Behe on LYST

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A second highly selected gene, LYST, is associated with pigmentation, and changes in it are probably responsible for the blanching of the ancestors’ brown fur. Computer analysis for the multiple mutations of the gene showed that they too were almost certainly damaging to its function.

In fact, of all the mutations in the seventeen genes that were most highly selected, about half were predicted to damage the function of the respective coded proteins. Furthermore, since most altered genes bore several mutations, only three to six (depending on the method of estimation) out of seventeen genes were free of degrading changes [fn 2]. Put differently, 65 to 83 percent of helpful, positively selected genes are estimated to have suffered at least one damaging mutation.

  • Darwin Devolves p. 21

fn 2 is Table S7 of Liu et al.

Can we work through this one item at a time to see what people agree with or disagree with?

228 thoughts on “Behe on LYST”

  1. J-Mac: You have just proven my point.

    I strongly doubt that, since you didn’t actually make a point.

    J-Mac: What’s at issue here is atherosclerosis, or the accumulation of plaque in the arteries:

    I get the impression that Behe accepts that the attenuation of cholesterol levels is the likely mechanism by which mutations in APOB confer their adaptive benefit. From his book (pp. 16-17):

    But what precisely did the changes in polar bear APOB do to it compared to that of other mammals? When the same gene is mutated in humans or mice, studies show it frequently leads to high levels of cholesterol and heart disease. The scientists who studied the polar bear’s genome detected multiple mutations in APOB. Since few experiments can be done with grumpy polar bears, they analyzed the changes by computer. They determined that the mutations were very likely to be damaging — that is, likely to degrade or destroy the function of the protein that the gene codes for.

    The only issue Behe cares about is about whether adaptation proceeds predominantly by the recruitment of mutations that degrade molecular function. In his latest piece, he is quite clear about his take-home message:

    For readers who don’t have time to read to the end, here are a couple of take-home lessons:

    * Experimental evidence strongly supports my conclusion (disputed without good reason by Lenski and others) that highly selected mutations in the polar bear genome work by breaking or blunting pre-existing functions.
    * A “function” of a protein is a lower-level molecular feature or activity, such as being a gear or a tether; it should not be confounded with higher-level phenotypic effects, such as “lowers cholesterol” or “makes the organism happy.” Ignoring the distinction leads to much confusion.

    emphasis mine.

    So what is at stake is whether the mutations break some molecular function or not.

  2. dazz: … and constantly challenges the evidence for it [common descent].

    Um. No. I challenge the reasoning, not the evidence.

    X is evidence for common descent says dazz. Why does that count as evidence for common descent dazz? Handwaving begins …

  3. Corneel: So what is at stake is whether the mutations break some molecular function or not.

    Break or blunt.

    So did you misrepresent Behe when you wrote:

    Corneel: Behe OTOH cited an example where the entire gene was knocked out obliterating ALL molecular functions of APOB.

  4. Mung: So did you misrepresent Behe when you wrote:

    Corneel: Behe OTOH cited an example where the entire gene was knocked out obliterating ALL molecular functions of APOB.

    I don’t think so. What makes you say that?

    Clearly, the knock-out simply nukes all of the molecular functions of APOB, whereas the fixed mutations in polar bears were conspicuously clustered in the domain encoding the surface region which contains the majority of functional domains for lipid transport. Behe has been glossing over the fact that the protein needs to fulfill multiple distinct functions, which is a curious oversight given his preoccupation with the molecular details.

    ETA: precision

  5. Mung: Um. No. I challenge the reasoning, not the evidence.

    X is evidence for common descent says dazz. Why does that count as evidence for common descent dazz? Handwaving begins …

    6 of one, half a dozen of the other. We still have no idea why you believe in common descent. You’ve been explained a thousand fucking times how common descent is inferred from the data and what’s the reasoning behind it. How many times have people linked to Theobald’s “29+ Evidences for Macroevolution” here at TSZ, ffs? Handwaving? What the hell are you talking about?

  6. dazz: You’ve been explained a thousand fucking times how common descent is inferred from the data and what’s the reasoning behind it.

    And yet you still can’t explain it and then blame me. Why don’t you start an OP and do something other than link to a page you’ve shown no evidence that you understand yourself?

  7. Corneel: What makes you say that?

    This:

    Nonetheless, there is no ambiguity about the mouse results. Simply by lowering the amount/activity of APOB, mice were protected from the effects of a high-fat diet. Deletion of one copy of the gene may have made the process of cholesterol removal more efficient, as Rasmus Nielsen speculated above about the polar bear, but it did so by decreasing the activity of mouse APOB.

    That flies directly in the face of your characterization.

    ETA:

    In 1995 researchers knocked out (destroyed) one of the two copies of the APOB gene in a mouse model — the same gene as has been selected in polar bears. Although APOB is itself involved in the larger process of the transport of cholesterol, mice missing one copy of the APOB gene actually had lower plasma cholesterol levels than mice with two copies.

    You make it sound like there was only one copy of the gene and that knocking it out destroyed all APOB function. That is not the case.

  8. Mung: Um. No. I challenge the reasoning, not the evidence.

    Do it formally. Or point to where it’s been done formally in such a way that you specifically stand by it. Or just whine on blogs the rest of your life. Take a stand. Start a blog. State your case in a single place that you can refer people to. Publish a paper. Or just whine on blogs the rest of your life.

    There’s no reason “citizen scientists” can’t change the paradigm. No reason except being unwilling to even try.

  9. Mung: Why don’t you start an OP and do something other than link to a page you’ve shown no evidence that you understand yourself?

    Why would I want to do that? What would be the point when much smarter and much more knowledgeable guys here have already explained those things ad nauseam? I don’t mind admitting I only understand some of it (enough of it to justify my beliefs, I reckon) but at least I don’t think I’m making ridiculous, fundamental reasoning blunders like you do.

  10. This is straight from Theobald’s piece:

    Douglas Theobald:
    What is Meant by “Scientific Evidence” for Common Descent?
    Scientific theories are validated by empirical testing against physical observations. Theories are not judged simply by their logical compatibility with the available data. Independent empirical testability is the hallmark of science—in science, an explanation must not only be compatible with the observed data, it must also be testable. By “testable” we mean that the hypothesis makes predictions about what observable evidence would be consistent and what would be incompatible with the hypothesis. Simple compatibility, in itself, is insufficient as scientific evidence, because all physical observations are consistent with an infinite number of unscientific conjectures. Furthermore, a scientific explanation must make risky predictions— the predictions should be necessary if the theory is correct, and few other theories should make the same necessary predictions.

    As a clear example of an untestable, unscientific, hypothesis that is perfectly consistent with empirical observations, consider solipsism. The so-called hypothesis of solipsism holds that all of reality is the product of your mind. What experiments could be performed, what observations could be made, that could demonstrate that solipsism is wrong? Even though it is logically consistent with the data, solipsism cannot be tested by independent researchers. Any and all evidence is consistent with solipsism. Solipsism is unscientific precisely because no possible evidence could stand in contradiction to its predictions. For those interested, a brief explication of the scientific method and scientific philosophy has been included, such as what is meant by “scientific evidence”, “falsification”, and “testability”.

    In the following list of evidences, 30 major predictions of the hypothesis of common descent are enumerated and discussed. Under each point is a demonstration of how the prediction fares against actual biological testing. Each point lists a few examples of evolutionary confirmations followed by potential falsifications. Since one fundamental concept generates all of these predictions, most of them are interrelated. So that the logic will be easy to follow, related predictions are grouped into five separate subdivisions. Each subdivision has a paragraph or two introducing the main idea that unites the various predictions in that section. There are many in-text references given for each point. As will be seen, universal common descent makes many specific predictions about what should and what should not be observed in the biological world, and it has fared very well against empirically-obtained observations from the past 150+ years of intense scientific investigation.

    It must be stressed that this approach to demonstrating the scientific support for macroevolution is not a circular argument: the truth of macroevolution is not assumed a priori in this discussion. Simply put, the theory of universal common descent, combined with modern biological knowledge, is used to deduce predictions. These predictions are then compared to the real world in order see how the theory fares in light of the observable evidence. In every example, it is quite possible that the predictions could be contradicted by the empirical evidence. In fact, if universal common descent were not accurrate, it is highly probable that these predictions would fail. These empirically validated predictions present such strong evidence for common descent for precisely this reason. The few examples given for each prediction are meant to represent general trends. By no means do I purport to state all predictions or potential falsifications; there are many more out there for the inquiring soul to uncover.

    Is that what you would call handwaiving when it comes to the reasoning behind what data counts as evidence for something and why? Give me a fucking break

  11. Mung [to Corneel]: That flies directly in the face of your characterization.
    You make it sound like there was only one copy of the gene and that knocking it out destroyed all APOB function. That is not the case.

    That would be the implication, I guess, if and only if you are unaware that mice are diploid.
    There’s a certain minimal level of competence that one assumes. In error, apparently. Sigh.
    Still no-one is willing to check the bibliography for mouse ApoB references, huh?

  12. DNA_Jock: Still no-one is willing to check the bibliography for mouse ApoB references, huh?

    Doesn’t appear to be a bibliography.

  13. dazz: This is straight from Theobald’s piece:

    Great. You’re capable of copying and pasting. Soon you’ll able to do simple arithmetic. In a few more decades you may be capable of explaining the reasoning for your beliefs. But I’m not going to hold my breath.

  15. OMagain: whine on blogs the rest of your life.

    Is that going to be the name of your first published paper?

    Catchy title. Be interesting to see how the peer review process goes.

  16. DNA_Jock: With great care. That’s really my point…

    Would it kill you to be more specific???
    You said it yourself you make predictions based on evolution…
    Is there another kind of great care specifically for evolutionary predictions?

  17. DNA_Jock: Could you help me out — Mung is otherwise engaged — what does Behe say in the new book about Farese?

    Is this the paper you have been so mystical about?

    Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1774-8.
    Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes.
    Farese RV Jr1, Ruland SL, Flynn LM, Stokowski RP, Young SG.

    Abstract
    Apolipoprotein B is synthesized by the intestine and the liver in mammals, where it serves as the main structural component in the formation of chylomicrons and very low density lipoproteins, respectively. Apolipoprotein B is also expressed in mammalian fetal membranes. To examine the consequences of apolipoprotein B deficiency in mice, we used gene targeting in mouse embryonic stem cells to generate mice containing an insertional disruption of the 5′ region of the apolipoprotein B gene. Mice that were heterozygous for the disrupted apolipoprotein B allele had an approximately 20% reduction in plasma cholesterol levels, markedly reduced plasma concentrations of the pre-beta and beta-migrating lipoproteins, and an approximately 70% reduction in plasma apolipoprotein B levels. When fed a diet rich in fat and cholesterol, heterozygous mice were protected from diet-induced hypercholesterolemia; these mice, which constitute an animal model for hypobetalipoproteinemia, should be useful for studying the effects of decreased apolipoprotein B expression on atherogenesis. The breeding of heterozygous mice yielded no viable homozygous apolipoprotein B knockout mice. Most homozygous embryos were resorbed by midgestation (before gestational day 11.5); several embryos that survived until later in gestation exhibited exencephalus. The embryonic lethal phenotype was rescued by complementation with a human apolipoprotein B transgene–i.e., human apolipoprotein B transgenic mice that were homozygous for the murine apolipoprotein B knockout mutation were viable. Our findings indicate that apolipoprotein B plays an essential role in mouse embryonic development.”

    If yes, I have referred to it in my comments to Corneel reg embryo development in KO. Behe referred to it or similar studies with same results…

  18. Corneel: I strongly doubt that, since you didn’t actually make a point.

    J-Mac: What’s at issue here is atherosclerosis, or the accumulation of plaque in the arteries:

    I get the impression that Behe accepts that the attenuation of cholesterol levels is the likely mechanism by which mutations in APOB confer their adaptive benefit. From his book (pp. 16-17):

    Boy! Can’t you even distinguish the mechanism from the effect of whatever that mechanism may be?!
    The effect is atherosclerosis. The mechanism of its cause, or prevetion, is at issue here…whether it is high or low receptor affinity or another mechanism…
    When you figure out the difference, let me know…

  19. Thanks. That’s what I thought would be the case.
    Here’s what it looks like from where I am.
    Behe realizes, upon seeing the review in Science, that he made an unwarranted assumption about the nature of the mutations in Liu et al. There is, in fact, no reason to suppose that they are “damaging”. I will leave it to his fans to decide how damaging that discovery is to his thesis.
    In an attempt to save face, he pulls up the Wikipedia page on ApoB and cites the observation from Farese 1995 that what Farese thinks is a knock-out mutation is embryonic lethal when homozygous, but the heterozygote appears protected from diet-induced hypercholesterolemia.
    This appears to be the sum total extent of his research, used to sustain his thesis that “blunting or breaking” the ApoB gene is what allowed polar bears to adapt to a higher fat diet. I would like you to pause and consider the utter insanity of this position. Behe is hanging his hat, in what to all intents and purposes appears to be a post hoc Wikipedia-driven rationalization, on a single paper from 1995.
    This is an immensely complicated field with thousands of publications. But Behe found a paper that is consistent with his position. That’s all the research he needs to do.
    A couple of things amuse me.
    1) Nobody would rely on the idea that an insertion into exon 4 was a null allele; Farese’s “knockout” produces the N-terminal portion of ApoB — it could easily cause weird results in the heterozygote. Abberant trafficking, perhaps?
    Should I mention the tissue-specific RNA-editing that produces a truncated polypeptide? It’s right there in the Wikipedia article…
    2) What is not in the wikipedia article is the other paper from 1995, from Huang et al (J Clin Invest. 1995 Nov;96(5):2152-61.).
    THEY actually did the knock-out properly: they deleted the first three exons, and did back-crosses. They found similar embryonic lethality for the homozygote, but they did not see the weird resistance to diet-induced hypercholesterolemia that Farese saw and that Behe hung his hat on. Huang, with their more rigorous knock-out, saw neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. That’s not going to be adaptive, kiddo.

    What a shoddy piece of work.

  20. DNA_Jock: That would be the implication, I guess, if and only if you are unaware that mice are diploid.
    There’s a certain minimal level of competence that one assumes. In error, apparently. Sigh.
    Still no-one is willing to check the bibliography for mouse ApoB references, huh?

    Even okapidazz knows how to Google… so what’s your point, Jock?

    I copied the abstract of FARESE you have been so keen to review with pictures of mice embryo knock outs…
    Tell us the Darwin Devolves hidden killer you have found there…😉

  21. DNA_Jock:
    Thanks. That’s what I thought would be the case.
    Here’s what it looks like from where I am.
    Behe realizes, upon seeing the review in Science, that he made an unwarranted assumption about the nature of the mutations in Liu et al. There is, in fact, no reason to suppose that they are “damaging”. I will leave it to his fans to decide how damaging that discovery is to his thesis.
    In an attempt to save face, he pulls up the Wikipedia page on ApoB and cites the observation from Farese 1995 that what Farese thinks is a knock-out mutation is embryonic lethal when homozygous, but the heterozygote appears protected from diet-induced hypercholesterolemia.
    This appears to be the sum total extent of his research, used to sustain his thesis that “blunting or breaking” the ApoB gene is what allowed polar bears to adapt to a higher fat diet. I would like you to pause and consider the utter insanity of this position. Behe is hanging his hat, in what to all intents and purposes appears to be a post hoc Wikipedia-driven rationalization, on a single paper from 1995.
    This is an immensely complicated field with thousands of publications. But Behe found a paper that is consistent with his position. That’s all the research he needs to do.
    A couple of things amuse me.
    1) Nobody would rely on the idea that an insertion into exon 4 was a null allele; Farese’s “knockout” produces the N-terminal portion of ApoB — it could easily cause weird results in the heterozygote. Abberant trafficking, perhaps?
    Should I mention the tissue-specific RNA-editing that produces a truncated polypeptide? It’s right there in the Wikipedia article…
    2) What is not in the wikipedia article is the other paper from 1995, from Huang et al (J Clin Invest. 1995 Nov;96(5):2152-61.).
    THEY actually did the knock-out properly: they deleted the first three exons, and did back-crosses. They found similar embryonic lethality for the homozygote, but they did not see the weird resistance to diet-induced hypercholesterolemia that Farese saw and that Behe hung his hat on. Huang, with their more rigorous knock-out, saw neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. That’s not going to be adaptive, kiddo.

    What a shoddy piece of work.

    You have typed all this in less than a minute??? 😉

  22. DNA_Jock: 2) What is not in the wikipedia article is the other paper from 1995, from Huang et al (J Clin Invest. 1995 Nov;96(5):2152-61.).
    THEY actually did the knock-out properly: they deleted the first three exons, and did back-crosses. They found similar embryonic lethality for the homozygote, but they did not see the weird resistance to diet-induced hypercholesterolemia that Farese saw and that Behe hung his hat on. Huang, with their more rigorous knock-out, saw neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. That’s not going to be adaptive, kiddo.

    Is this the Darwin Devolves revolver study, Jock?

    “apo B gene knockout in mice results in embryonic lethality in homozygotes and neural tube defects, male infertility, and reduced HDL cholesterol ester and apo A-I transport rates in heterozygotes.
    Huang LS1, Voyiaziakis E, Markenson DF, Sokol KA, Hayek T, Breslow JL.

    Abstract
    apo B is a structural constituent of several classes of lipoprotein particles, including chylomicrons, VLDL, and LDL. To better understand the role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse. Homozygous apo B deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some live-born heterozygotes developing hydrocephalus. The majority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were decreased in heterozygotes, presumably contributing to the decreased LDL levels through decreased synthesis of apo B-containing lipoproteins. Kinetic studies indicated that heterozygotes had decreased transport rates of HDL cholesterol ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged, the mechanism for decreased apo A-I transport must be posttranscriptional. Heterozygotes also had normal cholesterol absorption and a normal response of the plasma lipoprotein pattern to chronic consumption of a high fat, high cholesterol, Western-type diet. In summary, we report a mouse model for apo B deficiency with several phenotypic features that were unexpected based on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. This model presents an opportunity to study the mechanisms underlying these phenotypic changes.”
    😉

  23. ROFL, no J-Mac.
    While I was typing, you were busy shooting yourself in the foot. My comment was a response to Mung, not you. And the reason I was asking about Farese, is because Behe cited it online, this week, to support his case. I was pretty sure that he was picking cherries out of his ass, but I needed one of you suckers who bought his book to confirm for me that there is no mention of Farese in the book, thereby confirming that it was a total ad hoc defense. While I was waiting, I discovered the awesome wikiepedia connection.
    I read Farese the day that Behe first cited it. I also read Huang 1995: you should read it too: it is much more rigorous.
    Your condescension is delightfully misplaced.

  24. Good. You can cut and paste. Now try reading for comprehension, in particular the paragraph that begins “While this work was in preparation, Farese et al…”
    LOL

  25. DNA_Jock:
    ROFL, no J-Mac.
    While I was typing, you were busy shooting yourself in the foot. My comment was a response to Mung, not you. And the reason I was asking about Farese, is because Behe cited it online, this week, to support his case. I was pretty sure that he was picking cherries out of his ass, but I needed one of you suckers who bought his book to confirm for me that there is no mention of Farese in the book, thereby confirming that it was a total ad hoc defense. While I was waiting, I discovered the awesome wikiepedia connection.
    I read Farese the day that Behe first cited it. I also read Huang 1995: you should read it too: it is much more rigorous.
    Your condescension is delightfully misplaced.

    I DIDN’T buy his book…you know… lol
    Read my previous comment AGAIN about FARESE or similar studies….
    Don’t jump into conclusions next time…😂🤣

  26. J-Mac,

    I was pretty sure that he was picking cherries out of his ass,

    I did not realize he had this special talent 🙂

  27. colewd:
    J-Mac,

    I did not realize he had this special talent 🙂

    Jock got into a sock… He had thought he set me up but he got too anxious and pulled the trigger too early and shot himself in the ass instead… 🤣
    He is trying to recover from the “polar bear white fur coat” embarrassment… but he is not the only one…Behe scored so big on it, he didn’t even mention it in his last rebuttal to Lenski and the other less known musketeers…😂

  28. Mung: You make it sound like there was only one copy of the gene and that knocking it out destroyed all APOB function. That is not the case.

    Ah, OK. I see why it sounded like that to you. No, a complete gene knock-out* destroys all function of the product it encodes, but heterozygotes have the spare copy of course. Things got lost in translation I suppose. It doesn’t really affect my argument though.

    * which apparantly it is not. That’s zealous, DNA_Jock.

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