Friday, June 04, 2010

IDiots Do Arithmetic a Second Time - Same Result

Yesterday I wrote an article about Richard Sternberg and his lack of knowledge of molecular biology. I also took a swipe at his poor arithmetic skills, based on his misunderstanding of biology [Creationists, Introns, and Fairly Tales]. Read the comments to see why we still refer to Intelligent Design Creationists as IDiots.

Imagine my surprise when Sternberg responded with a "correction"! [Let's Do the Math Again].
Earlier today I criticized Calvin College biologist Steve Matheson’s incorrect view of “junk” DNA. Matheson had argued in February that the human genome contains about 190,000 introns (stretches of non-protein-coding DNA that interrupt protein-coding genes), of which “only a handful” had important functional roles. “How many? Oh, probably a dozen,” he wrote, “but let's be really generous. Let's say that a hundred introns in the human genome are known to have ‘important functional roles.’ Oh fine, let's make it a thousand.”

On the contrary, I pointed out that at least 90% of genes are alternatively spliced, meaning that 0.9 x 190,000 = 171,000 introns are involved in alternative splicing, an essential process that helps to ensure that the proper proteins are made at the correct developmental stage and in the appropriate cells and tissues.

Along comes University of Toronto biochemist Larry Moran, an outspoken Darwinist who hates the Center for Science and Culture so much he would probably heap abuse on us for saying that the Earth goes around the Sun. Sure enough, Moran wasted no time jumping on me for being an “Intelligent Design Creationist.” He posted the relevant portion of my critique and concluded: “It's up to you, dear readers, to figure out all the things wrong with this explanation. You can start with the math. Arithmetic isn't one of their strong points.”
A few minor corrections ...
  1. I am not a Darwinist [Why I'm Not a Darwinist]
  2. I don't hate the Center for Science and Culture. I mock it. It's a joke.
  3. Richard Sternberg supports intelligent design and be believes in a creator who used intelligent design to create life. Therefore, he is an Intelligent Design Creationist.
So let’s do the math. Again. I will make the task easy for everyone—even Moran and Matheson:

Step 1. There are ~25,000 protein-coding genes in the human genome.
Step 2. There are 190,000 introns/25,000 protein-coding genes = 7.6 introns/gene on average.
Step 3. Ninety percent (possibly more) of gene transcripts undergo alternative splicing. Hence, 0.9 x 25,000 = 22,500 genes (actually, their RNAs) undergo alternative splicing.

Therefore, 22,500 genes x 7.6 introns/gene = 171,000 introns involved in alternative splicing.

This is just a rough estimate, of course. And as I wrote in my original critique of Matheson, even if I’m off by a factor of two we are still left with far more functional introns than Matheson acknowledges. This compels me to ask Steve Matheson: How exactly did you come up with your estimates? And what about you, Larry Moran? What sort of arithmetic are you using?
I'm using arithmetic that's based on an understanding of basic molecular biology and the scientific literature.

We could quibble about the number of introns—I think it's closer to 150,000. We could quibble about the number of protein encoding genes—the most accurate number is 20,500. We could quibble about how many genes exhibit alternative splicing—I think it's about 5%, not 95%. You can't be expected to know the facts and the controversies since this is way outside your area of expertise.

So, let's assume your facts are correct. If 90% of genes exhibit alternative splicing then this means 22,500 genes. You got that calculation right. The minimum number of introns that must be involved in alternative splicing is one (1) per gene. That means at least 22,500 introns involved in alternative splicing. You made the mistaken (and stupid) assumption that every intron in a gene had to be alternatively spliced.

The fact that you repeated this false assumption, even after being warned, does not enhance your credibility. I conclude that you don't understand RNA processing or alternative splicing. In spite of your ignorance you wrote up a posting attacking Steve Matheson and defending your colleague Steve Meyer. That's why we call you IDiots.


22 comments:

  1. Hmmm. When is an intron not an intron? When it's an exon. 'True' introns are never involved in alternative splicing. If a segment is never included in a protein, then it's unambiguously an intron. If a segment is always included intact in every variant , then it's an unambiguous exon.

    The rest are part-timers, and you calls 'em as you sees 'em. "Intron"/"exon" status is relative to a particular translated protein, not the DNA or initial mRNA transcript. The elements doing the excision and splicing contain the code.

    The fact that exons are bounded creates a gap into which 'useless' sequence can squeeze. As long as the ends are recognised, the rest of the intron can do what it likes.

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  2. Larry, you wrote:
    Richard Sternberg supports intelligent design and be believes in a creator who used intelligent design to create life.
    Are you sure about that last part? I don't know whether Sternberg is a theist, much less a creationist. But I've never bothered to check, because I don't care.

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  3. I also think it is quite egotistical of ID creationists to focus an argument on introns/exons. Just because we happen to be euks doesn't necessarily mean we are the pinnacle of "evolutionary success" or an "intelligent design".

    I guess it irks me that the argument neglects the largest and most diverse biomass on earth (bacteria and archaea). I wonder how the lack of intron/exon structure fits into the ID model?

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  4. Steve Matheson says,

    I don't know whether Sternberg is a theist, much less a creationist.

    I suppose you could be a theist who doesn't believe in a creator god. It's theoretically possible. Do you know of any examples? Until I see one, I'll continue to assume that all theists are creationists.

    I suppose you could be a supporter of intelligent design without actually believing in a supernatural designer or creator. Do you know of any examples?

    I think I'm on pretty solid ground using the term Intelligent Design Creationist to describe Sternberg. If he writes in and declares that he doesn't believe in a creator God then I'll retract.

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  5. I don't know much about what Sternberg believes. His Wikipedia entry (as of today) says that he "is not a proponent of intelligent design." It also says that he's a Roman Catholic, and that does make him a theist who believes in a creator God. Whether that makes him an "intelligent design creationist," I don't know, and I certainly don't care.

    Yes I think you can accept ID without asserting supernatural action; I guess you'd have to posit alien superintelligence. And a deist comes pretty close to your first description. But no matter; I was just curious about why you identified Sternberg as a believer.

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  6. Alien superintelligence doesn't explain where the aliens came from, so that's not really valid to say they don't believe in a supernatural creator. They just move it one step back. The aliens either are the result of natural process, thereby showing they don't believe in intelligent design, or the aliens have to be a result of the supernatural. A lack of supernatural violates ID because one of the key assumptions of ID is that life is too complex to come from natural processes.

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  7. You DO realize that your defense doesn't actually address the criticism you made about his arithmetic skills, right? (Twice, by now). See, your complaint was about his math skills: "I also took a swipe at his poor arithmetic skills, based on his misunderstanding of bilogy". The problem is that his math is right, but by your criticism his biology is wrong.

    But I suppose it's funnier to claim that he can't do math ...

    Come on, be fair, and admit when you overstate an objection.

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  8. Actually, especially since by your own argument he could be right:

    "The minimum number of introns that must be involved in alternative splicing is one (1) per gene. That means at least 22,500 introns involved in alternative splicing. You made the mistaken (and stupid) assumption that every intron in a gene had to be alternatively spliced. "

    So, yeah, at least 22,500. But if it happened to be the case that all of the introns WERE involved in alternative splicing, he'd be right (I hasten to add that I don't think that actually happens). Thus, to get a reasonable discussion at this point between the two of you either he'd have to prove that they are all involved, you'd have to prove that one intron is always involved, or we'd have to calculate the average number of introns involved in alternative splicing. Since I don't have data and would therefore want to just make a rough estimate, I'd presume that the number of introns involved is basically evenly distributed (ie there's no particular reason for lesser or greater numbers of introns to be involved, so you should see an even distribution of the numbers of introns involved) I'll round the 7.6 up and get an average of 4 (8/2). Someone can correct me if I'm making a mistake on my averaging based on equal distribution. That would give about 90,000. You can round the 7.6 down and get 78750. All are pretty close to that "factor of 2" comment that he made.

    Now, none of this works at all if the biology is wrong, but if he's assuming (wrongly) high and you're assuming (wrongly) low, then neither of you are getting it right.

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  9. So, um, does Evolution News and Views allow comments?

    If not, one wonders why.

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  10. FWIW, Wikipedia quotes this PubMed article as saying that "in humans, over 80% of genes are alternatively spliced", not 5%.

    Other than that, I agree that the guy is way out of his league here.

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  11. The minimum number of introns that must be involved in alternative splicing is one (1) per gene.

    I hate to get involved in in this discussion, but given that we're discussing alternative splicing, shouldn't there at least be 2 introns involved, to provide the alternative splice junctions?

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  12. @Corneel,

    shouldn't there at least be 2 introns involved, to provide the alternative splice junctions?

    I guess since every gene has 2 ends, they take the exon-delimiting role that introns do internally. And not every exon is a full-time exon. That is, AAA-intron-BBB could be expressed AAA, BBB, AAABBB or BBBAAA. Only 2 of those are splices, strictly speaking, but hey!

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  13. @ Allan Miller

    Thanks for your comment

    Yes, that should work. I also realised that a single intron may contain multiple 5' or 3' splice sites.

    cheers

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  14. Larry: "[Sternberg] made the mistaken (and stupid) assumption that every intron in a gene had to be alternatively spliced."

    I think it's worse than that. Not only did Stenrberg make that ridiculous assumption, but he laid it out as the most accurate estimate. He could have at least made it seem as if he wasn't hopelessly biased if he said that this is the least conservative and least probably estimate, but he didn't. Sternberg is engaging in rhetoric, not science.

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  15. You made the mistaken (and stupid) assumption that every intron in a gene had to be alternatively spliced.

    So, if 90% of all high speed collisions (between two cars) have a fatality. And the average number of people in a car is two and there are 10,000 high speed collisions, Stenburm would claim there are .9 * 10,000 * 2* 2 = 36,000 fatalities rather than the correct .9 * 10,000 = 9,000 fatalities?

    I suppose you could be a theist who doesn't believe in a creator god. It's theoretically possible. Do you know of any examples? Until I see one, I'll continue to assume that all theists are creationists.

    Um, are you using "theist" is some way I don't know? If by theist you mean believe in god I can give Jimmy Carter as a theist who isn't a creationist among thousands of others. (I actually don't know any creationists.) But if theist means something else... well, not really worth quibbling over.

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  16. Allan:Now, none of this works at all if the biology is wrong, but if he's assuming (wrongly) high and you're assuming (wrongly) low, then neither of you are getting it right.

    Okay, I know less biology than Sternberg (i.e. I know *none*) but if this is just a matter of random distribution and probability wouldn't the following argument hold?

    90% of genes are alternatively spliced (whatever that means). That means 10% of genes are *not* alternatively spliced. If a gene has 7.8 introns (whatever those are) and none are "involved" (whatever that means) then the odds of a specific intron *not* being involved is the 7.8th root of 1/10 or in other words 75 percent chance of *not* being involved. This means a specific intron has a 25% chance of being involved. Hence .25 * 190,000 = 14,000 are involved.

    I mean, that's math, right?

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  17. Ooops

    .25 * 190,000 = 48,000.

    Don't know *what* key I hit on my calculator to get what I got above.

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  18. 5% of genes are alternatively spliced? That isn't an up to date estimate. Sampling the latest literature it now seems that a substantial percentage (at least 60%) of human genes are the result of intron fcnality in alternative splicing. (Molecular Cell Biology Sixth Edition pg. 126). That text was from 2007. More recent publications say it's 80% and "constantly being revised upwards".

    And this fcnality is signficant as multidomain protiens, for one example, are typical products of this process that play important roles in cellular function and many human diseases are the result of mutations wrt to splice site selection. Molecular Cell Biology Sixth Edition pg. 126, pg. 334)

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  19. Dan says,

    5% of genes are alternatively spliced? That isn't an up to date estimate.

    Yes it is. You may not agree with me but you can be assured that I have read the very latest literature on the subject and I stick by my estimate in spite of what some people say.

    How to Evaluate Genome Level Transcription Papers
    Two Examples of "Alternative Splicing"
    An Example of Faulty Logic from Cold Spring Harbor
    The Frequency of Alternative Splicing
    Making Sense in Biology

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  20. Larry Moran, you said that you stick to the 5% estimate. That is intriguing as the current understanding as expressed in the standard texts (the one I cited earlier) attributes a much larger percentage of human genes to alternative splicing.

    Has there been more recent work that suggests a lower percentage? Can you provide a reference for the 5% estimate? Or can you briefly explain how you interpret the data to come to the 5% estimate?

    Thanks

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  21. Dan asks,

    Can you provide a reference for the 5% estimate? Or can you briefly explain how you interpret the data to come to the 5% estimate?

    I look at specific examples of predicted alternative splicing for those well-studied genes where the structure of the protein is known. As a general rule the predicted variants make no sense whatsoever. They can easily be explained as splicing artifacts.

    I also note that some labs have been studying these gene for decades but have never found any trace of the predicted splice variants.

    Then I look to see if the alternative splice pattern is conserved in other mammals. It's not. I conclude from this that most alternative splicing is an artifact - much like the artifacts associated with unusual transcripts and ESTs.

    The advocates of alternative splicing interpret the lack of conservation differently. They take it as evidence that they have discovered the mechanism of speciation. For them, alternative splicing is what makes humans different from other apes so you don't expect conservation!

    The bottom line is that alternative splicing doesn't hold up when you start to look at specific examples. That's why the predictions are disappearing from the annotated genes in Entrez. At least, they're disappearing from those genes that have been well-studied.

    The only way out of this is to imagine that alternative splicing is only common in those genes that haven't been well-studied. That doesn't seem to me like a good argument.

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  22. Thanks for your explanation. You said: "As a general rule the predicted variants make no sense whatsoever. They can easily be explained as splicing artifacts."


    I assume you mean splicing artifacts unrelated to introns. Can you give some examples of where the previously predicted isoforms turned out to make no sense?

    Would it be correct to say that you think all alternatively spliced genes conserved as synapomorphies in taxon are then real examples of intron fcnality?

    In your framework, Fibronectin and Beta-Globin would represent true intron based alternative spliced genes, because they have been well studied, right?

    So if genes have been well studied, have isoforms related to introns, and are conserved as synapomorphies then you would consider them legitimate?

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