models used in genetics is simple. The authors of studies almost never try to make the simplest effort to justify these kinds of parameters against the archaeological or fossil record. Their conclusions -- in this case, the significant finding of ancient admixture -- depend on some range of values for these other parameters.
Now, Wall and colleagues take a fundamentally different approach than I would use. I would draw upon non-genetic sources of information about these parameters, to increase confidence about the others. In contrast, they performed a broader range of simulations, attempting to find maximum likelihood estimates for all the parameters simultaneously.
The problem with that approach is that it's hard to say that some other parameters may not have been more important. Consider recent positive selection. As I mentioned above, a recent positively selected mutation could in principle create a pattern like that described for an introgressive allele -- at least under the statistics used in this paper. The chances are low for any randomly chosen mutation under positive selection, because a new positively selected mutation isn't likely to be linked to other rare mutations -- it's much more likely to be linked to common polymorphisms. But if we actually have many hundreds, or even thousands, of recently selected alleles (as we do in humans), then there is a pretty good chance that some of them will look like introgression under the test used here. Another scenario that could mimic introgression under this statistical approach is long-standing balancing selection.
There are probably too many genes on these lists for all of them to reflect selective balances or recent positive selection -- there are a lot of recently selected genes, but few of them will have the specific kind of linkage that would show up as significant in this study. But I think the authors could do more to validate the demographic model against non-genetic evidence. Besides that, there is plenty of morphological evidence for gene flow among these ancient human populations. The authors would be well-served to work more directly with the morphological record of human evolution -- when they write that:
To our knowledge, the question of ancient admixture in other parts of the world has been relatively neglected by the evolutionary genetics community
it is both true and sad. There is abundant anatomical evidence addressing the issue of genetic continuity or gene flow in parts of the world other than Europe.
UPDATE (2009-05-08): Dienekes also looks at the paper, and suggests that finding evidence for ancient population structure in Europe and East Asia may be no big deal, because it may simply derive from population structure within Africa before the putative out-of-Africa migration. I'd have to review the data to be sure, but it seems to me there are two arguments against that explanation:
1. The East Asian and European comparisons come up with different genes showing evidence of putative introgression. There's not a lot of overlap between the sets. If this were merely ancient East African genes, we'd expect the populations outside Africa to have the same ones. And the numbers had actually been cut down by the serial founder effect scenario (Chinese having undergone more and larger bottlenecks), then we'd expect China to have a subset of the European introgressive genes. I wouldn't go out on a limb about this without looking at the actual frequencies of the supposed ancient alleles, but the pattern isn't consistent with Europe and China being drawn randomly from the same ancient African population.
2. The entire point of the out-of-Africa replacement idea is to draw humans from an unstructured ancient population. Humans have to be inbred to explain the low genetic variation today. A long bottleneck in Africa is one explanation for this inbreeding -- but the bottleneck has to have been severe, down to an effective size around 10,000, and it has to be very long. A long history of population structure within Africa works against that bottleneck -- population structure featuring several partially isolated populations would prevent the kind of inbreeding that a long bottleneck could create. If Wall and colleagues are correct, we would have to scrap the long bottleneck idea and come up with some other explanation for high inbreeding. There are some others, as I've pointed out before.
There are other arguments against exclusive continuity outside Africa, and in favor of some significant -- perhaps overwhelming -- gene flow from Africa into the rest of the world during the late Pleistocene. But no other argument is exclusive of some continuity outside Africa. And if we don't need the bottleneck anymore, accepting some continuity is the reasonable explanation for the facts that don't fit, including the observations in this paper and the morphological and archaeological evidence suggesting continuity.
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