In the post below I alluded to the views of R. A. Fisher. This was a moderately dangerous move on my part because many of Fisher’s views have been transmitted only through later researchers, who may have lacked a clear understanding of what Fisher himself was trying to say. Heap on top of that the reality that the debate between Fisher and Sewall Wright was often abstruse for the evolutionary biologists who nevertheless managed to take sides and transmit their understandings of the conflict, and it’s a recipe for misrepresentation. With that in mind let me enter into the record an email from a friend who has engaged in a deep reading of Fisher, and attempted to understand his reasoning (no, this is not A. W. F. Edwards!):
A few days ago I was browsing Haldane’s Sieve,when I stumbled upon an amusing discussion which arose on it’s “About” page. This “inside baseball” banter got me to thinking about my own intellectual evolution. Over the past few years I’ve been delving more deeply into phylogenetics and phylogeography, enabled by the rise of genomics, the proliferation of ‘big data,’ and accessible software packages. This entailed an opportunity cost. I did not spend much time focusing so much on classical population and evolutionary genetic questions. Strewn about my room are various textbooks and monographs I’ve collected over the years, and which have fed my intellectual growth. But I must admit that it is a rare day now that I browse Hartl and Clark or The Genetical Theory of Natural Selection without specific aim or mercenary intent.
Like a river inexorably coursing over a floodplain, with the turning of the new year it is now time to take a great bend, and double-back to my roots, such as they are. This is one reason that I am now reading The Founders of Evolutionary Genetics. Fisher, Wright, and Haldane, are like old friends, faded, but not forgotten, while Muller was always but a passing acquaintance. But ideas 100 years old still have power to drive us to explore deep questions which remain unresolved, but where new methods and techniques may shed greater light. A study of the past does not allow us to make wise choices which can determine the future with any certitude, but it may at least increase the luminosity of the tools which we have iluminate the depths of the darkness. The shape of nature may become just a bit less opaque through our various endeavors.
The Pith: Natural selection comes in different flavors in its genetic constituents. Some of those constituents are more elusive than others. That makes “reading the label” a non-trivial activity.
As you may know when you look at patterns of variation in the genome of a given organism you can make various inferences from the nature of these patterns. But the power of those inferences is conditional on the details of the real demographic and evolutionary histories, as well as the assumptions made about the models one which is testing. When delving into the domain of population genomics some of the concepts and models may seem abstruse, but the reality is that such details are the stuff of which evolution is built. A new paper in PLoS Genetics may seem excessively esoteric and theoretical, but it speaks to very important processes which shape the evolutionary trajectory of a given population. The paper is titled Distinguishing between Selective Sweeps from Standing Variation and from a De Novo Mutation. Here’s the author summary:
Considerable effort has been devoted to detecting genes that are under natural selection, and hundreds of such genes have been identified in previous studies. Here, we present a method for extending these studies by inferring parameters, such as selection coefficients and the time when a selected variant arose. Of particular interest is the question whether the selective pressure was already present when the selected variant was first introduced into a population. In this case, the variant would be selected right after it originated in the population, a process we call selection from a de novo mutation. We contrast this with selection from standing variation, where the selected variant predates the selective pressure. We present a method to distinguish these two scenarios, test its accuracy, and apply it to seven human genes. We find three genes, ADH1B, EDAR, and LCT, that were presumably selected from a de novo mutation and two other genes, ASPM and PSCA, which we infer to be under selection from standing variation.
The dynamic which they refer to seems to be a reframing of the conundrum of detecting hard sweeps vs. soft sweeps. In the former you case have a new mutation, so its frequency is ~1/(2N). It is quickly subject to natural selection (though stochastic processes dominate at low frequencies, so probability of extinction is high), and adaptation drives the allele to fixation (or nearly to fixation). In the latter scenario you have a great deal of extant genetic variation, present in numerous different allelic variants. A novel selection pressure reshapes the frequency landscape, but you can not ascribe the genetic shift to only one allele. It is no surprise that the former is easier to model and detect than the latter. Much of the evolutionary genomics of the 2000s focused on hard sweeps from de novo mutations because they were low hanging fruit. The methods had reasonable power to detect them (as well as many false positives!). But of late many are suspecting that hard sweeps are not the full story, and that much of evolutionary genetic process may be characterized by a combination of hard sweeps, soft sweeps (from standing variation), various forms of negative selection, not to mention the plethora of possibilities which abound in the domain of balancing selection.
Many of the details of the paper may seem overly technical and opaque (and to be fair, I will say here that the figures are somewhat difficult to decrypt, though the subject is not one that lends itself to general clarity), but the major finding is straightforward, and illustrated in figure 4 (I’ve added labels):
One of the weird things about genetics is that it encompasses both the abstract and the concrete. The formal and physical. You can talk to a geneticist who is mostly interested in details of molecular mechanisms, and is steeped in structural biology. For these people genes are specific and material things. In contrast there are other geneticists who focus more on genes as units of analysis. In this case genes are semantic labels for the mediators within an intersection of phenomena. Recall that genetics predates the knowledge of its concrete substrate by 50 years! By the 1920s Mendelian genetics had been fused with evolutionary biology to create a systematic framework in which we could understand the patterns of inheritance across the generations. In the 1950s the DNA revolution was upon us, but as W. D. Hamilton recalls this had only a minimal impact on the evolutionary genetic thinkers of the era. With the Lewontin and Hubby allozyme paper in the mid-1960s this sort of benign disciplinary evasion was no longer possible; the field of molecular evolution came into its own.*
Today with genomics these human-imposed artificialities are fading away. Consider the concept of genetic recombination. Originally an abstraction in a formal Mendelian system, today it is of great interest to molecular biologists who are curious as to its exact mechanism and purpose, and genomicists who are interested in the constraints upon the phenomenon due to its physical parameters (e.g., recombination hotspots). If we were to discover alien beings I assume that there would be some sort of genetics in an abstract sense. But would they package their genes in chromosomes? Would their complex organisms tend toward dioecy? I wouldn’t be surprised if the genetics of alien species have their own particular kinks subject to the contingent nature of the physical scaffolding of the process.
Implicit in the title The Origin Of Species is the question: why the plural? In other words, why isn’t there a singular apex species which dominates this planet? One can imagine an abstract system where natural selection slowly but gradually sifts through variation and designs a best-of-all-replicators. And yet on the contrary it seems that our planet has exhibited an overall tendency of going from lower to higher diversity. The age of stromatolites may be the last epoch when we had the best-of-all-replicators.
Sad news. John Hawks passes along that James F. Crow has died. Further mention from the National Center For Science Education. A little over 5 years ago I sent Crow an email with only minimal expectation of response, asking about an interview. He responded in less than 24 hours! I think it says a lot about the man that he would respond to sincere questions out of the blue from basically a nobody. Here is his Wikipedia entry. And remember that Genetics has commissioned a series of retrospective essays in Crow’s honor.
Genetics is powerful. The origins of the field predate Gregor Mendel, and go further back to plain human common sense. Crude theories of inheritance in the 19th century gave way in the early 20th to Mendelism, which happens to be a very powerful formal system for predicting the patterns of transmission of information from generation to generation. But I suspect that the popular accolades showered upon genetics would be more muted if it were not for the concrete discovery of the biophysical medium of that pattern of inheritance, DNA. By visualizing strands of DNA packaged into chromosomes one can gain a substantive understanding of Mendelian processes previously somewhat abstracted (e.g., recombination). In concert with the centrality of genetics at the heart of evolutionary science has been the ascendance of its methods in the older field of systematics. The phylogenetic tree is not only intuitive, but it has concrete reality in the sequences of base pairs or structural elements within the genome.
Whatever skepticism there might be about the dynamic phenomenon of evolution, the material aspect of modern genetics rooted in molecular biology is one of he primary wedges by which one can introduce an element of doubt into minds of a skeptic. The correlation between phylogeny and sequence identity of organisms which were previously adduced to exhibit some sort of biological relationship on the tree of life can not be dismissed out of hand. But this mode of thinking has limits, albeit due to the quirks of human psychology.
A friend pointed me to the heated comment section of this article in Nature, Rebuilding the genome of a hidden ethnicity. The issue is that Nature originally stated that the Taino, the native people of Puerto Rico, were extinct. That resulted in an avalanche of angry comments, which one of the researchers, Carlos Bustamante, felt he had to address. Eventually Nature updated their text:
CORRECTED: This article originally stated that the Taíno were extinct, which is incorrect. Nature apologizes for the offence caused, and has corrected the text to better explain the research project described.
Here’s Wikipedia on the Taino today:
“Is Evolution Predictable?” asks a piece in Science. Here’s the first paragraph:
If one could rewind the history of life, would the same species appear with the same sets of traits? Many biologists have argued that evolution depends on too many chance events to be repeatable. But a new study investigating evolution in three groups of microscopic worms, including the strain that survived the 2003 Columbia space shuttle crash, indicates otherwise. When raised in a lab under crowded conditions, all three underwent the same shift in their development by losing basically the same gene. The work suggests that, to some degree, evolution is predictable.
The “some degree” part is the catch. I’m a big fan of general ideas, but the more I learn about evolution the more suspicious I become of broad truths. A given dynamic often has some degree of validity, but extending it too far leads to error or confusion in innumerable specific cases. Evolution may be the most robust and powerful theory for deductive inference in biology, but even here rationalism has its limits. For example, before the rise of molecular methods in exploring polymorphism the debates as to the nature of genetic variation in natural populations tended to focus on outcomes based on adaptive pressures. One school followed R. A. Fisher and argued that polymorphism was strongly constrained by negative selection, with periodic bouts of genetic diversity at a given locus as a positively selected allele was in transience between ~0% and ~100%. Sewall Wright on the other hand suggested that balancing selection (e.g., frequency dependence, heterozygote advantage, environmental heterogeneity) would maintain polymorphism within a population. The logic in both cases was clear, crisp, and plausible. But it turned out that in a deep way the argument was in the “not even wrong category.” Neutral theory and its heirs pointed out, correctly it seems, that at the molecular level most variation was driven by non-adaptive forces such as random genetic drift. Though some thinkers had conceptualized the model in its broad outlines prior to the empirical results, it was the latter which crystallized the need for a robust model and marginalized the older debate centered around adaptation and natural selection. But even here neutrality is not a model to explain it all. There are cases where adaptation and natural selection are relevant. In some instances you see classical dynamics with transients generated by positive selection sweeping through populations, and in other cases balancing dynamics may be operative. The overall point is that we must always be careful about bald assertions of the form “the latest research overturns….” in this area. Evolution is such a sprawling and cosmopolitan intellectual empire. Nature is subtle and richly textured, and our conceptual frameworks map onto the shape of reality only coarsely.
As for the paper itself, it’s nice and elegant. Patrick Phillips, who knows a thing or two about evolution and elegans is quoted in Science as saying that “”It’s an amazing study….” The letter to Nature is Parallel evolution of domesticated Caenorhabditis species targets pheromone receptor genes. Here’s the abstract:
The Pith: The human X chromosome is subject to more pressure from natural selection, resulting in less genetic diversity. But, the differences in diversity of X chromosomes across human populations seem to be more a function of population history than differences in the power of natural selection across those populations.
In the past few years there has been a finding that the human X chromosome exhibits less genetic diversity than the non-sex regions of the genome, the autosome. Why? On the face of it this might seem inexplicable, but a few basic structural factors derived from the architecture of the human genome present themselves.
First, in males the X chromosome is hemizygous, rendering it more exposed to selection. This is rather straightforward once you move beyond the jargon. Human males have only one copy of genes which express on the X chromosome, because they have only one X chromosome. In contrast, females have two X chromosomes. This is the reason why sex linked traits in humans are disproportionately male. For genes on the X chromosome women can be carriers of many diseases because they have two copies of a gene, and one copy may be functional. In contrast, a male has only a functional or nonfunctional version of the gene, because he has one copy on the X chromosome. This is different from the case on the autosome, where both males and females have two copies of every gene.
This structural divergence matters for the selective dynamics operative upon the X chromosome vs. the autosome. On the autosome recessive traits pay far less of a cost in terms of fitness than they do on the X chromosome, because in the case of the latter they’re much more often exposed to natural selection via males. In the rest of the genome recessive traits only pay the cost of their shortcomings when they’re present as two copies in an individual, homozygotes. A simple quasi-formal example illustrates the process.
Update: John Hawks’ lab is working in the same area, and he disagrees with the specific results presented here. Always reminds you to be careful about sexy results presented at conference! (someone should do a study!)
So claimed Peter Parham at a Royal Society meeting last week, Human evolution, migration and history revealed by genetics, immunity and infection. You can actually listen to the talk by pulling down the mp3 file. To get the part about human evolution and introgression, jump to 24 minutes in.
Here is the general sketch: It looks like ~50 percent of the HLA Class I alleles in Europeans derive from Neandertals, ~70-80 percent of HLA Class I alleles in East Asians derive from Denisovans, and that and ~90-95 percent of HLA Class I alleles in Papuans derive from Denisovans. If you recall, ~2.5% of the total genome content of non-Africans seems to be Neandertal, while ~5% of the total genome content of Papuans seems to be Denisovan. The total genome content proportions are rough estimates, there may be some wiggle room in there. But you can see that the HLA allele admixture estimates from these ancient Eurasian lineages is greater by an order of magnitude. Why?
Physicists’ study of evolution in bacteria shows that adaptations can be undone, but rarely. Ever since Charles Darwin proposed his theory of evolution in 1859, scientists have wondered whether evolutionary adaptations can be reversed. Answering that question has proved difficult, partly due to conflicting evidence. In 2003, scientists showed that some species of insects have gained, lost and regained wings over millions of years. But a few years later, a different team found that a protein that helps control cells’ stress responses could not evolve back to its original form.
Here are the primary results:
Last summer I made a thoughtless and silly error in relation to a model of human population history when asked by a reader the question: “which population is most distantly related to Africans?” I contended that all non-African populations are equally distant. This is obviously wrong on the face of it if you look at any genetic distance measures. West Eurasians, even those without recent Sub-Saharan African admixture (e.g., North Europeans) are closer than East Eurasians, who are often closer than Oceanians and Amerindians. One explanation I offered is that these latter groups were subject to greater genetic drift through a series of population bottlenecks. In this framework the number of generations until the last common ancestor with Sub-Saharan Africans for all groups outside of Africa should be about the same, but due to evolutionary factors such as more extreme genetic drift or different selective pressures some non-African groups had diverged more from Africans than others in terms of their genetic state. In other words, the most genetically divergent groups in relation to Africans did not diverge any earlier, but simply diverged more rapidly.
Dienekes Pontikos disagreed with such a simple explanation. He argued that admixture or gene flow between Africans and non-African groups since the last common ancestor could explain the differences. I am now of the opinion that Dienekes may have been right. My own confidence in the “serial bottleneck” hypothesis as the primary explanation for the nature of relationships of the phylogenetic tree of human populations is shaky at best. Why my errors of inference?
There were two major issues at work in my misjudgments of the arc of the past and the topology of the present. In the latter instance I saw plenty of phylogenetic trees which illustrated clearly the variation in genetic distance from Africans for various non-African groups. Why didn’t I internalize those visual representations? It was I think the power of the “Out of Africa” (OoA) with replacement paradigm. Even by the summer of 2010 I had come to reject it in its strong form, due to the evidence of admixture with Neanderthals, and rumors of other events which were born out to be true with the publishing of the Denisovan results. But to a first approximation the clean and simple OoA was still looming so large in my mind that I made the incorrect inference, whereby all non-Africans are viewed simply as a branch of Africans without any particular differentiation in relation to their ancestral population. Secondarily, I also was still impacted by the idea that most of the genetic variation you see in the world around us has its roots tens of thousands of years ago. By this, I mean that the phylogeographic patterns of 25,000 years in the past would map on well to the phylogeographic patterns of the present. This assumption is what drove a lot of phylogeography in the early aughts, because the chain of causation could be reversed, and inferences about the past were made from patterns of the present. My own confidence in this model had already been perturbed when I made my errors, but it still held some sort of sway in my head implicitly I believe. It is one thing to move on from old models explicitly, but another thing to remove the furniture from your cognitive basement and attic.
I have moved further from my preconceptions between then and now. It took a while to sink in, but I’m getting there. A cognitive “paradigm shift” if you will. In particular I am more open to the idea of substantive back migration to Africa, as well as secondary migrations out of Africa. A new paper in Genome Research is out which adds some interesting details to this bigger discussion, and seems to weigh in further against my tentative hypothesis that serial bottlenecks and genetic drift can explain variation in distance to Africans of various non-African groups. Human population dispersal “Out of Africa” estimated from linkage disequilibrium and allele frequencies of SNPs:
Yesterday I alluded to the Court Jester hypothesis of evolutionary change, which is often contrasted with the Red Queen hypothesis. The main embarrassment for me as a person who fancies himself a fan of evolutionary process is that I hadn’t ever heard of the Court Jester Hypothesis before yesterday. Therefore I went back to the paper which outlined many of the basic ideas of the model in 2001, Distinguishing the effects of the Red queen and Court Jester on Miocene mammal evolution in the northern Rocky Mountains. To be fair, the hypothesis itself is a tightening of a range of ideas which were long in the air. I did know, for example, about the Turnover-pulse hypothesis. These are all a set of models which emphasize the abiotic selective pressures on life forms, as opposed to the biotic ones. An abiotic pressure would be something like the Younger Dryas cold snap. A biotic pressure might be an exotic invasive species spreading through the landscape.
In my own mind selection is selection, so I didn’t distinguish them too stridently. In fact, most people seem to have abiotic pressures in mind when they conceive of natural selection, so I generally prefer to emphasize the competition and cooperation between and within species. Additionally, it seems that biotic models are more formally tractable and elegantly constructed (I know much of climate change is cyclical, but I assume that “catastrophe” exhibits a poisson distribution?). I generally lack the “thick” knowledge to really make sense of a lot of detailed natural historical treatments, so I probably avoided them because I didn’t think I’d get much out of them. In hindsight, this seems foolish and shortsighted. Rather like economists focusing on equilibrium states because of their ease of modeling when periodic exogenous shocks are a major variable within our real lives.
The Pith: This post explores evolution at two different scales: the broad philosophical and the close in genetic. Philosophically, is evolution a highly contingent process which is not characterized by much replication of form and function? Or, is evolution at the end of the day aiming for a few set points which define the most optimal fitness positions possible? And how do both of these models relate to the interaction across genes, epistasis? In this post I review a paper which shows exactly how historical contingency could work through gene-gene interactions on the molecular genetic scale.
Imagine if you will a portal to another universe which you have access to. By fiat let’s give you a “pod” which allows you to move freely throughout this universe, and also let’s assume that you can travel fast enough to go from planet to planet. What if you see that on all the planets there’s a sludgy living “goo” of some sort? To complexify the issue imagine that upon further inspection the goo is divided between a predominant photosynthetic element, and “parasitic” heterotrophs. But aside from these two niches there’s little diversity to be seen in this cosmos. The “climax ecology” of all the planets resemble each other, in case after case convergent evolution toward the one-morphology-to-out-fit-them-all. We could from these observations construct a general theory of evolution which deemphasizes the role of contingency. In other words, there are broad general dynamics which shape and prune the tree of life in this hypothetical universe so that there is always a final terminal steady-state of the most fit morphology.
A model of evolution as a process of very general principles which converges upon a small finite range of optimal solutions has been promoted by paleontologists such as Simon Conway Morris. Stephen Jay Gould was a famous expositor of the inverse position, which emphasized chance and contingency. Gould’s suggestion was that if you ran the evolutionary experiment anew the outcomes each time would likely differ. In The Ancestor’s Tale Richard Dawkins leans toward the former position, insofar as he does assent to the proposition that evolutionary dynamics do inevitably forward certain broad trends, irrespective of the specific historical sequence of states antecedent to the terminus. More fanciful and speculative extrapolations of this logic are used to justify the ubiquity of a humanoid morphology in science fiction. The theory goes that a bipedal organism whose upper limbs are free to manipulate tools is going to be the likely body plan of intelligent aliens (though they will also have easy to add nose frills and such).
The Pith: In this post I review a paper which covers the evolutionary dimension of human childbirth. Specifically, the traits and tendencies peculiar to our species, the genes which may underpin those traits and tendencies, and how that may relate to broader public health considerations.
Human babies are special. Unlike the offspring of organisms such as lizards or snakes human babies are exceedingly helpless, and exhibit an incredible amount of neoteny in relation to adults. This is true to some extent for all mammals, but obviously there’s still a difference between a newborn foal and a newborn human. One presumes that the closest analogs to human babies are those of our closest relatives, the “Great Apes.” And certainly the young of chimpanzees exhibit the same element of “cuteness” which is appealing to human adults. Still there is a difference of degree here. As a childophobic friend observed human infants resemble “larvae.” The ultimate and proximate reason for this relative underdevelopment of human newborns is usually attributed to our huge brains, which run up against the limiting factor of the pelvic opening of women. If a human baby developed for much longer through extended gestation then the mortality rates of their mothers during childbirth would rise. Therefore natural selection operated in the direction it could: shortening gestation times. You might say that in some ways then the human newborn is an extra-uterine fetus.
A new paper in PLoS Genetics attempts to fix upon which specific genomic regions might be responsible for this accelerated human gestational clock. An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing:
Diversity is a major question in evolutionary biology. In particular, why is there so much diversity, so that the tree of life manifests a multitude of morphs? Might there not be some supreme replicator which emerges from the maelstrom to conquer all before it? This is actually the scenario which unfolds in much of science fiction, with monomorphic grey goo eating everything in its path (a more aesthetically differentiated variant of the super-species emerges in Brian W. Aldiss’ Helliconia Winter). As it is, life on earth does not seem to be converging upon an optimum phenotype for all individuals. In contrast, it seems to be going in the opposite direction broadly speaking (thinking on billion year scales), with the shift from the monotony of communal cyanobacteria to the riotous diversity of tropical forest biomes and coral reefs.
There are many ways you might be able to explain this diversity. Temporal and spatial heterogeneity produces perpetually shifting selection pressures, resulting in transient morphs one after the other. Negative frequency dependent selection, whereby the fitness of a phenotype runs up against its own success. This dynamic is one of the drivers of the Red Queen Hypothesis; the evolutionary arms race in some cases witnessing the resurrection of old techniques against which defenses are no longer recalled. Then there is the possibility that the lack of natural selection as an efficacious evolutionary force could allow for the diversification of phenotypes through random drift. Finally, it may simply be that the gusher of mutation is powerful enough that novelty overwhelms selection and drift’s attempt to pare it back.
A new paper in Nature offers up another possibility. It does so by examining the fact that biological diversity remains operative even within a homogenized chemostat. A chemostat in this context refers to a controlled environment where inputs and outputs are balanced to maintain constant equilibrium conditions for a bacterialculture. Therefore, an unbeatable strategy should emerge in this medium perfectly tailored to the environmental constants, resulting in a homogeneous biota to match. Empirically this is not what occurs. So some explanation is warranted.
I was semi-offline for much of last week, so I only randomly heard from someone about the “Science paper” on which Molly Przeworski is an author. Finally having a chance to read it front to back it seems rather a complement to other papers, addressed to both man and beast. The major “value add” seems to be the extra juice they squeezed out of the data because they looked at the full genomes, instead of just genotypes. As I occasionally note the chips are marvels of technology, but the markers which they are geared to detect are tuned to the polymorphisms of Europeans.
Efforts to identify the genetic basis of human adaptations from polymorphism data have sought footprints of “classic selective sweeps” (in which a beneficial mutation arises and rapidly fixes in the population). Yet it remains unknown whether this form of natural selection was common in our evolution. We examined the evidence for classic sweeps in resequencing data from 179 human genomes. As expected under a recurrent-sweep model, we found that diversity levels decrease near exons and conserved noncoding regions. In contrast to expectation, however, the trough in diversity around human-specific amino acid substitutions is no more pronounced than around synonymous substitutions. Moreover, relative to the genome background, amino acid and putative regulatory sites are not significantly enriched in alleles that are highly differentiated between populations. These findings indicate that classic sweeps were not a dominant mode of human adaptation over the past ~250,000 years.