The Function Wars: Part IV

The world is not inhabited exclusively by fools and when a subject arouses intense interest and debate, as this one has, something other than semantics is usually at stake.
Stephan Jay Gould (1982)This is my fourth post on the function wars.

The first post in this series covered the various definitions of "function" [Quibbling about the meaning of the word "function"]. In the second post I tried to create a working definition of "function" and I discussed whether active transposons count as functional regions of the genome or junk [The Function Wars: Part II]. I claim that junk DNA is DNA that is nonfunctional and it can be deleted from the genome of an organism without affecting its survival, or the survival of its descendants.

In the third post I discussed a paper by Rands et al. (2014) presenting evidence that about 8% of the human genome is conserved [The Function Wars: Part III]. This is important since many workers equate sequence conservation with function. It suggests that only 8% of our genome is functional and the rest is junk. The paper is confusing and I'm still not sure what they did in spite of the fact that the lead author (Chris Rands) helped us out in the comments. I don't know what level of sequence similarity they counted as "constrained." (Was it something like 35% identity over 100 bp?)

My position if is that there's no simple definition of function but sequence conservation is a good proxy. It's theoretically possible to have selection for functional bulk DNA that doesn't depend on sequence but, so far, there are no believable hypothesis that make the case. It is wrong to arbitrarily DEFINE function in terms of selection (for sequence) because that rules out all bulk DNA hypotheses by fiat and that's not a good way to do science.

So, if the Rands et al. results hold up, it looks like more that 90% of our genome is junk.

Let's see how a typical science writer deals with these issues. The article I'm selecting is from Nature. It was published online yesterday (Aug. 6, 2014) (Woolston, 2014). The author is Chris Woolston, a freelance writer with a biology background. Keep in mind that it was Nature that started the modern functions wars by falling hook-line-and-sinker for the ENCODE publicity hype. As far as I know, the senior editors have not admitted that they, and their reviewers, were duped.

When will they ever learn?

On most days I'm an optimist. I think that eventually the truth will win out and all you have to do is convince people that they are misguided. That's why I spend so much time discussing the view of Intelligent Design Creationists. On the good days, I firmly believe that if I can show them what science is all about then they will come around to accepting evolution.

I cherish a few modest successes over the years. For example, a few months ago I tried to teach David Klinghoffer and his friends about modern concepts of evolution and genetics. The example I used was the 98% sequence similarity between the human and chimp genomes. I showed him that the similarity is quite consistent with our understanding of Neutral Theory and random genetic drift [Why are the human and chimpanzee/bonobo genomes so similar?].

A remarkable thing happened. Some of the Intelligent Design Creationists on Evolution News & Views (sic) and Uncommon Descent actually agreed with me! They tried to explain to their fanatical friends that chimps and humans really do share a common ancestor and that the differences between them are explained by evolutionary theory. (I've included links to all the posts at the bottom of this post.)

Just when you think you are making some progress, the IDiots prove you wrong. Yesterday on Uncommom Descent there was a post on the topic of the similarity between chimps and humans [At last, a proposed answer re 98% human-chimpanzee similarity claim]. The author was probably Barry Arrington posting as "News." Here's the relevant part of that post ...

From this comment (by Gordon Davisson, in response to this post):

In other words, I’m agreeing with Denyse here:

BUT claimed 98% similarity due to a common ancestor (a claim that hundreds of science writers regularly make, in support of common descent) *undermines anything else they have to say on the subject.*

I do not know how to put the matter more simply than this: A person who does not see the problem is not a credible source of information.

He responds:

…just disagreeing about which side is not credible. Take the 98% similarity figure as an example: one of the basic principles of science is that you must follow the evidence. If the evidence supports the 98% figure, and that conflicts with your intuition, then you either have to throw that intuition into the trash bin, or stop claiming to be doing science.

No. Absolutely not.

One should never discard intuitions formed from experience, especially about vast claims. Chimpanzees are so obviously unlike humans – in any way that matters – that claimed huge similarities only cast doubt on genetic science.

This is called, among other things, wanting to have your cake an eat it too. The IDiots want you to believe that they accept all of modern science and that their "theory" is consistent with the evidence.

On the other hand, if the science of genetics leads to conclusions that contradict your "intuition" then the science must be wrong.

We've known for decades that this is how the IDiots really think but it's interesting to see someone like Barry Arrington express it so openly.

Now all we have to do is sit back and wait for the more intelligent IDiots to point out that we've been through all that a few months ago and Barry's intuition is wrong. Instead, what we're seeing is Barry Arrington doubling down [Sun orbits Earth vs. Chimps are people too – the differences].

This is not a good day. It's hard for me to remain optimistic.

An Intelligent Design Creationist explains why chimpanzees and humans are so similar
IDiots respond to the evidence for evolution of chimpanzees and humans
A creationist illustrates the argument from ignorance while trying to understand population genetics and Neutral Theory
Breaking news: Creationist Vincent Torley lies and moves goalposts
Vincent Torley apologizes and claims that he is not a liar
Vincent Torley tries to understand fixation
On the frustration of trying to educate IDiots
Why creationists think they are more open-minded than scientists
What would happen if Intelligent Design Creationists understood evolution?
Branko Kozulic has questions about fixation
Branko Kozulic responds
Branko Kozulic responds: Part II

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Stephen Meyer isn't keeping up

There are so many problems with Darwin's Doubt that one hardly knows where to begin. For me, the most important problem is that Meyer dismisses all the evidence for pre-Cambrian ancestors. These ancestors had most of the genes necessary to make all the animals that arose during the Cambrian explosion.

Our current model for evolution and development is that small changes in the regulation and timing of key developmental genes are responsible for big phenotypic differences, including new animal body plans. The data shows that all the animal phyla have similar genes and that there aren't very many genes whose origins can be traced to the Cambrian.

... those ignorant of history are not condemned to repeat it; they are merely destined to be confused.

Stephen Jay Gould
Ontogeny and Phylogeny (1977)This model was popularized by Stephen Jay Gould in his 1977 book Ontogeny and Phylogeny. Meyer disputes this model. He claims that massive amounts of new information (= new genes) arose at the time of the Cambrian explosion. He claims that this cannot be explained by any naturalistic means; therefore, god(s) must have made those strange Cambrian animals. (Presumably, the gods are also responsible for making them go extinct.)

Charles Marshall, a paleontologist at UC Berkeley (USA) wrote a critical review of Darwin's Doubt [When Prior Belief Trumps Scholarship]. Here's part of what Marshal wrote in September 2012.

Why don't scientists believe in a creator?

Gordon E. Mullings ("kairosfocus") just can't understand why scientists haven't become believers in a creator who designs life [BA77′s observation: "many influential people in academia simply don’t want Design to be true no matter what evidence . . ."]. He quotes BA77 (really!) ...

The inimitable BA77 observes:

I [used] to think that if ID could only get its evidence to the right people in the right places then they would change their mind about Darwinian evolution and we would have a fundamental ‘paradigm shift’ from the ‘top down’. But after a few years of banging my head on that wall to no avail, I realized that it is not a head problem with these people so much as it is a heart problem. i.e. many influential people in academia simply don’t want Design to be true no matter what evidence you present to them. Indeed, in many educational institutions, there is a systematic effort in academia to Expel anyone who does not toe the Darwinian party line.

He concludes: "Thus the growth in popular support for ID has been more of a ‘bottom up’ affair."

Mullings presents a diagram that's supposed to demonstrate the evidence for Intelligent Design Creationism (right, above).

There are many reasons why "people in academia" have not been convinced by "evidence" like that presented by Bill Dembski. The most important reason is that the "evidence" isn't really evidence at all. It has been refuted repeatedly by people who know what they are talking about. There is no evidence for the existence of a creator who meddles in the affairs of living organisms.

But the real reason why people like BA77 and kairosfocus are puzzled has nothing to do with evidence. They believe in the existence of gods(s); therefore; they already believe in a creator so it's no big leap to "make sense" of biology in the light of god(s). What they don't understand is that for nonbelievers the "evidence" of Intelligent Design Creationism (if it existed) is only a small part of the path towards believing in a divine creator.

It's a heart problem. Intelligent Design Creationists are absolutely convinced that god(s) exist so they don't realize that Dembski's argument falls into category of "extraordinary claim" since it requires the existence of creators. It's not sufficient just to cast doubt on evolution and question scientific evidence. You also have to propose an alternative explanation and that hypothesis includes evidence for the designer. That kind of extraordinary claim requires extraordinary evidence and the IDiots haven't even come close to providing it.¹

People like Gordon E. Mullings and BA77 have been trying to convince "infuential people in academia" for over 200 years. Generation after generation of academics have rejected their "evidence" and their logic. It's about time that the IDiots came to grips with the truth; namely, that they don't have any proof of the existence of god(s) and they never will.

They also need to stop fooling themselves about their "success" among the general public. Belief in god(s) is declining all over the world.

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1. As most of you already know, the IDiots try to avoid talking about the Intelligent Design Creator. They claim that the "evidence" for his/her/their existence stands on it's own. All they want is for you to accept the "evidence" for the existence of god(s). What you do with that "evidence" is up to you. They aren't concerned about that part because they've already taken the leap.

Atheists really do believe in god!!!

Last year at this time I was in Copenhagean, Denmark. This is a country full of people who don't believe in god(s). At least they think they don't believe in gods. Turns out they are probably wrong according to Casey Luskin [Evolutionary Studies Suggest that Atheists, Whatever They Say to the Contrary, Really Do Believe in God].

Luskin thinks that evolution is true after all, especially when it supports his prejudices beliefs. He quotes some really silly articles that make a really silly claim; namely, that it's impossible for all those Danes to have abandoned belief in gods because lack of belief in gods is psychologically impossible. We have evolved to believe in Loki and Freyr and there's no escaping our evolutionary destiny.

Just when you think that the IDiots can't get any stupider, they come up with something like this.

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Taking the Behe challenge!

Michael Behe thinks the main thesis of his book, The Edge of Evolution, has been vindicated by a recent paper (Summers et al., 2014). He is wrong, as I discussed in a previous post [Michael Behe and the edge of evolution].

PZ Myers and Ken Miller have already made the same points that I make but the IDiots never listen when their view are challenged. Instead, they go on the attack and claim that the latest publications refute evolution and support Intelligent Design Creationism.

Behe is certain that he's right. He's so certain that he has issued a challenge to Myers and Miller [An Open Letter to Kenneth Miller and PZ Myers]. I'm going to try and do some calculations to meet his challenge but I'm not certain if I'm doing them correctly. Please help me find any mistakes.

Michael Behe and the edge of evolution

Michael Behe's book, The Edge of Evolution, is very interesting. His main thesis is that there are some genotypes that are beyond the reach of evolution. His examples include genotypes where two or three mutations have to occur simultaneously in order to achieve an effect. The probability to this happening is extremely remote but it could happen in some populations with very large effective population sizes.

The reason why mutations have to happen simultaneously in the same organism, according to Michael Behe, is because any one of them, by itself, is detrimental. This defines the edge of evolution because it's a result that cannot be achieved by mutation and selection (or by drift).

Behe is correct. If a given phenotype absolutely requires that two mutations happen simultaneously then this is going to be almost impossible in most species.

IDiot book by Stephen Meyer can't be refuted by scientists

The IDiots at the Discovery Institute have evolved something that they think is a winning strategy. They publish a book that has lots of scientific-sounding words then they embark on a massive publicity campaign to promote it as the latest scientific breakthroughs showing that evolution is wrong (and, therefore, God did it). Then they wait for the bad reviews to come in and concentrate on rebutting the reviewers. They get as much publicity by pretending that the reviewers are biased as they do from selling the books in the first place.

They use four main tactics to avoid admitting that they are wrong [see What Do You Do When All the Reviews Are Bad?]. One of them is to claim that all the reviewers are ignoring the main arguments in the book. That's what Stephen Meyer does in the video below. It's titled, "The Biggest Failure of Critics." (Warning, this has been tested with the Mark X Irony Meter and it passes. I can't guarantee that earlier models will survive.)

The Function Wars: Part III

This is Part III of several "Function Wars"¹ posts.

How much of the human genome is conserved?

The first post in this series covered the various definitions of "function" [Quibbling about the meaning of the word "function"]. In the second post I tried to create a working definition of "function" and I discussed whether active transposons count as functional regions of the genome or junk [The Function Wars: Part II]. I claim that junk DNA is DNA that is nonfunctional and it can be deleted from the genome of an organism without affecting its survival, or the survival of its descendants.

The best way to define "function" is to rely on evolution. DNA that is under selection is functional. But how can you determine whether a given stretch of DNA is being preserved by natural selection? The easiest way is to look at sequence conservation. If the sequence has not changed at the rate expected of neutral changes fixed by random genetic drift then it is under negative selection. Unfortunately, sequence conservation only applies to regions of the genome where the sequence is important. It doesn't apply to DNA that is selected for its bulk properties.

The most important rule for publishing a paper on alternative splicing

I'm not a big fan of alternative splicing. I think it falls into the same category as pervasive transcrition—most of it is accidental [see Alternative Splicing and Why IDiots Don't Understand How Science Works and A Challenge to Fans of Alternative Splicing ]. The error rate for splicing is known to be high [Splicing Error Rate May Be Close to 1% ].

I just read a paper about alternative splicing in Science (Lo et al., 2014) and it annoys me that a key piece of data was left out. The missing data is the abundance of the rare transcripts that are presumed to be genuine, alternatvely spliced, variants. Are they present at more than one copy per cell?

We need to know this in order to decide whether the detection of alternatively spiced variant is biologically significant. You should not be able to publish a paper on this topic without presenting your data on relative and absolute abundance [see Extraordinary Claims about Human Genes and How to Evaluate Genome Level Transcription Papers]. Surely this is obvious, having just been through the ENCODE publicity hype disaster.

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Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P. X-L, Yang, K-F. Au, W. H. Wong, M. Guo, M. Zhang, and P. Schimmel1 (2014) Human tRNA synthetase catalytic nulls with diverse functions. Science 345:328-332. [doi: 10.1126/science.1252943]

Walter Gehring (1939 - 2014)

I just learned today that Walter Gehring died in a car accident in Greece on May 29th. I learned of his death from the obituary by Michael Levine in Science [Walter Gehring (1939–2014)]. There's another obituary on the Biozentrum (Basel, Switzerland) website [Obituary for Walter Gehring (1939 – 2014)]. He was only seven years older than me.

I first met Walter Gerhing when I was a post-doc in Alfred Tissières lab in Geneva (Switzerland) in the mid-1070s. The two labs collaborated on cloning and characterizing the major heat shock gene (Hsp70) of Drosophila melanogaster. Paul Schedl and Spyros Artavanis-Tsakonis made the library in Gehring's lab in 1976-1977 and Marc-Edouard Mirault and I isolated the mRNA for screening and then identified the genes we cloned. The result was three papers in Cell (see below). (John Lis, then in David Hogness' lab, was cloning the same gene.)

I met Gerhing dozens of times but I only had a few conversations with him one-on-one. We always talked about evolution. I always found him to be very charming and very curious and not embarrassed to admit that he didn't know something. Other post-docs and students in his lab have different impressions.

As Michael Levine puts it ...

An amazing group of students and postdocs was attracted to the Gehring lab over the years: Eric Wieschaus (Nobelist), Christianne Nüsslein-Volhard (Nobelist), David Ish-Horowicz, Spyros Artavanis-Tsakonas, Paul Schedl, Alex Schier, Georg Halder, Hugo Bellen, and Markus Affolter, to mention just a few. I worked closely with two of my future lifelong friends and colleagues: Ernst Hafen and Bill McGinnis. The lab was an absolute blast, but a strange mix of anarchy and oppression. Walter permitted considerable independence, but was hardly laissez-faire. He could be confrontational, and did not hesitate to call us out (particularly me) when he felt we were misbehaving.

I found Walter to be a complicated character. He had the mannerisms of an authoritative Herr Doktor Professor, but was also folksy and unaffected and always ready to laugh and joke. He sometimes felt competitive with his students and postdocs, but was also highly supportive and proud of our independent careers. In short, I believe the key to Walter's success was his yin and yang embodiment of old-world scholar and modern competitive scientist. He was able to exude charm and empathy, but nothing we did seemed to be quite good enough. In other words, tough love, possibly the perfect prescription for eliciting the very best efforts from his students and postdocs.

Walter Gehring was one of a small group people who changed the way I think about science.

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Artavanis-Tsakonas, S., Schedl, P., Mirault, M.-E., Moran, L. and J. Lis (1979) Genes for the 70,000 dalton heat shock protein in two cloned D. melanogaster DNA segments. Cell 17, 9-18. [doi: 10.1016/0092-8674(79)90290-3]

Moran, L., Mirault, M.-E., Tissières, A., Lis, J., Schedl, P., Artavanis-Tsakonas, S. and W.J. Gehring (1979) Physical map of two D. melanogaster DNA segments containing sequences coding for the 70,000 dalton heat shock protein. Cell 17, 1-8. [doi: 10.1016/0092-8674(79)90289-7]

Schedl, P., Artavanis-Tsakonas, S., Steward, R., Gehring, W. J., Mirault, M.-E., Goldschmidt-Clermont, M., Moran, L. and A. Tissières (1978) Two hybrid plasmids with D. melanogaster DNA sequences complementary to mRNA coding for the major heat shock protein. Cell 14, 921-929. [doi: 10.1016/0092-8674(78)90346-X]

How many genes do we have and what happened to the orphans?

How many genes in the human genome? There's only one correct answer to that question and that's "we don't know."

The main problem is counting the number of genes that produce functional RNA molecules. The latest Ensembl results are based on build CRch37 from February 2009 and the GENCODE annotation from last year (GENCODE 19) [see Human assembly and gene annotation and Harrow et al., 2014]

The most recent estimates are 20,807 protein-encoding genes, 9,096 genes for short RNAs, and 13,870 genes for long RNAs. This gives 43,773 genes. Nobody knows for sure how many of the putative genes for RNAs actually exist. They may only be a few thousand functional genes in this category.

It's a lot easier to figure out whether a gene really encodes a functional protein so most of the annotation effort is focused on those genes. I want to draw your attention to a recent paper by Ezkurdia et al. (2014) that discusses this issue. The authors begin with a bit of history ...

Transcription Initiation Sites: Do You Think This Is Reasonable? (revisited)

I'm curious about how different people read the scientific literature. My way of thinking about science is to mentally construct a model of how I think things work. The more I know about a subject, the more sophisticated the model becomes.

When I read a new paper I immediately test it against my model of how things are supposed to work. If the conclusions of the paper don't fit with my views, I tend to be very skeptical of the paper. Of course I realize that my model could be wrong and I'm always on the lookout for new results that challenge the current dogma, but, in most cases, if the paper conflicts with current ideas then it's probably flawed.

This is what people mean when they talk about making sense of biology. The ENCODE papers don't make sense, according to my model of how genomes work so I was immediately skeptical of the reported claims. The arseniclife paper conflicted with my understanding of the structure of DNA and how it evolved so I knew it was wrong even before Rosie Redfield pointed out the flaws in the methodology.

Finding the "perfect" enzyme

I got an email message yesterday from a student who is taking a summer course in biochemistry. His professor asked the class to find "most efficient enzyme known to man." The professor gave them a hint by telling them that the enzyme had something to do with nucleotide biosynthesis. The student contacted me because some of my blog posts popped up on Goggle. He (the student) was a bit confused about how to define the "perfect" enzyme.

There are two different ways of defining the "perfect" enzyme and both of them are wrong because there's no such thing. The common textbook definition picks up on the idea that the "perfect" enzyme catalyzes a reaction every time it encounters a substrate(s). These enzyme rates are referred to as "diffusion-controlled" rates since the rate is limited only by the rate at which substrate diffuses into the reaction site on the enzyme. Some enzymes can even catalyze reactions that are slightly faster than the diffusion-controlled limit.

Here's what Voet & Voet (4th edition) say (page 490) ...

The Central Dogma according to Riken

You may never have heard of Riken. Here's what they say on their website [Riken] ...

RIKEN is Japan's largest comprehensive research institution renowned for high-quality research in a diverse range of scientific disciplines. Founded in 1917 as a private research foundation in Tokyo, RIKEN has grown rapidly in size and scope, today encompassing a network of world-class research centers and institutes across Japan.

They've published a video on the Central Dogma. Here's how they describe it ...

The 'Central Dogma' of molecular biology is that 'DNA makes RNA makes protein'. This anime shows how molecular machines transcribe the genes in the DNA of every cell into portable RNA messages, how those messenger RNA are modified and exported from the nucleus, and finally how the RNA code is read to build proteins.

The video was made by RIKEN Omics Science Center (RIKEN OSC) for the exhibition titled 'Beyond DNA' held at National Science Museum of Japan. RIKEN OSC has published in Nature Genetics on the regulation of RNA expression in human cancer cells.

Most of you know that I have a different view of The Central Dogma of Molecular Biology but that's not what I want to discuss here. Watch the video. Do you think it's a good idea to show this process as well-designed little machines and ships? It sure gets the IDiots excited {RIKEN’s 10-minute antidote to atheism: see for yourself].

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