I do enjoy a good Pinker-dunking in the morning

Did you know that Steven Pinker’s Enlightenment Now is full of misleading claims and false assertions? It is! And this article takes an interesting approach to documenting it: the author focuses on one chapter, on a topic he knows well, and contacts a bunch of people Pinker references and asks them if he represented their views correctly. A surprising number say no, and explain why.

I am not a fan of neo-liberal techno-optimism, as you might guess. It’s always just some well-off dude trying to persuade people that we can ignore systemic injustice because he’s doing just fine.

Do not ever read Steve Pinker’s Twitter feed

I made the mistake. His latest 3:

  • Stop worrying about the opioid crisis! It’ll get better! Heath Ledger and Prince will rise from the grave!

  • You should probably vote for some Democrats, even though they have problems. Maybe there are a few problems on the Republican side, but I don’t see them, because my rose-colored glasses make red parties invisible.

  • It’s only a few bombs! We don’t need to worry until at least 0.05% of the public are sending bombs through the mail to elected officials.

So, really, just don’t bother reading Pollyanna Pinker. It’ll make you angrier, and we’ve got a surplus of rage right now. Just read this and laugh.

At least he’s the favorite scientist of cockroaches everywhere.

Steven Pinker and the New York Times are making us dumber

Because I exposed Steven Pinker’s atrociously bad arguments, I have now been accused of “smearing” and “distorting” Pinker’s words, and gotten all kinds of fun hate mail. Alas, nobody has been able to show where my arguments actually distort Pinker’s claims; he really does argue that “political correctness” is driving people to the alt-right, and that there are all these “facts” that Leftist Academics refuse to discuss on campus, which drives students further right when they discover that they’ve been lied to. It is a bullshit contrafactual, wrong and dishonest in every way, and the best people can do is say, “well, there’s some parts afterwards that are more nuanced, and you ignored those”. Nope, that’s irrelevant. When someone states outright lies, it doesn’t matter if later they say something else.

But that’s the fallback everyone is resorting to: it’s the logical equivalent of someone pointing out that Trump said something that was outright racist, while others refuse to acknowledge it and instead like to mention how he had a taco salad, so he’s not that bad. It’s not relevant. Quit dancing around the facts. I addressed Pinker’s lies, specifically. No one has refuted the fact that he did speak dishonestly.

If you want a perspective that’s less pissed-off than mine, I recommend Thomas Smith’s latest podcast. He thinks maybe I was a leetle too aggressively in-Pinker’s-face, to put it mildly, but then I think he’s a leetle too charitable, but then I also think maybe he’s new to Pinker’s history of making shitty arguments. Pinker is an advocate for evolutionary psychology, he criticized the March for Science as anti-science PC/identity politics/hard-left rhetoric (gosh, how many dog-whistles can you pack in a phrase?), he invoked the second law of thermodynamics to explain poverty, he endorsed the absurdities of Gamergate and Christina Hoff Sommers, and wrote the most arrogant piece on scientism ever. I say this not as a rabid anti-Pinker zealot — you can also find articles praising bits and pieces of Pinker’s work in my archives — but as someone who doesn’t just assume that Harvard confers infallibility with tenure, and who actually suspects that many aspects of Harvard reinforce an ugly sense of entitlement. He’s just really bad at thinking about way too many things.

Smith does point out something I could have been clearer about. If you look at the kinds of arguments Pinker often makes, they reduce to blaming the Left/Progressives/Liberals for things that the Right/Republicans/racists do. Somehow it’s always possible to make the worst things the alt-right does entirely the fault of those who oppose them, and also, he never bothers to say what we’re supposed to do instead. Encourage racists? Say kind things about them? Compromise on fundamental issues: suggest that maybe black people are only a little bit inferior rather than a lot inferior?

Even when they vaguely puzzle out this point, Pinker supporters don’t understand it. What does Jesse Singal say in the New York Times?

The clip was deeply misleading. If you watch the whole eight-minute video from which it was culled, it’s clear that Mr. Pinker’s entire point is that the alt-right’s beliefs are false and illogical — but that the left needs to do a better job fighting against them.

No. He clearly says that the alt-right’s beliefs are the fault of the “PC” Left, which says nothing about making better arguments to oppose them, and is a falsehood. His talk was about doling out the blame to the Left, not about fighting the alt-right. If you listen to the whole 8-minute video, what you hear is Pinker first saying that you can’t voice certain facts on campus, then stating those facts (self-refutation, anyone?), then explaining that his facts are more complex than he let on,
which is what the college professors he’s blaming already do.

But then this kind of disingenuous denial of reality, of focusing superficially on he said/she said note-taking, is exactly what the New York Times specializes in.

If you ever doubted that Steven Pinker’s sympathies lie with the alt-right

Just watch this clip.

He starts out by explaining that the alt-right are highly literate, highly intelligent people who have been radicalized by exposure to true statements that have never been voiced on college campuses. You see, once Leftist dogma has been exposed as a falsehood, these bright young people just take the red pill and veer way off in the opposite direction.

You might be wondering, as I was, what were these True Facts that have triggered the defection of these brilliant students from progressive causes? Give me specific examples! He obliges.

  • Capitalist societies are better than communist ones. How odd. I don’t see anyone insisting on that: instead, I see a lot of academics who point out the flaws in capitalism, which, apparently, are lies and don’t exist. Then he makes it worse by using as more specific examples the difference between North and South Korea (I’ve never met anyone who thinks North Korea is a better place to live than South Korea.) or between East and West Germany before the fall of the Berlin wall. You will rarely encounter a more pure and absolutely dishonest straw man.

    How about if the comparison is between, say, a ragingly capitalist country like the USA, and a socialist democracy like Sweden? It gets a bit less obvious.

  • Men & women are not identical in their life priorities or sexuality. Again, who is arguing that men and women are identical? He says there is someone on the Harvard campus who argues this, but doesn’t bother to name names. Generally what I’ve seen on the left is approval and encouragement of differences — that men and women are different, but that the bigger differences are between individuals, and that those differences should be respected. We do object to being compelled to fit into the straitjacket of just two stereotypical gender roles. We also don’t think you can go from a karyotype to a flawless description of life priorities or sexuality.

  • Different ethnic groups commit violent crimes at different rates. Oh, yeah, he went there. Look at crime statistics and all those violent black criminals! We’re done, that’s all the analysis you need to do (and, by the way, those leftist college professors do not deny the statistics at all). But why do black communities have higher crime rates? It wouldn’t have anything to do with poverty, or discriminatory policing, or the existence of laws that basically criminalize being poor, would it?

    And of course he brings up that always-useful distinction, that Islamic people are more likely to be suicide bombers, as if that were the sole kind of violence that one ethnic group can perpetrate on another. How many Muslims have been killed by Christians? This is not to excuse either kind of violence, but to point out that playing selective games with the statistics to ignore institutionalized violence is profoundly dishonest.

I’m just going to have to say it outright: Pinker is lying here. These are all ideas that are routinely discussed at universities. The leftist positions he is caricaturing are far less dogmatic than he is claiming, and the alt-right positions far more so. There is no censorship that prevents addressing them; there is an expectation of greater, more evidence-based rigor in any discussion of such complex social, economic, and historical issues, and trying to pull the kind of misrepresentations and naive assertion of stereotypes that Pinker is babbling about here will get your arguments slapped down hard. I am shocked that a Harvard professor would promote such ignorance and falsehoods.

Here’s a longer clip in which Pinker goes on to say the same sort of things that are routinely said in classrooms, all while doubling down and saying the “politically-correct left” is not allowing them to be said. He is completely un-self-aware. I guess it only counts if a politically incorrect person like Pinker says them as if they were his own novel idea, rather than the mundane substance of typical classroom discussions.

Tackling Pinker’s defense of evolutionary psychology

I previously addressed the criticisms of my criticisms of evolutionary psychology by Jerry Coyne; Now I turn to the criticisms of my criticisms he solicited from Steven Pinker. This is getting a bit convoluted, so let me first state the basics.

I dislike evolutionary psychology. Pinker is an advocate for evolutionary psychology. What brought on this back-and-forth was that I was a member of a panel at a science fiction convention that discussed evo psych; I made a few brief comments on my blog that were capsule summaries of my discussion there. In the section below, the paragraphs preceded by an “M:” and in italics are my words excerpted from those comments; the parts preceded by a “P:” are Pinker’s commentary. All clear?

M: Fundamental assumptions of evo psych: That you can infer an adaptive history from the distribution of current traits — that they are adaptations at all is an assumption usually not founded in evidence (this is not to deny that that there are features that are clearly the product of selection, but that you can’t pick an arbitrary attribute and draw elaborate scenarios for its origins). . .

P: Of course “arbitrary” and “elaborate” are the straw-man giveaways here. What about carefully selected attributes, and minimal assumptions about phylogeny with a focus on function, as we do for other organs? You can ask what the spleen is for – and it would be perverse to do physiology without asking such a question – without “drawing elaborate scenarios for its origins.”

Whoa, whoa, whoa — that skips right over the really important word: “adaptive”. Start there. That’s my primary objection, the habit of evolutionary psychologists of taking every property of human behavior, assuming that it is the result of selection, building scenarios for their evolution, and then testing them poorly.

We already know that that is impossible. The repertoire of human behavior is so complex and rich, and relatively recently evolved, that to argue that every behavior is the product of specific selection imposes an untenable genetic load. The bulk of the genetic foundation of our psychology (and I agree that there must be one!) must be byproducts and accidents. The null hypothesis of evolutionary psychology should be that a behavior is non-adaptive, yet for some reason all I ever see is adaptive hypotheses.

The spleen is an interesting example. There are components of the spleen that are definitely functional and almost certainly adaptive: its functions as a blood reservoir, as an element of the immune system, as part of the erythrocyte cycling mechanism. You can examine the evolution of those functions phylogenetically; for instance, some teleosts lack the erythropeotic functions of the spleen, while the majority use it as a blood reservoir. You can begin to dissect its history comparatively, by looking at what has a clear functional role and looking at the pattern of emergence of those properties.

What you can’t do is pick any particular property of the spleen and invent functions for it, which is what I mean by arbitrary and elaborate. For instance, the spleen is located in most people in the upper left quadrant of the abdomen; are you going to make an adaptive case for why it’s on the left rather than the right? The actual reason almost certainly has nothing to do with adaptation or selection, and everything to do with historical and developmental mechanisms that are neutral with respect to selection.

M:. . . That behavioral features that have been selected for in our history are represented by modular components in the brain – again with rare exceptions, you can’t simply assign a behavioral role to a specific spot in the brain, just as you can’t assign a behavior to a gene.

P: No one in Ev Psych points to specific spots in the brain – that’s cognitive neuroscience, not evolutionary psychology. The only assumption is that there are functional circuits, in the same way that a program can be fragmented across your hard drive.

Now this is one of my peeves with evolutionary psychology. The evo psych literature is thick with papers emphasizing “modularity”; that evolutionary psychology FAQ I referenced before makes it clear that it’s an important concept in the field (and also ties it to concepts in computer science). Yet it is meaningless. Sometimes there’s the implication that the “module” is a discrete element in the brain, but it’s never clear whether they’re talking about a genetic module (an epistatic network of genes) or a neural module (an interconnected network of neurons), and when pressed, they retreat, as Pinker does here, to an admission that it could be just about anything scattered anywhere in the brain.

So my question is…why talk about “modules” at all, other than to reify an abstraction into something misleadingly concrete? Evolutionary psychologists don’t do neurobiology, and they don’t do genetic dissections, and they don’t do molecular genetics, so why do they insist on modularity? It’s premature and a violation of Occam’s razor to throw the term around, and also completely unnecessary — a behavior could be a product of diffuse general phenomena in the brain without diminishing its importance at all.

M: . . . That the human brain is adapted to a particular environment, specifically the African savannah, and that we can ignore as negligible any evolutionary events in the last 10,000 years, that we can ignore the complexity of an environment most of the evo psych people have never seriously studied, and that that environment can dictate one narrow range of outcomes rather than permit millions of different possibilities.

P: The savannah is a red herring – that’s just a convenient dichotomization of the relevant continuum, which is evolutionary history. A minimal commitment to “pre-modern” gives you the same conclusions. By saying that the brain could not have been biologically adapted to stable government, police, literacy, medicine, science, reliable statistics, prevalence of high-calorie food, etc., you don’t need to go back to the savannah; you just need to say that these were all relevantly recent in most people’s evolutionary history. The savannah is just a synechdoche.

Ah, a synechdoche. This is the evolutionary psychology version of the religious argument that it’s “just a metaphor.”

Again, this is a peeve I have with the field. I agree with the general principle that of course the brain is a product of our evolutionary history, and that there is almost certainly a foundation of genetically defined, general psychological properties of the mind…and that a great many specific psychological properties are not biologically adapted. Pinker is writing good common sense here.

But over and over, you see evolutionary psychologists falling into this trap of examining a behavior and then fitting it to some prior specific environment. They talk of a Savannah Mind or they generalize it to the Environment of Evolutionary Adaptedness. It’s another reification of the unknown. You don’t like “savannah”? Change it to “Pleistocene”. It’s just as broad and meaningless. It’s an attempt to reduce the complex and diverse to a too simple unit.

M: I’d also add that most evo psych studies assume a one-to-one mapping of hypothetical genes to behaviors. . .

P: Completely untrue – this was Gould’s claim in the 1970s, which confused a “gene for x” (indispensable in any evolutionary thinking, given segregation) in the sense of “increases the probability of X, averaging over environments and other genes” with “a gene for X” in the sense of “necessary and sufficient for X.” Every honest biologist invokes “gene for X” in the former sense; evolution would be impossible if there were no additive effects of genes. No one believes the latter – it’s pure straw.

By one-to-one, I mean the assumption that a behavior trait can be mapped to a contribution from a gene that was subject to selection for that trait; that it might be an additive property of a pleiotropic gene will be nominally noted, as Pinker does here, but operationally ignored. Remember, the issue is not whether genes contribute to our psychology, a point I totally agree with, but whether we can assign a selective origin to a behavior. That is a much, much harder problem.

M [continuation of previous sentence]:. . . and never actually look at genes and for that matter, ignore most human diversity to focus on a naive typological simplicity that allows them to use undergraduate psych majors at Western universities as proxies for all of humanity”

P: It’s psychologists, not evolutionary psychologists, who focus on Western undergrads –field research and citations of anthropology are vastly more common in ev psych than in non-ev-psych. PZ is engaging in prosecution here, not analysis – he’s clearly ignorant of the sociology of the fields.

As for diversity – is he arguing for genetic differences among human groups, a la Herrnstein & Murray?

First, this has already been addressed by Stephanie Zvan: when you look in the evolutionary psychology journals at papers identified as evolutionary psychology, you find…a focus on Western undergrads. I throw up my hands in exasperation. Look at the actual work done in your field, not the abstract ideal you hold in your head. I get my vision of evolutionary psychology by reading the papers.

Secondly, what a weirdly off-target attempt at ad hominem. Once again, my criticisms are being addressed by imagining motives; in Jerry Coyne’s critique, I’m an uber-liberal offended at the consequences a genetic component to behavior might have on my egalitarian biases; now Pinker takes a swipe by tarring me with the likes of Herrnstein & Murray. Make up your minds!

For the record, of course there are genetic differences in human populations! It’s an open question whether any of them make significant contributions to human psychology, however. I’m open to evidence either way.

But my remark was about cultural diversity (which also, by the way, exists). Setting aside the notion of a genetic component for now, we know that culture creates different minds. How can you analyze the causes of a behavior if your work focuses on a relatively uniform sample?

M: Developmental plasticity vitiates most of the claims of evo psych. Without denying that some behaviors certainly have a strong biological basis, the differences in human behaviors are more likely to be a product of plasticity than of genetic differences. . .

P: Plasticity is just learning at the neural level, and learning is not an alternative to innate motives and learning mechanisms. Plasticity became an all-purpose fudge factor in the 1990s (just like “epigenetics” is today). But the idea that the brain is a piece of plastic molded by the environment is bad neuroscience. I reviewed neural plasticity in the chapter “The Slate’s Last Stand” in The Blank Slate, with the help of many colleagues in neuroscience, and noted that the plasticity that allows feedback during development and learning during ontogeny is superimposed on an innate matrix of neural organization. For example if you silence *all* synaptic activity in the brain of a developing mouse with knock-outs, the brain is pretty much normal.

Speaking of straw men…I found The Blank Slate entirely unreadable, unlike most of Pinker’s books, because of the gigantic straw man erected in the title. This flailing against me is a product of this weird idea that I reject the contribution of our genes to our minds, but just as there are no evolutionary psychologists who believe everything in our brains is genetically predetermined, there is no such thing in serious science as a “blank slater”.

There is a continuum, and we’re arguing about degrees. For example, take a child of French parents and raise them in the United States, they’ll grow up speaking fluent English (or Spanish, depending on the household), and vice versa — an American child raised in France will speak French like a native. There is no genetic component to the details of language. Yet when you compare diverse languages you can start to pick out commonalities, and when you look at the neural substrates of language you do see shared anatomy and physiology — I do not hesitate to accept that there is an evolved component of human language. The differences between speakers are learned, the universals may well be biological.

Which means that when evolutionary psychologists try to parse out variations between different groups, racial or sexual, I suspect it’s most likely that they are seeing cultural variations, so trying to peg them to an adaptive explanation is an exercise in futility. When evolutionary psychologists try to drill down and identify the shared components, I’m much more willing to see their efforts as interesting.

That last sentence by Pinker is a lovely example of nonsensical denial of the importance of plasticity. “Pretty much normal” means that on broad, superficial inspection the various components of the brain are present — hindbrain, midbrain, forebrain, various nuclei and pathways, they’re all there. I’ve seen the same thing in zebrafish: the peripheral motor nerves I studied as a graduate student form perfectly normally even if you knock out all the acetylcholine receptors, so that the muscles are totally unresponsive to physiological inputs.

This does not surprise me. Most of the patterning of the brain is set up in the embryo before neuronal connectivity is established; the clock-like activity of mitotic rate genes defines the size of various bits of the brain; adhesive and repulsive cell surface interactions lay out the major pathways. Does Pinker think someone trained in developmental neurobiology would expect that the brain would collapse into a formless blob in the absence of action potentials and synaptic transmission?

But it is still absurd to call the deprived brain “pretty much normal”. When you look deeper, you find subtle and important differences. The clearest examples are found in experiments with visually deprived cats: sew one eyelid shut, or both, or alternate, in a young kitten, and you can find all kinds of changes in visual processing, detectable at both the physiological and anatomical levels. The visual cortex forms, projections from the lateral geniculate terminate in roughly the right place, but they absolutely depend on visual input to fine tune their connections. Human children born with visual deficits in one eye will also have lifelong deficits in visual processing, even if the original problem is corrected.

Try raising a child without contact with other humans. I guarantee you that their brains, when physically examined, would look “pretty much normal”…but does anyone really believe that psychologically, on the level evolutionary psychologists study brains, that they’d be “pretty much normal”?

This is “pretty much normal” behavior from evolutionary psychologists, though. Point out that that their inferences about neuronal circuitry are bogus, they tell you that they don’t study neurons anyway; tell them that the behaviors they study are awfully plastic and flexible, and presto, hey, look, brains and neurons are patterned by genetic elements. The sleight of hand is impressive, except when you realize that science shouldn’t be about magic tricks.

The 2013 Dawkins Award goes to … Steven Pinker

Who well deserves it, I think. It’s “presented every year to honor an outstanding atheist whose contributions raise public awareness of the nontheist life stance.” Very laudatory and gratifying press release here.

I just finished reading his Better Angels of Our Nature: Why violence has declined. I thought it a well-reasoned and researched testament to the power of humanism and a excellent resource for rebutting the folks who think the world is worse than it has ever been and people never more wicked. One would think that evidence to the contrary would be welcome … but it’s not. My neo-pagan spiritual friends would have none of it. I hold out even less hope for the Jehovah’s Witnesses.

Last year’s recipient was also excellent: Eugenie Scott. Perhaps not quite a ‘mirror’ representative of  “the uncompromising nontheist life stance of Dr. Richard Dawkins” — but quite solid on the raising of the public awareness of science. Pinker, then, is a twofer.


He’s also an excellent speaker. I plan on attending the Atheist Alliance of America’s national convention to see him receive the Dawkins. It’s taking place on  Aug 30 – Sept 2 … in Boston. The Alliance’s conventions are imo one of the best. Everyone should go. And now there’s Pinker to tempt you.

(from Sastra)

Pinker explains Group Selection

I found this very satisfying: Steven Pinker summarizes all the problems with group selection. It’s a substantial essay, but if you just want the gist of it, here’s the conclusion.

The idea of Group Selection has a superficial appeal because humans are indisputably adapted to group living and because some groups are indisputably larger, longer-lived, and more influential than others. This makes it easy to conclude that properties of human groups, or properties of the human mind, have been shaped by a process that is akin to natural selection acting on genes. Despite this allure, I have argued that the concept of Group Selection has no useful role to play in psychology or social science. It refers to too many things, most of which are not alternatives to the theory of gene-level selection but loose allusions to the importance of groups in human evolution. And when the concept is made more precise, it is torn by a dilemma. If it is meant to explain the cultural traits of successful groups, it adds nothing to conventional history and makes no precise use of the actual mechanism of natural selection. But if it is meant to explain the psychology of individuals, particularly an inclination for unconditional self-sacrifice to benefit a group of nonrelatives, it is dubious both in theory (since it is hard to see how it could evolve given the built-in advantage of protecting the self and one’s kin) and in practice (since there is no evidence that humans have such a trait).

Group selection is one of those ideas people succumb to all the time…but it’s also a fringe concept that demands really good evidence before anyone should believe it, and no one seems to be able to come up with any.

Steve Pinker’s hair and the muscles of worms

I’ve been guilty of teaching bean-bag genetics this semester. Bean-bag genetics treats individuals as a bag of irrelevant shape containing a collection of alleles (the “beans”) that are sorted and disseminated by the rules of Mendel, and at its worst, assigns one trait to one allele; it’s highly unrealistic. In my defense, it was necessary — first-year students struggle enough with the basic logic of elementary transmission genetics without adding great complications — and of course, in some contexts, such as population genetics, it is a useful simplification. It’s just anathema to anyone more interested in the physiological and developmental side of genetics.

The heart of the problem is that it ignores the issue of translating genotype into phenotype. If you’ve ever had a basic genetics course, it’s quite common to have been taught only one concept about the phenotype problem: that an allele is either dominant, in which case it is expressed as the phenotype, or it’s recessive, in which case it is completely ignored unless it’s the only allele present. This idea is so 19th century — it’s an approximation made in the complete absence of any knowledge of the nature of genes.

And the “one gene, one trait” model violates everything we do know about the phenotype and genotype. Every gene is pleiotropic — it influences multiple traits to varying degrees. Every trait is multigenic — multiple genes contribute to the expression of every phenotypic detail. The bean-bag model is totally inadequate for describing the relationship of genes to physiology and morphology. Instead of a bean-bag, I prefer to think of the genome as comparable to a power spectrum, an expression of the organism in a completely different domain. But I wrote about that previously, and I’ll make this explanation a little simpler.

Here’s the problem: you can’t always reliably predict the phenotype from the genotype. We have a skewed perspective on the problem, because historically, genetics has first searched for strong phenotypes, and then gone looking for the genetic cause. We’ve been effectively blind to many subtle phenotypic effects, simply because we don’t know how to find them. When we go the other way, and start by mutating known genes and then looking for changes in the phenotype, we’re often surprised to discover no detectable change. One of the classic examples is the work of Elkins (1990), who found that mutating a neural cell adhesion gene, Fasciclin I, did not generate any gross defects. Mutating another gene, a signal transduction gene called Abelson tyrosine kinase, similarly had no visible effects. Mutating the two together, though — and this is a major clue to how these strange absences of effect could work — did produce gross and obvious effects on nervous system development.

Providing another great example, Steve Pinker examined his own genome, and discovered that his genes said he was predisposed to be red-haired and at high risk for baldness. If you’ve seen Steve Pinker, you know he’s neither.

How can this be? As any geneticist will tell you, the background — the other alleles present in the organism — are important in defining the pattern of expression of a specific gene of interest. One simple possibility is that the genome contains redundancy: that a trait such as adhesion of axons in the nervous system or the amount of hair on the head can be the product of multiple genes, each doing pretty much the same thing, so knocking out one doesn’t have a strong effect, because there is a backup present.

Genetic interactions provide a general model for incomplete penetrance. Representation of a negative (synergistic) genetic interaction between two genes A and B.

So Steve Pinker could have seen that he has a defective Gene A, which is important in regulating hair, but maybe there’s another Gene B lurking in the system that we haven’t characterized yet, and which can compensate for a missing Gene A, and he has a particularly strong form of it. One explanation for a variable association between an allele and the phenotype, then, is that we simply don’t have all the information about the multigenic cause of the phenotype, and there are other genes that can contribute.

This doesn’t explain all of the observed phenomena, however. Identical twins who share the same complement of alleles also exhibit variability in the phenotype; we also have isogenic animal lines, where every individual has the same genetic complement, and they also show variability in phenotype. This is the problem of penetrance; penetrance is a genetics term that refers to the likelihood that an individual carrying an allele will actually express the phenotype associated with that allele…and it’s not always 100%.

Again, the explanation lies in the other genes present in the organism. No gene functions all by itself; its expression is dependent on a cloud of other proteins — transcription factors, enhancers, chaperones — all of which modulate the gene of interest. We also have to deal with statistical variation in the degree of expression of all those modulatory factors, which vary by chance from cell to cell, and so the actual degree of activation of a gene may follow a kind of bell curve distribution. In the cartoon below, the little diamonds represent these partners; sometimes, just by chance, they’ll be present in sufficiently high numbers to boost Gene B’s output enough to fully compensate for a defective Gene A; in other cases, just by chance, they’re too low in concentration to adequately compensate for the absence.

Genetic interactions provide a general model for incomplete penetrance. A model for incomplete penetrance based on variation in the activity of genetic interaction partners.

What the above cartoon illustrates is the concept of developmental noise, the idea that the cumulative total of statistical variation in gene expression during development can produce significant phenotypic variation in the absence of any differences in the genotype. Developmental noise is a phrase bruited about quite a bit, and there’s good reason to think it’s valid: we can see quantitative variation in gene expression with molecular techniques, for instance. But at the same time we have other concepts, like redundancy and canalization, that work to buffer variation and produce reliable outputs from developmental processes, so we don’t have many good examples where we can directly correlate subtle variation at the molecular level with clear morphological differences.

To test that, we have to go to simple animal models (it turns out that Steve Pinker is a rather intractable experimental animal). And here we have a very nice example in the nematode worm, C. elegans. In these experiments, the investigators were dealing with an isogenic strain — the genetic background was identical in all of the animals — raised in a uniform environment. They were looking at a mutant in the gene tbf9, which causes defects in muscle formation, but only 50% penetrance; that is, half the time, the mutants appeared completely normal, and the other half of the time they had grossly abnormal muscle development.

Genetic interactions provide a general model for incomplete penetrance. Inactivation of the gene tbx-9 in C. elegans results in an incompletely penetrant defect, with approximately half of embryos hatching with abnormal morphology (small arrow).

See the big red question mark? That’s the big question: can we trace the abnormal phenotype all the way back to random fluctuations in the expression of other genes in the animal? Yes, they can, otherwise it would never have been published in Nature and I wouldn’t be writing about it now.

In this case, they have a situation analogous to the Gene A/Gene B cartoons above. Gene B is tbx-9; Gene B is a related gene, a duplicate called tbx-8 which acts as a redundant copy. In the experiments below, they knock out tbx-9 with a mutation, and then measure the quantity of other genes in the system using a very precise technique of quantitative fluorescence. Below, I’ve reproduced the entirety of their summary figure, because it is awesome — I just love the idea of being able to count the number of molecules expressed in a developing system. In order to avoid overwhelming everyone, though, I’ll just describe a couple of the panels to give you the gist of the work.

First, just look at the top left panel, a. It’s a plot of the level of expression of the tbx-8 gene over time, where each line in the plot is a different animal. The lines in black are in the wild type animal, with fully functional copies of bothe tbx-8 and tbx-9, and you should be able to see that there’s a fair amount of variation in expression, about two-fold, in different individuals. The lines in green are from animals mutant for tbx-9; it’s messy, but statistically what happens when tbx-9 is knocked out, more tbx-8 gene product is produced.

Panel e, just below it, shows the complementary experiment: the expression of tbx-9 is shown for both wild type (black) and animals with tbx-8 knocked out. Here, the difference is very clear: tbx-9 levels are greatly elevated in the absence of tbx-8. This shows that tbx-8 and tbx-9 are actually tied together in a regulatory relationship where levels of one rise in response to reduced levels of the other, and vice versa.

(Click for larger image)

Early inter-individual variation in the induction of ancestral gene duplicates predicts the outcome of inherited mutations. a, Quantification of total green fluorescent protein (GFP) expression from a tbx-8 reporter during embryonic development in WT (black) and tbx-9(ok2473) (green) individuals. Each individual is a separate line. a.u., Arbitrary units. b, Boxplot of tbx-8 reporter expression (a) showing 1.2-fold upregulation in a tbx-9 mutant at comma stage (~290 min, P=1.6×3 10-3, Wilcoxon rank test). c, Expression of tbx-8 reporter in a tbx-9(ok2473) background for embryos that hatch with (red) or without (blue, WT) a morphological defect. d, Boxplot of c showing tbx-8 expression is higher in tbx-9 embryos that develop a WT phenotype (blue) compared with those that develop an abnormal (red) phenotype at comma stage (P= 6.1×10-3). e, Expression of a ptbx-9::GFP reporter in WT (black) and tbx-8(ok656) mutant (green). f, Boxplot of tbx-9 reporter showing 4.3-fold upregulation at comma stage (~375 min, P=3.6×10-16). g, Expression of tbx-9 reporter in a tbx-8(ok656) mutant background, colour code as in
c. h, Boxplot of g showing tbx-9 expression is higher in tbx-8 embryos that develop a WT phenotype (P=0.033). i, Expression of a pflh-2::GFP reporter in WT (black) and flh-1(bc374) mutant (green). j, Boxplot of flh-2 reporter expression (i) showing 1.8-fold upregulation in a flh-1 mutant at comma stage (~180 min, P=2.2×10-16). k, Bright-field and fluorescence image of an approximate 100-cell flh-1; pflh-2::GFP embryo. Red arrow indicates the local expression of flh-2 reporter quantified for flh-1 phenotypic prediction.
l, Boxplot showing higher flh-2 reporter expression at approximate 100 cells for WT (blue) compared with abnormal (red) phenotypes (P=0.014). Boxplots show the median, quartiles, maximum and minimum expression in each data set.

Now skip over to the right, to panel c. All of the lines in this plot are of tbx-8 expression in tbx-9 mutants, and again you see a wide variation in levels of gene expression. In addition, the lines are color-coded by whether the worm developed normally (blue), or had the mutant phenotype (red). The answer: worms with low tbx-8 levels were more likely to have the abnormal phenotype than those with high levels.

Panel g, just below it, is the complementary analysis of tbx-9 levels in tbx-8 mutants, and it gives the same answer.

Obviously, though, there is still a lot of variability unaccounted for; having relatively high levels of one or the other of the tbx genes didn’t automatically mean the worm developed a wild-type phenotype. There’s got to be something more that is varying. Look way back to the second cartoon I showed, with the little diamonds representing the cloud of transcription factors and chaperone proteins that modulate gene expression. Could there also be correlated variation there? And yes, there is. The authors looked at a chaperone protein called daf-21 that is associated with the tbx system, and found, in mutants for tbx-9, that elevated levels of daf-21 were associated with wildtype morphology (in blue), while lowered levels of daf-21 were associated with the mutant phenotype.

(Click for larger image)

Expression of daf-21 reporter in a tbx-9(ok2473) mutant background. Embryos that hatch into phenotypically WT worms (blue) have higher expression than those hatching with a morphological defect (red) at the comma stage (P=1.9×10-3).

I know what you’re thinking: there isn’t a perfect correlation between high daf-21 levels and wildtype morphology either. But when they do double-label experiments, and take into account both daf-21 and tbx-8 levels in tbx-9 mutants, they found that 92% of the animals with greater than median levels of expression of both daf-21 and tbx-8 had wildtype morphology. It’s still not perfect, but it’s pretty darned good, and besides, it’s no surprise that there are probably other modulatory factors with statistical variation lurking in the system.

What should you learn from this? Developmental noise is real, and is a product of statistical variation in the degree of expression of multiple genetic components that contribute to a phenotype. We can measure that molecular variation in living, developing systems and correlate it phenotypic outcomes. None of this is surprising; we expect that the process of gene expression is going to be a bit noisy, especially in these transcriptional regulators that are present in low concentration in the cell, anyway. But the other cool thing we can observe here is that having multiple noisy systems that interact with each other can produce a more reliable, robust signal and contribute to the fidelity of developmental outcomes.

Burga A, Casanueva MO, Lehner B (2011)
Predicting mutation outcome from early stochastic variation in genetic interaction partners. Nature 480(7376):250-3.

Elkins T, Zinn K, McAllister L, Hoffmann FM, Goodman CS (1990)
Genetic analysis of a Drosophila neural cell adhesion molecule: interaction of fasciclin I and Abelson tyrosine kinase mutations. Cell 60(4):565-75.

(Also on FtB)

Steve Pinker’s hair and the muscles of worms

I’ve been guilty of teaching bean-bag genetics this semester. Bean-bag genetics treats individuals as a bag of irrelevant shape containing a collection of alleles (the “beans”) that are sorted and disseminated by the rules of Mendel, and at its worst, assigns one trait to one allele; it’s highly unrealistic. In my defense, it was necessary — first-year students struggle enough with the basic logic of elementary transmission genetics without adding great complications — and of course, in some contexts, such as population genetics, it is a useful simplification. It’s just anathema to anyone more interested in the physiological and developmental side of genetics.

The heart of the problem is that it ignores the issue of translating genotype into phenotype. If you’ve ever had a basic genetics course, it’s quite common to have been taught only one concept about the phenotype problem: that an allele is either dominant, in which case it is expressed as the phenotype, or it’s recessive, in which case it is completely ignored unless it’s the only allele present. This idea is so 19th century — it’s an approximation made in the complete absence of any knowledge of the nature of genes.

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