Ford Doolittle talks about transposons, junk DNA, ENCODE, and how science should work

Here's more from the interview with Ford Doolittle [The Philosophical Approach: An Interview with Ford Doolittle].

Gitschier: I want to close with what you describe as your “latest rant.” How did you get on function?

Doolittle: Well, I’ve always been on that.

Back in 1980, people were talking about transposable elements as if their function was to speed evolution; that they exist because of their future utility. And I’ve never liked that kind of idea. I didn’t like it in terms of introns. And Dawkins had just published The Selfish Gene in 1978.

Carmen Sapienza, a student of mine who now works on eukaryotic imprinting, and I wrote a paper which was rejected by Science after seven referees. But we heard that Leslie Orgel and Francis Crick were working on something like this, so we sent it to them. They said, “If you submit it to Nature, we will tell Nature not to publish ours without publishing yours, and to publish yours first,” etc., which was very nice.

That paper, seemingly now very simplistic, said you don’t need to suppose that transposable elements are there for the purpose of speeding evolution. These are selfish things, and natural selection will favor such elements that can make copies of themselves in genomes and then spread horizontally to other genomes within the species. These are basically parasites. I think many people would now accept this, but it was radical at the time.

People don’t like to think that the human genome has junk in it. This came back when the ENCODE papers came out a few years ago and were touted as spelling the “demise of junk DNA.” That got my dander up.

I wrote a perspective in PNAS, and Dan Graur had a much more vituperative thing in Genome Biology and Evolution. I don’t think the ENCODE people have given up; they had a kind of semi-apology in PNAS, which wasn’t really an apology.

It is the same as the tree of life issue, but until we actually have some agreement about what we mean by words we are going to get into these arguments, and in my mind, there are two devastating things you can say about the ENCODE people.

One is that they completely ignored all that history about junk DNA and selfish DNA. There was a huge body of evidence that excess DNA might serve some structural role in the chromosomes, but not informational. They also ignored what philosophers of biology have spent a lot of time asking: what do you mean by “function?” And you can mean one of two things: we might mean either what natural selection favored, which is what I think most biologists mean, or we might mean what it does. Some people might say, “Well the function of this gene is in the development of cancer,” but they don’t really mean that natural selection put it there so that it would cause cancer. These are not-so-subtle differences.

I think many molecular biologists and genomicists, in particular, think that each and every nucleotide is there for a reason, that we are perfect organisms. It is almost as if we were still theists thinking God doesn’t make junk; we just now think natural selection doesn’t make junk. I think there is a deep issue about the extent to which we are noisy creatures and the extent to which we are finely honed machines. I think the latter view informs much of genomics, and I think it is false.

ENCODE wouldn’t have got funded had they said 80% of the human genome is just junk, transposable elements.

Gitschier: It is justifying itself, post hoc. They are the big players with a lot of money. It’s like a machine—“We can do it, so let’s just do it!”

Doolittle: It’s a juggernaut is what you are saying.

My other objection is that it is false ontology. I think all of our science suffers not only from the big science motivation, but from what I call “positivism.”

A couple of times we submitted papers saying, “Everybody’s doing something this way, and it doesn’t work, and it is wrong to do it this way.” And Nature would write back, “We’re not interested in negative reports like this. What does work?” And we say, “We don’t give a damn what does work, it is important to know that what people are doing now is not working.”

There is no critique in science, very little. You can’t actually say, “This doesn’t mean what people say it means.” You’ve got to be “positive;” you’ve got to be moving the program forward all the time. I don’t think that is right.

Now, and down the road, we’re going to tackle directly relevant questions, like what is the meaning of function in the concept of genomics? There are legitimate evolutionary constructs in which you can address transposable elements, and people have not really explored that. Questions about the tree of life, again, and some of the questions we’ve been through are things that continue to interest me and which have a strong philosophical component as well as a data-related component. That’s what I’m interested in pursuing.

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Ford Doolittle talks about the tree of life

There's an interview with Ford Doolittle in PLoS Genetics [The Philosophical Approach: An Interview with Ford Doolittle].

Ford has lots of things to say about the origin of introns, the tree of life, transpsosons, ENCODE, and the meaning of "function." Here's the bit about the tree of life.

Why did they bury Darwin in Westminster Abbey?

I'm gradually starting to work on my book about evolution by accident. The first chapter is "Darwin Died in 1882." The point I'm making is that evolutionary biology is a 21st century discipline not one that's stuck in the nineteenth century.

I was re-reading an old article from the 2006 issue of Skeptical Inquirer with the title¹ I picked for this blog post. The author is W.G. Weyant, an historian at the University of Calgary (Calgary, Alberta, Canada). He says,

Why, then, did they bury Darwin in Westminster Abbey? The brief answer is "because he was dead," but that, while true, clearly is not the whole story."

The whole story is interesting because it reflects the attitudes of late Victorian society in England. This was a time when scientists were honored even if, or especially because, their ideas were upsetting. It appears to be an age when smart, rational, people were admired.

I don't know if this is still true in Europe but it's not true in Canada and it's certainly not true in the USA. Actors and singers are admired, but not intellectuals. I wonder what late Victorian society would have thought on seeing the memorial services for Francis Crick and Michael Jackson? I wonder what they would have thought of Ted Cruz?

Weyant also writes,

Approximately a decade after publication of the "Origin of Species" in 1859, most educated Englishmen, including many of the clergy, had accepted the fact of evolution. More that a few of them were uneasy about where the evidence and their reason were taking them, but they went nevertheless.

That's an interesting way of putting it. Today, we see many people who are faced with the same uneasiness but the response is quite different. When the choice is faith or facts, they choose not to follow the path of reason.

I think we're finally beginning to realize that science and religion are not compatible, confirming the worst fears of educated Victorians back in 1882. Jerry Coyne's new book is likely going to start a serious debate, one that has been largely ignored in the interests of accommodationism.

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1. I wasn't the first to do this; see Why did they bury Darwin in Westminster Abbey?

Jerry Coyne is coming to Toronto!

Save this date: June 10, 20015.

Jerry Coyne is coming to Toronto to talk about his book. He'll be arriving from Vancouver and Imagine No Religion 2015. I'll see him there but I'm not sure I'll be back in Toronto in time. [Centre for Inquiry Canada: Jerry Coyne]

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Are biochemistry instructors going to treat evolution as a core concept or are they going to teach to the MCAT?

The American Society for Biochemistry and Molecular Biology (ASBMB) has recommended that biochemistry courses concentrate on core concepts rather than details. It has defined five categories of core concepts that are essential in understanding biochemistry and molecular biology [see ASBMB Core Concepts in Biochemistry and Molecular Biology: Molecular Structure and Function].

Theme

Better BiochemistryI strongly support the concept of teaching core concepts even though I disagree with many of the actual concepts that are proposed. Here are the five core concepts with links to my discussions.

1. evolution [ASBMB Core Concepts in Biochemistry and Molecular Biology: Evolution ]
2. matter and energy transformation [ASBMB Core Concepts in Biochemistry and Molecular Biology: Matter and Energy Transformation]
3. homeostasis [ASBMB Core Concepts in Biochemistry and Molecular Biology: Homeostasis]
4. biological information [ASBMB Core Concepts in Biochemistry and Molecular Biology: Biological Information]
5. macromolecular structure and function [ASBMB Core Concepts in Biochemistry and Molecular Biology: Molecular Structure and Function]

Molecular Evolution Exam - April 2015

Here's the final exam in my course. Students have to answer the first two questions and three of the next five questions. How would you do?

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1. Choose a subtopic from your essay and explain it better than you did in your essay and/or rebut the comments and criticisms made by the marker/grader.


2. Michael Lynch says in The Origins of Genome Architecture ....
   

   Nothing in Evolution Makes Sense Except in the Light of Population Genetics
   Evolution is a population genetic process governed by four fundamental forces, which jointly dictate the relative abilities of genotype variants to expand through a species. Darwin articulated a clear but informal description of one of those forces, selection (including natural and sexual selection), whose central role in the evolution of complex phenotypic traits is universally accepted, and for which an elaborate formal theory in terms of changing genotype frequencies now exists. The remaining three evolutionary forces, however, are non-adaptive in the sense that they are not the function of the fitness properties of individuals: mutation (broadly including insertions, deletions, and duplications) is the fundamental source of variation on which natural selection acts; recombination (including crossing-over and gene conversion) assorts variation within and among chromosomes; and random genetic drift insures that gene frequencies deviate a bit from generation to generation independently of other forces. Given the century of theoretical and empirical work devoted to the study of evolution, the only logical conclusion is that these four broad classes of mechanisms are, in fact, the only fundamental forces of evolution. Their relative intensity, directionality, and variation over time define the way in which evolution proceeds in a particular context.

   Do you agree with Lynch that “Nothing in Evolution Makes Sense Except in the Light of Population Genetics”? If so, why isn’t population genetics taught in introductory biology courses? If not, why not?


3. Imagine that identical female twins were born to a woman in 1000 AD. Imagine that you could find a direct descendant of each twin in 2015. If you sequence the complete genomes of the descendants, approximately how many differences would you expect to find? How do these compare to the differences between any two randomly selected individuals from the same part of the world? Explain your reasoning and describe any assumptions you make. Think carefully before you answer. The second question is the most important one. (Human mutation rate = 130 mutations per generation. Haploid genome size = 3.2 × 10⁹ bp.)


4. Why do some scientists think that there is no unique tree of life?


5. Many people believe that recombination evolved because it increases genetic variation in a population and this provided a selective advantage over species that didn’t have recombination. Do you agree with this explanation for the evolution of recombination? Why, or why not? What are the other possibilities?


6. What is “evolvability ”and why could it be important in evolution? Why are some scientists skeptical of this claim?


7. Richard Dawkins once wrote,
   

   Even the most ardent neutralist is quite happy to agree that natural selection is responsible for all adaptation. All he is saying is that most evolutionary change is not adaptation. He may well be right, although one school of geneticists would not agree. From the sidelines, my own hope is that the neutralists will win, because this will make it so much easier to work out evolutionary relationships and rates of evolution. Everybody on both sides agrees that neutral evolution cannot lead to adaptive improvement, for the simple reason that neutral evolution is, by definition, random, and adaptive improvement is, by definition, non-random. Once again, we have failed to find any alternative to Darwinian selection, as an explanation for the feature of life that distinguishes it from non-life, namely adaptive complexity.
   
   Richard Dawkins (1986) The Blind Watchmaker. p. 304

   Can you describe situations in Richard Lenski’s ongoing evolution experiment where neutral or deleterious alleles were essential for adaptive change?

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Nature reviews Nessa Carey's book on junk DNA

Read it at" Genetics: We are the 98%. Here's the important bit ...

Finally, Junk DNA, like the genome, is crammed with repetitious elements and superfluous text. Bite-sized chapters parade gee-whizz moments of genomics. Carey's The Epigenetics Revolution (Columbia University Press, 2012) offered lucid science writing and vivid imagery. Here the metaphors have been deregulated: they metastasize through an otherwise knowledgeable survey of non-coding DNA. At one point, the reader must run a gauntlet of baseball bats, iron discs, Velcro and “pretty fabric flowers” to understand “what happens when women make eggs”. The genome seems to provoke overheated prose, unbridled speculation and Panglossian optimism. Junk DNA produces a lot of DNA junk.

The idea that the many functions of non-coding DNA make the concept of junk DNA obsolete oversells a body of research that is exciting enough. ENCODE's claim of 80% functionality strikes many in the genome community as better marketing than science.

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Nessa Carey doesn't understand junk DNA

Nessa Carey is a science writer with a Ph.D. in virology and she is a former Senior Lecturer in Molecular Biology at Imperial College, London.

She has written a book on junk DNA but it's not available yet (in Canada). Judging by her background, she should be able to sort through the controversy and make a valuable contribution to informing the public but, as we've already noted Nessa Carey and New Scientist don't understand the junk DNA debate.

Casey Luskin has a copy of the book so he wrote a blog post on Evolution News & Views. He's thrilled to find someone else who dismisses junk DNA and "confirms" the predictions of Intelligent Design Creationism. I hope Nessa Carey is happy that the IDiots are pleased with her book [New Book on "Junk DNA" Surveys the Functions of Non-Coding DNA].

Human mutation rates - what's the right number?

There's some controversy over the rate of mutations in humans. The latest summary comes from science journalist Ewen Callaway, a Senior Reporter for Nature, writing on March 10, 2015: DNA mutation clock proves tough to set.

Theme

Mutation

-definition
-mutation types
-mutation rates
-phylogeny
-controversies
Let's review what we know. The first thing we have to do is define "mutation" [What Is a Mutation?]. A mutation is any alteration of the nucleotide sequence of a genome. It includes substitutions, insertions, and deletions.

The mutation rate can be described and defined in many ways. For most purposes, we can assume that it's equivalent to the error rate of DNA replication since that accounts for the vast majority of substitutions. Substitutions are far more numerous than most insertions and deletions. (But see, Arlin Stoltzfus on The range of rates for different genetic types of mutations).

Happy 10th birthday to YouTube!

The first video was posted to YouTube on April 23, 2005 [see YouTube]. I took this photo (right) a few years ago near my daughter's place in Playa Vista, California. It's a production facility, YouTube Space LA, on the site of the former Howard Hughes airport.

The main purpose of this post is to give me an excuse to post one of my granddaughter's favorite YouTube videos (below top). She's a big fan of YouTube and so is my two year old grandson—he likes videos of rocket launches (below bottom).

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Does natural selection constrain neutral diversity?

Razib Khan is an adaptationist and he's discovered a paper that gets him very excited: Selectionism Strikes Back!.

Here's the paper and the abstract.

Corbett-Detig, R.B., Hartl, D.L., Sackton, T.B. (2015) Natural Selection Constrains Neutral Diversity across A Wide Range of Species. PLoS Biology Published: April 10, 2015 doi: 10.1371/journal.pbio.1002112

The neutral theory of molecular evolution predicts that the amount of neutral polymorphisms within a species will increase proportionally with the census population size (Nc). However, this prediction has not been borne out in practice: while the range of Nc spans many orders of magnitude, levels of genetic diversity within species fall in a comparatively narrow range. Although theoretical arguments have invoked the increased efficacy of natural selection in larger populations to explain this discrepancy, few direct empirical tests of this hypothesis have been conducted. In this work, we provide a direct test of this hypothesis using population genomic data from a wide range of taxonomically diverse species. To do this, we relied on the fact that the impact of natural selection on linked neutral diversity depends on the local recombinational environment. In regions of relatively low recombination, selected variants affect more neutral sites through linkage, and the resulting correlation between recombination and polymorphism allows a quantitative assessment of the magnitude of the impact of selection on linked neutral diversity. By comparing whole genome polymorphism data and genetic maps using a coalescent modeling framework, we estimate the degree to which natural selection reduces linked neutral diversity for 40 species of obligately sexual eukaryotes. We then show that the magnitude of the impact of natural selection is positively correlated with Nc, based on body size and species range as proxies for census population size. These results demonstrate that natural selection removes more variation at linked neutral sites in species with large Nc than those with small Nc and provides direct empirical evidence that natural selection constrains levels of neutral genetic diversity across many species. This implies that natural selection may provide an explanation for this longstanding paradox of population genetics.

It is impossible for someone like me to evaluate this paper. Can someone take a look to see if it's valid?

How many selective sweeps must there every 50,000 years in order to remove substantial amounts of neutral diversity from junk DNA?

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Mississauga Mayor Bonnie Crombie agrees to abide by Surpeme Court ruling banning prayers at city council

Shortly after being elected last Fall, the new Mayor of Mississauga, Bonnie Crombie, decided that the City Council would continue to say a prayer before each council meeting. She voted in favor of continuing the practice even though she heard the arguments against it and even though she knew that the Ontario Court of Appeal (in 1999) had ruled it illegal [Mississauga council debates removing Lord’s Prayer from meetings].

Crombie, who is Catholic, said she doesn’t have a problem with the recitation of the prayer. But, she does want to touch base with the municipality’s 11 councillors to get their opinions.

She has already heard lot of different ideas from her peers, such as leaving the practice the way it is to replacing it with a non-denominational blessing to even rotating a prayer from a different faith before each meeting.

"I don’t think there’s anything wrong with (reciting the prayer)," said Crombie. "But, I am asking each councillor about it and there is a diversity of opinion."

...

Larry Moran, who described himself as an atheist, is also a University of Toronto professor and an advisory fellow with the Centre for Inquiry Canada, an organization he said strongly supports the separation of religion and government.

He wrote a blog post condemning the practice in Mississauga earlier this year and Moran estimates about 30 per cent of Canadians aren’t religious. He strongly believes the Lord’s Prayer before council should come to an end.

"There is no reason to invoke any of the gods at a public meeting of any government body," said Moran. "It sends the wrong message to … citizens who don’t believe in those gods or who believe in other gods. Nobody has been able to tell me why religion has to be mixed in with government business."

Now Bonnie Crombie says she will obey the law—no mention of fairness or of consideration for non-Christians in the community. Oh well, at least she's not going to fight it and cost the city lots of money.

The Toronto Star reports that the mayor of Oshawa plans to ignore the Supreme Court decision. I bet he backs down after talking to the city lawyers [Oshawa mayor plans to keep Lord’s Prayer].

Brampton Mayor Linda Jeffrey stopped the practice of reciting the Lord's Prayer before council meetings earlier in the year and today Mississauga Mayor Bonnie Crombie indicated her council will now do the same, after the Supreme Court decision. At the beginning of the year she supported keeping the Lord's Prayer in Mississauga council meetings.

"Today’s ruling sets a precedent and the City of Mississauga will abide by the Supreme Court’s ruling," Crombie said.

At the beginning of the year Crombie supported keeping the Lord's Prayer in Mississauga council meetings, after Councillor Carolyn Parrish had pushed to remove it from council meetings.

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Story-telling and the origin of eukaryotes

Austin Booth and Ford Doolittle have just published a paper that discusses the origin of eukaryotes (Austin and Doolittle, 2015). They point out that many of the stories about this event are not grounded in fact. Read the paper.

Writing for public audiences, and often even for themselves, biologists are not loath to make simplifying claims about uniqueness and importance that are rhetoric disguised as fact. Such generalizations serve purposes in the doing of science, but are often not themselves testable scientific claims and are subject to biases. Evolutionary biology may be especially vulnerable to hype, as suggested by the frequency with which revolutionary evolutionary claims in top-notch journals are debunked. Additionally, anthropocentrism, as it grades into "zoocentrism" and then "eukaryocentrism," surely remains a subtle distorter of objectivity.

Our aim here is to critique general claims about the uniqueness and special importance of eukaryogenesis, with an aim to making them more open to question and conceptual and empirical analysis. We ask (i) whether eukaryogenesis entailed such a "genuinely unlikely sequence of events" as to justify belief in its uniqueness as a process, (ii) if, as is often claimed, eukaryogenesis has a problematic or unique theoretical status in evolutionary biology, (iii) what intrinsic features might have conferred on eukaryotes their presumed "richer evolutionary potential," and (iv) if this greater potential might be just a presumption, an illusion reflecting eukaryocentric bias.

There are many useful ways of understanding evolution, and their articulations can be intellectually valuable and experimentally fruitful. We advocate a more self-conscious pluralism that would require not that we stop telling eukaryogenesis stories but that we do recognize them for what they are. We do not claim to know whether there is any best story, any theory by which the apparent differential success of eukaryotes can be objectively probed and causally rationalized. What we have questioned here is whether premises of existing theories have been objectively formulated and whether, despite widespread acceptance that eukaryogenesis was "special," any such notion has more than rhetorical value.

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Booth, A. and Doolittle, W.F. (2015) Eukaryogenesis, how special really? Proc. Natl. Acad. Sci. (USA) Published online before print April 16, 2015 [doi: 10.1073/pnas.1421376112]

Canada bans prayers at city council meetings

The Supreme Court of Canada has ruled that prayers at the opening of city council meetings are not consistent with a secular society [Quebec town can’t have prayers at council meetings, top court rules].

The Supreme Court decision is at: Mouvement laïque québécois v. Saguenay (City). The decision appears to be unanimous (9:0) provided I'm reading it correctly.

The state’s duty of religious neutrality results from an evolving interpretation of freedom of conscience and religion. The evolution of Canadian society has given rise to a concept of this neutrality according to which the state must not interfere in religion and beliefs. The state must instead remain neutral in this regard, which means that it must neither favour nor hinder any particular belief, and the same holds true for non‑belief. The pursuit of the ideal of a free and democratic society requires the state to encourage everyone to participate freely in public life regardless of their beliefs. A neutral public space free from coercion, pressure and judgment on the part of public authorities in matters of spirituality is intended to protect every person’s freedom and dignity, and it helps preserve and promote the multicultural nature of Canadian society. The state’s duty to protect every person’s freedom of conscience and religion means that it may not use its powers in such a way as to promote the participation of certain believers or non‑believers in public life to the detriment of others. If the state adheres to a form of religious expression under the guise of cultural or historical reality or heritage, it breaches its duty of neutrality. The Tribunal was therefore correct in holding that the state’s duty of neutrality means that a state authority cannot make use of its powers to promote or impose a religious belief. Contrary to what the Court of Appeal suggested, the state’s duty to remain neutral on questions relating to religion cannot be reconciled with a benevolence that would allow it to adhere to a religious belief.

This seems so obvious to most people that it's a wonder why anyone ever thought that reciting prayers at city council meetings was justified.

Now, let's see how long it takes for other cities to stop the practice.

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Hat Tip: Canadian Atheist

The Virtual Cell Animation Collection

I'm interested in science education in general and teaching biochemistry and molecular biology in particular. A recent publication in PLoS Biology caught my eye ...

Reindl, K.M., White, A. R., Johnson, C., Vender, B., Slator, B.M., and McClean, P. (2105) The Virtual Cell Animation Collection: Tools for Teaching Molecular and Cellular Biology. PLoS Biology 13(4): e1002118 DOI: 10.1371/journal.pbio.1002118

The paper focuses on the value of short animations for teaching biochemistry and molecular biology to advanced high school students and college students.

There's nothing in the paper about the scientific accuracy of the presentations or the pedagogical approach and this is unfortunate. The animations only show complex eukaryotic cells in spite of the fact that the American Society for Biochemistry and Molecular Biology recommends an evolutionary approach to teaching. The fact that the videos emphasize eukaryotes leads to some interesting descriptions of fundamental processes.

Look at the video on transcription regulation for example [Regulated Transcription]. The textbooks teach this using simple systems such as E. coli transcription then they move on to more complex prokarotic systems such as the lac operon. Then they cover the eukaryotic examples pointing out how they differ from the simple bacterial systems. This has always been a successful approach to teaching the basic concepts of transcription and transcription regulation. ¹

Is the approach taken by the authors of The Virtual Cell Animation project better? I don't think so. What do you think? Does anyone out there teach transcription without introducing it first in bacteria?

Let's not forget my favorite example of biochemical misconceptions: the Citric Acid Cycle. Did you know that it's sometimes called the "tricarboxylic acid cycle" because three CO₂ molecules are released for every pyruvate molecule? ²

The carboxylate groups on citrate, isocitrate etc. are shown as -COOH instead of COO^- as in the textbooks. I don't know why they did this ... it leads to some extra protons being released in the reactions.

The authors make a very common mistake with succinate dehydrogenase. They show FADH₂ as one of the products of the reaction whereas the IUBMB database shows that the real final product is QH₂ [see Succinate Dehydrogenase]. I don't understand why biochemistry teachers can't check out a leading textbook (or the scientific literature) before producing a video.

Did you know that some of the reactions of glycolysis are irreversible? Check out the video on Glycolysis to find out which reactions have this interesting property. ³ There is no video on gluconeogenesis and that's surprising because the synthesis of glucose is far more important than glycolysis in most species.

I wonder if the editors of PLoS bothered to watch the videos or whether they just assumed that they were scientifically accurate and pedagogically sound? I'm guessing that they didn't see the need to review the videos and simply concentrated on whether all the words in the article were spelled correctly.

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1. There's a separate video on the lac Operon. How many errors, flaws, or missed opportunities, can you spot?

2. Silly me. I always though it had something to do with the fact that two of the key intermediates (citrate and isocitrate) were tricarboxylic acids. Most of the others are dicarboxylic acids.

3. Maybe I'm quibbling. In my textbook I describe these reactions as "metabolically irreversible" because the activities of the enzymes are regulated. That's not the same as saying that the reactions are irreversible.