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Monday, August 24, 2015

The genealogy of Jesus

I saw this at The Cloisters when I was in New York last week. It's very hard to read1 so I'm not sure if it's accurate.

Here's what the Metropolitan Museum of Art has to say about The Compendium of History through the Genealogy of Christ by Peter of Poitiers.
Admirable for its concision and graphic boldness, this imposing scroll presents a history of the known world from the creation of Adam until the birth of Jesus. It is a teaching tool—a graphic summary of a classroom text. The ancestry of Jesus, traced back to the first man, is shown through a stemma (a system of lines and framed circles that runs down the center of the scroll’s length). Noteworthy ancestors, including King David with his harp, are pictured at regular intervals along the stemma. Successions of biblical rulers, as well as the lineage of ancient rulers of the Near East, Greece, and Rome appear on less elaborate stemmata that diverge from, converge with, and run parallel to that central history.
Sounds authentic to me. I wonder who is listed as the father of Jesus and if the genealogy covers the ancestors of Mary all the way back to Eve?

Peter of Poiters lived in England and the scroll was created in the 1200s. I bet he had lots of fun searching ancestry.com and all the census records from Ur and Egypt.

Here's photo that I took at The Cloisters.


1. It was in a dark corner and my Latin is a bit rusty.

IDiots, suckers, and the octopus genome

The genome of the small octopus, Octopus bimaculoides has recently been sequenced. The results are reported in Nature (Albertin et al., 2015).

The octopus is a cephalopod along with squid and cuttlefish. These groups diverged about 270 million years ago making them more distantly related than humans and platypus. As expected, the octopus genome is similar to other mollusc genomes but also shows some special derived features. Some gene families have been expanded—a feature often found in other genomes.

Sunday, August 23, 2015

Comets and meteorites CAN NOT create a primordial soup in the ocean

I want to talk about two recent press releases on the origin of life.

The first one is from the BBC and it talks about the work of Haruna Sugahara and Koicha Mimura who presented their results at a recent conference [Comet impacts cook up 'soup of life']. They noted that the impact of a comet carrying organic molecules can produce more complex organic molecules.

The second report is from ScienceDaily. It reports a similar study by Furukawa et al. (2015) who examined the idea that the impact of meteorites in the primitive ocean could create more complex organic molecules than those already found in meteors [Meteorite impacts can create DNA building blocks].

What am I doing on my summer vacation?

Here's what I'm doing this summer (right) when I'm not fighting creationists, writing a book, giving talks, playing with the grandchildren, and visiting exotic cities in Canada and the United States.

I built the main part of the patio twenty years ago. I recall working on it for 6-8 hours at a stretch but today I'm pooped after three hours.

I think the stones have gotten heavier.


How do Intelligent Design Creationists deal with pseudogenes and false claims?

Some of the people who comment here have pointed out that this is the second anniversary of a post by Jonathan McLatchie on Evolution News & Views (sic): A Simple Proposed Model For Function of the Human Vitamin C GULO Pseudogene.

That post is significant for several reasons. Let's review a bit of background.

Intelligent Design Creationists have a problem with pseudogenes. Recall that pseudogenes are stretches of DNA that resemble a gene but they appear to be non-functional because they have acquired disruptive mutations, or because they were never functional to begin with (e.g. processed pseudogenes). All genomes contain pseudogenes. The human genome has more than 15,000 recognizable pseudogenes.1 This is not what you would expect from an intelligent designer so the ID crowd tries to rationalize the existence of pseudogenes by proposing that they have an unknown function.

Wednesday, August 19, 2015

The Burghers of Calais at the Metropolitan Museum of Art in New York

There are 13 casts of the famous sculpture by Rodin [The Burghers of Calais]. I've seen four of them (Paris, Washington, Los Angeles, New York). I took this photo today at the Metropolitan Museum of Art in New York.


The burghers thought they were sacrificing their lives to save the inhabitants of Calais, which was being starved into submission by Edward III of England in 1347. Their lives were spared after Queen Philippa convinced her husband to be lenient.

One of my ancestors is Paon de Roet. He was a knight in Queen Phillippa's retinue and was one of two knights assigned to protect the burghers of Calais. I descend from Paon de Roet's daughter, Katherine. Her sister, Philippa (named after the Queen), married a poet named Geoffrey Chaucer [My Connection to Geoffrey Chaucer and Medieval Science].


Monday, August 17, 2015

Do Canadians "believe" in evolution?

A recent post by some anonymous blogger named "Darwin Quixote" made the following claim [see comment in: Be Careful, Evolution is Behind You]. The discussion was about teaching evolution in Ontario (Canada) schools ....
Of course I agree that these topics should be required, but I would suggest that it’s even more important that human evolution be a required topic because only 51% of Ontarians believe that humans evolved. It is likely that a significant number of teachers fall into the 49% category, and therefore leaving this topic to the discretion of the teacher becomes problematic.
This didn't seem right to me so I checked the latest polls that I could find on the internet.

Here's one by Angus Reid in 2012: Believe In Evolution: Canadians More Likely Than Americans To Endorse Evolution. The results show that 60% of Ontarians believe the following statement: "Human beings evolved from less advanced life forms over millions of years."

24% of Ontarians thought that: "God created human beings in their present form within the last 10,000 years."

16% were not sure.

The results were somewhat different in other provinces. In Quebec, for example, the number of people who accepted evolution was 71% and only 13% believed in Young Earth Creationism. In Alberta only 48% of the population accepted evolution and 35% were Young Earth Creationists.

So Darwin Quixote was off by a bit (51% vs 60%) but not by much. However, I think he makes an error by assuming that a significant number of biology teachers (in high school) would be opposed to evolution and might not teach human evolution.


Summer Reading

These are the books I've read, or finished reading, this summer beginning in June.








This is the book that I'm re-reading very carefully.


This is still my favorite book



Friday, August 14, 2015

Teaching evolution in Ontario Schools

In Ontario (Canada) there is a province-wide curriculum that all public schools must follow. This includes the Roman Catholic separate schools that receive money from the province. This post is prompted by something written last month by an anonymous blogger who runs Darwnquixote. He claims that human evolution is not taught in Ontario schools [Be Careful, Evolution is Behind You]. Jerry Coyne picks up on this and launches into a tirade about the Ontario curriculum [Ontario schools require teaching evolution—except human evolution]. Coyne urges everyone to write letters of complaint to the Ontario Minister of Education. (Her name is Liz Sandals and she is an excellent (not perfect) Minister of Education.) Is it true that the Ontario curriculum does not teach that humans have evolved?

I've been quite impressed with the science and technology curriculum as revised in 2008 and I'm hearing good things about the next revision. The teaching of evolution, like all aspects of the curriculum, focuses on understanding the basic concepts and on encouraging students to think for themselves. Students learn about evolution and diversity in the primary grades where the emphasis is on the relationship of humans and other species [The Ontario Curriculum: Elementary: Science and Technology]. In grade 1 they learn that "Plants and animals, including people, are living things" (page 44) and in Grade 2 one of the "big ideas" is that humans are animals (page 58).

Wednesday, August 12, 2015

What is "PeerWise"?


I came across an interesting article about "PeerWise."

Hardy, J., Bates, S.P., Casey, M.M., Galloway, K.D., Galloway, R.K., Kay, A.E., Kirsop, P., and McQueen, H.A. (2015) Student-Generated Content: Enhancing learning through sharing multiple-choice questions. International Journal of Science Education 36: 2180-2194. [doi: 10.1080/09500693.2014.916831]

Abstract

The relationship between students' use of PeerWise, an online tool that facilitates peer learning through student-generated content in the form of multiple-choice questions (MCQs), and achievement, as measured by their performance in the end-of-module examinations, was investigated in 5 large early-years science modules (in physics, chemistry and biology) across 3 research-intensive UK universities. A complex pattern was observed in terms of which type of activity (writing, answering or commenting on questions) was most beneficial for students; however, there was some evidence that students of lower intermediate ability may have gained particular benefit. In all modules, a modest but statistically significant positive correlation was found between students' PeerWise activity and their examination performance, after taking prior ability into account. This suggests that engaging with the production and discussion of student-generated content in the form of MCQs can support student learning in a way that is not critically dependent on course, institution, instructor or student.
This sounds like a good way to encourage some student-centered learning in large classes. We have several biochemistry classes in our department that could benefit.

Does anyone have any experience with PeerWise?


The value of critique in science education

One of the most difficult concepts to get across to science educators (e.g. professors in a biochemistry department ) is the idea that students need to be exposed to ideas that you think are incorrect and they need to be given the opportunity to make a choice. It's part of critical thinking and it's part of a good science education. Part of the problem is that there's a general reluctance to even teach "ideas" as opposed to facts and techniques.

There's an extensive pedagogical literature on this but university professors are reluctant to admit that there might be better ways to teach. While browsing this literature, I came across a recent article by Henderson et al. (2015) that makes a good case.

David M. Raup (1933-2015)

David Raup died last month. He was 82 years old. Raup was a paleontologist at the University of Chicago, where he studied the big picture of the history of life, concentrating on mass extinctions. Here's an excerpt from the University of Chicago website [David Raup, paleontologist who transformed his discipline, 1933-2015].
Raup’s former students and colleagues uniformly praised his unique creativity along with his astute capabilities as an academic adviser, senior colleague and paleontological statesman. They remember him for the sweeping scope of the questions he asked, his analytical and quantitative rigor, and his skepticism and humility.

“David Raup ushered in a renaissance in paleontology,” said Raup’s former student and colleague Charles Marshall, SM’86, PhD’89, director of the University of California’s Museum of Paleontology and professor of integrative biology at UC Berkeley. “Before Dave, much of the discipline was centered on describing what was. Dave taught the discipline to think about the processes that might have generated the past record.”

Raup introduced statistical concepts to paleontology that treated the fossil record as an outcome of yet-to-be-discovered processes. Raup was widely known for the new approaches he brought repeatedly to paleontology, such as extensive computation, modern evolutionary biology, theoretical ecology and mathematical modeling.

As Marshall put it, Raup created new intellectual space for paleontology. “That was, in my opinion, his greatest contribution. It is not that Dave just transformed the discipline, but his students, and their students, continue to fill and expand that space,” Marshall said.

Another former student and colleague, Michael Foote, expressed similar sentiments.

“By any conception of what it means to be influential, Dave was one of the most influential paleontologists active during the second half of the 20th century,” said Foote, SM’88, PhD’89, a professor in geophysical sciences at UChicago. “In the areas he chose to touch, nobody, in my view, surpassed him.”
Raup hung out with the likes of John Sepkoski, Steven Stanley, and Stephen Jay Gould and they shared many of the same views on evolution. He was very good at describing those views in books for the general public and that's why I rate him as one of the best scientists who are also science writers [Good Science Writers: David Raup]. His book, Extinction: Bad Genes or Bad Luck? (1991), is one of my top five books on evolution [Top Five Books on Evolution]. Here's a quotation from the introduction to that book ...
I have taken the title of this book from a research article I published in Spain some years ago. I was concerned then with the failure of trilobites in the Paleozoic era. Starting about 570 million years ago, these complex, crab-like organisms dominated life on ocean bottoms—at least they dominated the fossil assemblages of that age. But through the 325 million years of the Paleozoic era, trilobites dwindled in numbers and variety, finally disappearing completely in the mass extinction that ended the era, about 245 million years ago.

My question in Spain is the one I still ask: Why? Did the trilobites do something wrong? Were they fundamentally inferior organisms? Were they stupid? Or did they just have the bad luck to be in the wrong place at the wrong time? The first alternative, bad genes, could be manifested by things like susceptibility to disease, lack of good sensory perception, or poor reproductive capacity. The second, bad luck, could be a freak catastrophe that eliminated all life in areas where tilobites happened to be living. The question is basically one of nature versus nurture. Is proneness to extinction an inherent property of a species—a weakness—or does it depend on vagaries of chance in a risk-ridden world?

Of course, the problem is more complex than I have presented it, just as the nature-nurture question in human behavior is complex. But in both situations, nature (Genetics) and nurture (environment) operate to some degree, and the challenge is to find out which process dominates and whether the imbalance varies in time and space. (pp. 5-6)
If you don't already own a copy of that book, you should buy one right now and read it. They may not be easy to get in the future and your life will be poorer if you don't learn about the difference between bad genes and bad luck.

Raup is famous for the Field of Bullets analogy to explain why extinction is as much bad luck as bad genes. He made a strong case for his belief that chance plays an important role in the history of life. He was not alone in making this claim but it doesn't seem to be popular these days for reasons that confound me. It's part of what I call Evolution by Accident. It means that if you replay the tape of life, things will come out very differently and there's no guarantee that sentient beings like ourselves will evolve [see Café Scientifique: Replaying the tape of life]. You don't have to agree with Raup, Gould, and other experts but if you want to participate in discussions of evolution you have to be familiar with this important concept.


Tuesday, August 11, 2015

More calls to extend the defunct Modern Synthesis

Once again, a group of scientists want to extend and revise the Modern Synthesis version of evolutionary theory in order to bring their pet projects into the mainstream. Once again, these scientists seem to have missed the real revolution that took place 45 years ago so they are attacking a strawman. And, once again, they seem to think that the core principles of evolutionary theory can be defined by how complex animals evolve, ignoring bacteria and single-cell eukaryotes that have been at the heart of the history of life for 3.5 billion years.

But the fact that some geniuses were laughed at does not imply that all who are laughed at are geniuses. They laughed at Columbus, they laughed at Fulton, they laughed at the Wright Brothers. But they also laughed at Bozo the Clown.
 &nbsp&nbsp&nbsp&nbsp&nbsp&nbsp&nbsp&nbsp&nbsp&nbsp &nbsp&nbsp&nbsp&nbsp&nbsp&nbsp&nbsp&nbsp&nbsp&nbspCarl Sagan
The paper by Laland et al. (2015) was published in Proceedings of the Royal Society (UK) Series B just this month (August, 2015). The usual suspects are included in the author list including three of the Altenberg 16: Eva Jablonka, Gerd B. Müller, and John Odling-Smee. This is the same group that defended the "yes" side when Nature posed the question, "Does evolutionary theory need a rethink?" back in October, 2014 [see Rethinking evolutionary theory ].

Four things that Francis Collins learned from sequencing the human genome

I've been doing a bit of research on the human genome in preparation for a book. This led me to an article published in 2003 by Francis Collins, former head of the Human Genome Consortium (Collins, 2003). It's mostly about how he deals with science and religion but there was an interesting description of what he learned from completing the human genome sequence.

Here's what he said ....
We discovered some pretty surprising things in reading out the human genome sequence. Here are four highlights.

1. Humans have fewer genes than expected. My definition of a gene here—because different people use different terminology—is a stretch of DNA that codes for a particular protein. There are probably stretches of DNA that code for RNAs that do not go on to make proteins. That understanding is only now beginning to emerge and may be fairly complicated. But the standard definition of “a segment of DNA that codes for a protein” gives one a surprisingly small number of about 30,000 for the number of human genes. Considering that we’ve been talking about 100,000 genes for the last fifteen years (that’s what most of the textbooks still say), this was a bit of a shock. In fact, some people took it quite personally. I think they were particularly distressed because the gene count for some other simpler organisms had been previously determined. After all, a roundworm has 19,000 genes, and mustard weed has 25,000 genes, and we only have 30,000? Does that seem fair? Even worse, when they decoded the genome of the rice, it looks as if rice has about 55,000 genes. So you need to have more respect for dinner tonight! What does that mean? Surely, an alien coming from outer space looking at a human being and looking at a rice plant would say the human being is biologically more complex. I don’t think there’s much doubt about that. So gene count must not be the whole story. So what is going on?

2. Human genes make more proteins than those of other critters. One of the things going on is that we begin to realize that one gene does not just make one protein in humans and other mammals. On the average, it makes about three, using the phenomenon of alternative splicing to create proteins with different architectures. One is beginning to recover some sense of pride here in our genome, which was briefly under attack, because now we can say, “Well, we don’t have very many genes but boy are they clever genes. Look what they can do!”

3. The male mutation rate is twice that of females. We also discovered that simply by looking at the Y chromosome and comparing it to the rest of the genome—of course, the Y chromosome only passes from fathers to sons, so it only travels through males—you can get a fix on the mutation rate in males compared to females. This was not particularly good news for the boys in this project because it seems that we make mistakes about twice as often as the women do in passing our DNA to the next generation. That means, guys, we have to take responsibility for the majority of genetic disease. It has to start somewhere; the majority of the time, it starts in us. If you are feeling depressed about that, let me also point out we can take credit for the majority of evolutionary progress, which after all is the same phenomenon.

4. “Junk” DNA may not be junk after all. I have been troubled for a long time about the way in which we dismissed about 95% of the genome as being junk because we didn’t know what its function was. We did not think it had one because we had not discovered one yet. I found it quite gratifying to discover that when you have the whole genome in front of you, it is pretty clear that a lot of the stuff we call “junk” has the fingerprints of being a DNA sequence that is actually doing something, at least, judging by the way evolution has treated it. So I think we should probably remove the term “junk” from the genome. At least most of it looks like it may very well have some kind of function.

Monday, August 10, 2015

Insulators, junk DNA, and more hype and misconceptions

The folks at Evolution News & Views (sic) can serve a very useful purpose. They are constantly scanning the scientific literature for any hint of evidence to support their claim about junk DNA. Recall that Intelligent Design Creationists have declared that if most of our genome is junk then intelligent design is falsified since one of the main predictions of intelligent design is that most of our genome will be functional.

THEME

Genomes & Junk DNA
They must be getting worried because their most recent posts sounds quite desperate. The last one is: The Un-Junk Industry. It quotes a popular press report on a paper published recently in Procedings of the National Academy of Sciences (USA). The creationists concede that the paper itself doesn't even mention junk DNA but the article in EurekAlert does.

Friday, August 07, 2015

Here's why you can ignore Günther Witzany

Günther Witzany is one of those people who think the Modern Synthesis needs to be overthrown but he missed the real revolution that took place in the late 1960s. He's part of The Third Way crowd that includes Denis Noble and Jim Shapiro [see Physiologists fall for the Third Way and The Third Fourth Way].

Susan Mazur interviews him for the Huffington Post [Günther Witzany: Modern Synthesis "Must Be Replaced," Communication Key to Evolution]. Recall that Susan Mazur is fixated on the Altenburg 16 and their attempts to radically revise evolutionary theory without understanding anything about Neutral Theory and random genetic drift. Günther Witzany is a philosopher. He was not one of the Altenberg 16 but he clearly wants to be part of the outer circle. It's not clear why anyone should consider him an expert on evolutionary biology.

Susan Mazur did us a great favor when she asked him if he would like to make a final point. His answer shows us why we can ignore him.
The older concepts we have now for a half century cannot sufficiently explain the complex tendency of the genetic code. They can't explain the functions of mobile genetic elements and the endogenous retroviruses and non-coding RNAs. Also, the central dogma of molecular biology has been falsified -- that is, the way is always from DNA to RNA to proteins to anything else, or the other "dogmas," e.g., replication errors drive evolutionary genetic variation, that one gene codes for one protein and that non-coding DNA is junk. All these concepts that dominated science for half a century are falsified now. ...
Thank-you Susan. Keep up the good work. Fools need to be exposed.


How to write about RNA

I find it very frustrating to read reports about RNA these days because the writers almost always misrepresent the history of the field and exaggerate the significance of recent discoveries. An article in the July 23, 2015 issue of Nature illustrates the problem. The article is written by Elie Dolgin (@ElieDolgin), a freelance science journalist based in Massachusetts (USA). He graduated from McGill University (Montreal, Quebec, Canada) with a degree in biology and obtained a Ph.D. in genetics and evolution from the University of Edinburgh (Edinburgh, Scotland, UK).

Thursday, August 06, 2015

On this day in 1945

At 8:15 AM on August 6, 1945 an atomic bomb was detonated over Hiroshima, Japan. Approximately 78,000 civilians were killed on that day. Six months later the death toll had risen to about 140,000 people.

There are many arguments in favor of dropping the bomb, just as there are many arguments against it. What's clear is that in the context of 2015 we are not in a good position to judge the actions of countries that had been at war for many years.

The most important lesson of Hiroshima is that war is hell and many innocent people die. It's all very well to enter into a war with the best of intentions—as the Japanese did on December 7, 1941—but it's foolish to pretend that when you start a war there won't be any suffering. When you do that, you can really say that the victims of Hiroshima will have died in vain.

The killing and maiming of civilians is an inevitable outcome of war, no matter how hard you might try to restrict your targets to military objectives. Before going to war you need to take the consequences into account and decide whether the cost is worth it.

Hiroshima was not a glorious victory. It was ugly, heartbreaking, and avoidable. War is not an end in itself, it is the failure of peace. War is not an instrument of foreign policy—it is an admission that you don't have a foreign policy.


[The top photograph shows the mushroom cloud over Hiroshima on the morning of August 6, 1945 (Photo from Encyclopedia Britanica: Hiroshima: mushroom cloud over Hiroshima, 1945. [Photograph]. Retrieved August 7, 2007, from Encyclopædia Britannica Online.

The bottom image is taken from a Japanese postcard (Horoshima and Nagassaki 1945). It shows victims of the attack on Hiroshima.]

WIlliam Provine doesn't like random genetic drift

William ("Will") Provine is an emeritus professor of history and of evolution at Cornell University (Ithaca, New YOrk, USA). He is no friend of creationism. Here's what Wikipedia has to say about him ...
Provine is an atheist, philosopher, and critic of intelligent design. He has engaged in prominent debates with theist philosophers and scientists about the existence of God and the viability of intelligent design. He has debated the founder of the intelligent design movement Phillip E. Johnson and the two have a friendly relationship. Provine has stated that he starts his course on evolutionary biology by having his students read Johnson's book "Darwin on Trial."

Provine is a determinist in biology, but not a determinist in physics or chemistry, thus rejecting the idea of free will in humans. Provine believes that there is no evidence for God, there is no life after death, there is no absolute foundation for right and wrong, there is no ultimate meaning for life, and that humans don't have free will.
When someone likes that publishes a book with the title, The 'Random Genetic Drift' Fallacy, I pay attention.

Tuesday, August 04, 2015

Orac responds to my post on teaching the controvery

Orac didn't like part of my post On teaching alternative medicine at the University of Toronto. Here's what I said a few days ago ...
From an academic pedagogical perspective, there’s nothing wrong with a course that has a reading list emphasizing quack medicine. This is the view that people outside of the university don’t understand. They appear to want to prevent students from ever learning about, or discussing, the anti-vax movement and how to deal with it.

They are wrong.
Orac took this personally and responded in a post of his own [On teaching pseudoscientific controversies in universities…].
Those of you who read the articles and have seen talks by supporters of science-based medicine like Steve Novella and myself will recognize this for the straw man that it is. We never say anything like this, that we want to prevent students from learning about or discussing the antivaccine movement. That is an assertion that is unsupported and, quite frankly, downright risible. So you should understand that I was more than a little pissed off when I read this part of Moran’s post. We never say that we don’t want alternative medicine to be taught or antivaccine views taught. (Indeed, I really wish that pediatrics residency programs, for instance, would do a better job of teaching antivaccine views, so that they don’t catch pediatricians by surprise when parents start expressing them.) What we complain about is the uncritical teaching of these topics, the teaching, for example, of alternative medicine modalities as though they had scientific merit. This is a massive problem in medical academia. I’ve lost track of how many times I’ve reiterated this very point going back at least a decade.
We agree. I wasn't referring to people like Orac who understand how universities should work. I was referring to those people outside of the university community who really do want to ban any mention of alternative medicine at universities. I guess I didn't make that clear.

I'm pretty sure that Orac knows about this crowd. They are totally opposed to the idea of teaching the controversy. They have some very strong views on what's right and what's wrong and they firmly believe that the only views that should ever be expressed in university classes are the ones they agree with.
In the end, my little fit of pique over Prof. Moran’s condescending and dismissive attitude towards those of us who were so outraged by this course being offered by U. of T. aside, we actually (mostly agree). Moran supports “teaching the controversy” with respect to evolution and with respect to alternative medicine. So do I. Where we disagree is over what “teaching the controversy” actually entails. Can Prof. Moran can honestly say that he wouldn’t be the least bit upset if his own department were to offer an entire course on “controversies in evolution” taught by Ken Ham, Casey Luskin, and a Discovery Institute fellow to be named later? That he would approve of such a class as a great way to “teach the controversy”? If he can, I’d say there’s a problem. If he can’t say that, I congratulate him. That’s the correct reaction. In that case, I also point out that he has no business being so contemptuous of our anger over a homeopath teaching a course in alternative medicine as a way of “teaching the controversy.”
As I said in my earlier post, the problem wasn't that an anti-vaccine point of view was being discussed in a university course. The problem was that the course was being taught by someone who wasn't qualified to offer a university course that encouraged critical thinking. That situation has been rectified.

I would love to invite Casey Luskin to come and give a few lectures on Intelligent Design Creationism to my students. It would be far better for them to hear the other side directly from the horse's mouth than filtered through me.


Sunday, August 02, 2015

On teaching alternative medicine at the University of Toronto

There's been a recent kerfluffle about a course called "Alternative Health: Practive and Theory" taught as part of a program in Health Studies at the University of Toronto's Scarborough campus (Toronto, Ontario, Canada).

Most of the readings in the course emphasized non-evidence-based medicine and health. The instructor was Beth Landau-Halpern, a homeopath who warns her patients about the dangers of vaccines [see Beth Landau-Halpern]. She's also the wife of Rick Halpern, the Dean and Vice-Principle of University of Toronto, Scarborough (UTSC). Ms. Landau-Halpern will no longer be teaching and the Dean has resigned [Rick Halpern Resigns].

Friday, July 31, 2015

For the King - Teaser Trailer

This is the game my son, Gordon Moran, and his friends at IronOak Games are developing. Please send him lots of money when Kickstarter is activated in September.

I'm buying a university and a professor character for the game. The professor will battle the forces of evil and superstition. Ms. Sandwalk is contributing enough for a medieval faire with lots of games where you can win prizes.

Find out more at http://www.ironoakgames.com.



Thursday, July 30, 2015

The next step in genomics

The draft sequence of the human genome was published in 2001. The "finished" version was published a few years later but annotation continues.

A massive amount of data on complex genomes has been published, especially on the human genome. The next step is to decide what this data means. Here are the most important questions from my perspective.

An accomodationist defends the science of the Pope in the journal Nature

I don't think scientific journals or scientific organizations should take a position on the conflict between science and religion but that doesn't mean they should stay away from the subject altogether. The journal Nature has just (July 28, 2015) published a defense of accomodationism written by David M. Lodge [Faith and science can find common ground]. Lodge describes himself as a "Protestant ecologist embedded for 30 years in a Roman Catholic university." The Catholic University is Notre Dame [see David M. Lodge].

His main argument is that the current Pope understands the science of the environment and has spoken out in favor of protecting the environment. David Lodge thinks this represents an accomomodation between science and religion.

Wednesday, July 29, 2015

Michael Lynch on modern evolutionary theory

Of the Five Things You Should Know if You Want to Participate in the Junk DNA Debate, the most difficult to explain is "Modern Evolutionary Theory." Most scientists think they understand evolution well enough to engage in the debate about junk DNA. However, sooner or later they will mention that junk DNA should have been deleted by selection if it ever existed. You can see that their worldview leads them to believe that everything in biology has an adaptive function.

It's been a few years since I posted Michael Lynch's scathing comments on panadaptationism and how it applies to understanding genomes [Michael Lynch on Adaptationism and A New View of Evolution]. You're in for a treat today.

Here's what you need to know about evolution in order to discuss junk DNA. The first quotation is from the preface to The Origins of Genome Architecture (pages xiii-xiv). The second quotations are from the last chapter (page 366 and pages 368-369.
Contrary to popular belief, evolution is not driven by natural selection alone. Many aspects of evolutionary change are indeed facilitated by natural selection, but all populations are influenced by nonadaptive forces of mutation, recombination, and random genetic drift. These additional forces are not simple embellishments around a primary axis of selection, but are quite the opposite—they dictate what natural selection can and cannot do. Although this basic principle has been known for a long time, it is quite remarkable that most biologists continue to interpret nearly aspect of biodiversity as an outcome of adaptive processes. This blind acceptance of natural selection as the only force relevant to evolution has led to a lot of sloppy thinking, and is probably the primary reason why evolution is viewed as a soft science by much of society.

A central point to be explained in this book is that most aspects of evolution at the genome level cannot be fully explained in adaptive terms, and moreover, that many features could not have emerged without a near-complete disengagement of the power of natural selection. This contention is supported by a wide array of comparative data, as well as by well-established principles of population genetics. However, even if such support did not exist, there is an important reason for pursuing nonadaptive (neutral) models of evolution. If one wants to confidently invoke a specific adaptive scenario to explain an observed pattern of comparative data, then an ability to reject a hypothesis based entirely on the nonadaptive forces of evolution is critical.

The blind worship of natural selection is not evolutionary biology. It is arguably not even science.

Michael Lynch
Despite the tremendous theoretical and physical resources now available, the field of evolutionary biology continues to be widely perceived as a soft science. Here I am referring not to the problems associated with those pushing the view that life was created by an intelligent designer, but to a more significant internal issue: a subset of academics who consider themselves strong advocates of evolution but who see no compelling reason to probe the substantial knowledge base of the field. Although this is a heavy charge, it is easy to document. For example, in his 2001 presidential address to the Society for the Study of Evolution, Nick Barton presented a survey that demonstrated that about half of the recent literature devoted to evolutionary issues is far removed from mainstream evolutionary biology.

With the possible exception of behavior, evolutionary biology is treated unlike any other science. Philosophers, sociologists, and ethicists expound on the central role of evolutionary theory in understanding our place in the world. Physicists excited about biocomplexity and computer scientists enamored with genetic algorithms promise a bold new understanding of evolution, and similar claims are made in the emerging field of evolutionary psychology (and its derivatives in political science, economics, and even the humanities). Numerous popularizers of evolution, some with careers focused on defending the teaching of evolution in public schools, are entirely satisfied that a blind adherence to the Darwinian concept of natural selection is a license for such activities. A commonality among all these groups is the near-absence of an appreciation of the most fundamental principles of evolution. Unfortunately, this list extends deep within the life sciences.

....

... the uncritical acceptance of natural selection as an explanatory force for all aspects of biodiversity (without any direct evidence) is not much different than invoking an intelligent designer (without any direct evidence). True, we have actually seen natural selection in action in a number of well-documented cases of phenotypic evolution (Endler 1986; Kingsolver et al. 2001), but it is a leap to assume that selection accounts for all evolutionary change, particularly at the molecular and cellular levels. The blind worship of natural selection is not evolutionary biology. It is arguably not even science. Natural selection is just one of several evolutionary mechanisms, and the failure to realize this is probably the most significant impediment to a fruitful integration of evolutionary theory with molecular, cellular, and developmental biology.

Natural selection is just one of several evolutionary mechanisms, and the failure to realize this is probably the most significant impediment to a fruitful integration of evolutionary theory with molecular, cellular, and developmental biology.It should be emphasized here that the sins of panselectionism are by no means restricted to developmental biology, but simply follow the tradition embraced by many areas of evolutionary biology itself, including paleontology and evolutionary ecology (as cogently articulated by Gould and Lewontin in 1979). The vast majority of evolutionary biologists studying morphological, physiological, and or behavioral traits almost always interpret the results in terms of adaptive mechanisms, and they are so convinced of the validity of this approach that virtually no attention is given to the null hypothesis of neutral evolution, despite the availability of methods to do so (Lande 1976; Lynch and Hill 1986; Lynch 1994). For example, in a substantial series of books addressed to the general public, Dawkins (e,g., 1976, 1986, 1996, 2004) has deftly explained a bewildering array of observations in terms of hypothetical selection scenarios. Dawkins's effort to spread the gospel of the awesome power of natural selection has been quite successful, but it has come at the expense of reference to any other mechanisms, and because more people have probably read Dawkins than Darwin, his words have in some ways been profoundly misleading. To his credit, Gould, who is also widely read by the general public, frequently railed against adaptive storytelling, but it can be difficult to understand what alternative mechanisms of evolution Gould had in mind.


Tuesday, July 28, 2015

I never expected this!

David Klinghoffer writes at Evolution News & Views (sic): In The New Yorker, Tom Wolfe Compares Persecution of Intelligent Design Advocates to the "Spanish Inquisition".
Interviewed by The New Yorker earlier this year, the great novelist and journalist Tom Wolfe acknowledged that he's writing a book about evolution -- actually, "a history of the theory of evolution from the nineteenth century to the present." No indication of what his overall thesis might be, but he "invokes the Spanish Inquisition when discussing how academics have cast out proponents of intelligent design for 'not believing in evolution the right way.'"



On the total length of all DNA molecules on the planet

If you were to line up all the DNA molecules from all the individuals in all the species on Earth, how long would it be? This is a kind of "Fermi question" or "Fermi problem." You should be able to estimate an answer based on what you know and reasonable assumptions.

Michael Lynch has a crude estimate in his book The Origins of Genome Architecture. Without reading the book, can you come up with an estimate of your own? Is it larger than the circumference of the Earth? Larger than the distance to Pluto? Longer than the distance to the nearest star (other than the sun) or the the center of the galaxy? Would the string of DNA molecules stretch to the nearest large galaxy (Andromeda)? Or, would it be even longer than that?

In case you've forgotten everything you once knew about the structure of DNA, here's a brief refresher: The Three-Dimensional Structure of DNA.

You may assume that all of the DNA molecules are in the standard B-form with the dimensions shown in the figure.

I will not accept any answers in archaic measurement units like leagues, miles, yojana, or cubits.


Readings from Trends in Biochemical Sciences on the Central Dogma

I'm re-reading The Inside Story edited by Jan Witkowski, the former editor-in-chief of Trends in Biochemical Sciences (TIBS). The book is a collection of essays that appeared in the journal. The collection centers around "the theme of the Central Dogma of molecular biology." Here's how Jan Witkowski describes the collection in the preface (page xii)...
When I came to look more closely, it was clear that the area the articles covered most comprehensively, where the most interesting selection could be made, was the Central Dogma, that is DNA, RNA, and protein synthesis. And the number of relevant articles was just right for the size of book we had in mind.
This explains the subtitle of the book, "DNA to RNA to Protein."

This is not going to be another complaint about misinterpretations of the Central Dogma. Quite the contrary, as we shall see.

The Forward was written by Tim Hunt who was the editor-in-chief from 1992-2000. He refers to "The General Idea."
"Jim, you might say, had it first. DNA makes RNA makes protein. That became the general idea." Thus did Francis Crick explain to Horace Judson years later, long after he had written with such clarity and force on the subject of protein synthesis in the 1958 Symposium on "The Biological Replication of Macromolecules" [see Crick, 1959). This article is celebrated for its prediction of the existence of tRNA (although by the time the article appeared in print, tRNA had been discovered), but it is chiefly worth reading and rereading, even today, for its enunciation of the two principles that together constitute the "General Idea." The first principle is the Sequence Hypothesis; the idea that the sequence of amino acids in proteins is specified by the sequence of bases in DNA and RNA. The second principle is the famous "Central Dogma"; not DNA makes RNA makes Protein, but the assertion that "Once information has passed into protein it cannot get out again." It isn't completely clear why one is a hypothesis and the other a dogma and the two together an idea. The Dogma stuck in some throats, mainly because it was called a dogma, with heavy religious overtones.
I quote Tim Hunt to show that there are some knowledgeable scientists who understand the Central Dogma [see The Central Dogma of Molecular Biology].

Hunt continues ...
Crick explains that calling it a dogma was a misunderstanding on his part: he thought the word stood for "an idea for which there was no reasonable evidence," blaming his "curious religious upbringing" for the error. But it probably wasn't that much of a mistake after all, for the Oxford Dictionary allows dogma to mean simply a principle, although the alternative "Arrogant declaration of opinion" is probably how most people who were not molecular biologists took it, considering its never modest author. That is probably how they were meant to take it, too. It was the most important article of faith among the circle of biologists centered on Watson and Crick and remained so for quite a long time until the mechanism of protein synthesis became clear. Crick said that if you did not subscribe to the sequence hypothesis and the central dogma "you generally ended up in the wilderness," although he did not offer alternative scenarios for public consumption, even though they probably played an important part in convincing him of the dogmatic status of the General Idea's second component.
This is the concept that I "grew up" with as a graduate student in the late 1960s. We saw the "General Idea" as an important concept and a way of understanding the data that was coming out of many labs working on DNA replication, transcription, and protein synthesis. We knew, especially after 1970 (Crick, 1970), that RNA could be used as a template to make DNA and that there were many types of RNA other than messenger RNA. We also knew that Francis Crick was a very smart man and it was unwise to disagree with him because he was usually right about big ideas.

Fig. 1. Information flow and the sequence hypothesis. These diagrams of potential information flow were used by Crick (1958) to illustrate all possible transfers of information (left) and those that are permitted (right). The sequence hypothesis refers to the idea that information encoded in the sequence of nucleotides specifies the sequence of amino acids in the protein.
At some point in the last 40 year the "General Idea" has been subverted in two ways.
  1. The Sequence Hypothesis has come to be interpreted as the Central Dogma. This is mostly due to Jim Watson who propagated this misinterpretation in his Molecular Biology of the Gene textbook.
  2. The Central Dogma is taken to mean that the ONLY important information in the genome is that which encodes proteins. It's assumed, incorrectly, that Crick meant to say that the role of all genes is to encode proteins.
One of the essays in The Inside Story is "Forty Years under the Central Dogma," published in 1998. The authors are Denis Thieffry and Sahotra Sarkar (Thieffry and Sarkar, 1998).

Here's how they explain some of the confusion about the Central Dogma ...
The most obvious interpretation of Crick’s original (1958) formulation of the Central Dogma is in negative terms. The Central Dogma only forbids a few types of information transfer, namely, from proteins to proteins and from proteins to nucleic acids. However, after its rapid adoption by most of the biologists interested in protein synthesis, it was most often interpreted or reformulated in a more restrictive way, constricting the flow of information from DNA to RNA and from RNA to protein (Fig. 1).

Figure 1 The Central Dogma as envisioned by Watson in 1965. ‘We should first look at the evidence that DNA itself is not the direct template that orders amino acid sequences. Instead, the genetic information of DNA is transferred to another class of molecules, which then serve as the protein templates. These intermediate templates are molecules of ribonucleic acid (RNA)...Their relation to DNA and protein is usually summarised by the formula (often called the central dogma).'

According to Watson’s autobiography, he had already derived this ‘formula’ (Fig. 1) in 1952. In fact, such schemes were commonly entertained during the early 1950s, at least among the biologists interested in protein synthesis. ... Much more restrictive than Crick’s original statement, Watson’s formula was immediately confronted with a series of possible exceptions, some of which are mentioned below. Crick, meanwhile, remained rather cautious in his interpretation of the Central Dogma. On several occasions, he felt it necessary to come back to his original idea and explicate what he thought to be its correct interpretation. For example, in 1970, Crick devoted a paper specifically to the Central Dogma, including a diagram reportedly conceived (but not published) in 1958.[see the figure at the top of this page]
The authors recognize several challenges to the Central Dogma, at least to the version preferred by Watson. There were two discoveries in the 1960s that seemed to threaten the Central Dogma. The first was the discovery that the genetic material of some viruses (e.g. TMV) was RNA, not DNA. The second was the discovery that RNA could be copied into DNA by reverse transcriptase. This was not a problem for Crick ....
These findings prompted Crick to write his 1970 piece for Nature, in which he explicitly showed how the new facts fitted into his scheme.
It's difficult to evaluate the importance of the Central Dogma in the 21st century because so many scientists don't understand it. The incorrect version seems to mostly serve as a whipping boy to promote "new" ideas that overthrow the strawman version of the Central Dogma.

Back in 1998, the authors of this article asked Crick what he thought of the Central Dogma ...
In a recent answer to a question addressing the relevance of these challenges, Crick stated that he still believes in the value of the Central Dogma today (F.H.C. Crick, pers. commun.). However, he also acknowledges the existence of various exceptions, most of which he regards as minor. For him, the most significant exception is RNA editing. Still, according to Crick, simplifications of the Central Dogma in terms such as ‘DNA makes RNA and RNA makes protein’ were clearly inadequate from the beginning.

Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163. [PDF]

Crick, F. (1970) Central Dogma of Molecular Biology. Nature 227, 561-563. [PDF file]

Thieffry, D. and Sarkar, S. (1998) "Forty years under the central dogma." Trends in Biochemical Sciences 23:312–316. [doi: 10.1016/S0968-0004(98)01244-4}

Monday, July 27, 2015

More confusion about the central dogma of molecular biology

I was doing some reading on lncRNAs (long non-coding RNAs) in order to find out how many of them had been assigned real biological functions. My reading was prompted by the one of the latest updates to the human genome sequence; namely, assembly GRCh38.p3 from June 2015. The Ensembl website lists 14,889 lncRNA genes but I'm sure that most of these are just speculative [Ensembl Whole Genome].

The latest review by my colleagues here in the biochemistry department at the University of Toronto (Toronto, Canada), concludes that only a small fraction of these putative lncRNAs have a function (Palazzo and Lee, 2015). They point out that in the absence of evidence for function, the null hypothesis is that these RNAs are junk and the genes don't exist. That's not the view that annotators at Ensembl take.

I stumbled across a paper by Ling et al. (2015) that tries to make a case for function. I don't think their case is convincing but that's not what I want to discuss. I want to discuss their view of the Central Dogma of Molecular Biology. Here's the abstract ...
The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual’s susceptibility to cancer.
This is getting to be a familiar refrain. I understand how modern scientists might be confused about the difference between the Watson and the Crick versions of the Central Dogma [see The Central Dogma of Molecular Biology]. Many textbooks perpetuate the myth that Crick's sequence hypothesis is actually the Central Dogma. That's bad enough but lots of researchers seem to think that their false view of the Central Dogma goes even further. They think it means that the ONLY kind of genes in your genome are those that produce mRNA and protein.

I don't understand how such a ridiculous notion could arise but it must be a common misconception, otherwise why would these authors think that non-coding RNAs are a challenge to the Central Dogma? And why would the reviewers and editors think this was okay?

I'm pretty sure that I've interpreted their meaning correctly. Here's the opening sentences of the introduction to their paper ...
The Encyclopedia of DNA Elements (ENCODE) project has revealed that at least 75% of the human genome is transcribed into RNAs, while protein-coding genes comprise only 3% of the human genome. Because of a long-held protein-centered bias, many of the genomic regions that are transcribed into non-coding RNAs (ncRNAs) had been viewed as ‘junk’ in the genome, and the associated transcription had been regarded as transcriptional ‘noise’ lacking biological meaning.
They think that the Central Dogma is a "protein-centered bias." They think the Central Dogma rules out genes that specify noncoding RNAs. (Like tRNA and ribosomal RNA?)

Later on they say ....
The protein-centered dogma had viewed genomic regions not coding for proteins as ‘junk’ DNA. We now understand that many lncRNAs are transcribed from ‘junk’ regions, and even those encompassing transposons, pseudogenes and simple repeats represent important functional regulators with biological relevance.
It's simply not true that scientists in the past viewed all noncoding DNA as junk, at least not knowledgeable scientists [What's in Your Genome?]. Furthermore, no knowledgeable scientists ever interpreted the Central Dogma of Molecular Biology to mean that the only functional genes in a genome were those that encoded proteins.

Apparently Lee, Vincent, Picler, Fodde, Berindan-Neagoe, Slack, and Calin knew scientists who DID believe such nonsense. Maybe they even believed it themselves.

Judging by the frequency with with such statements appear in the scientific literature, I can only assume that this belief is widespread among biochemists and molecular biologists. How in the world did this happen? How many Sandwalk readers were taught that the Central Dogma rules out all genes for noncoding RNAs? Did you have such a protein-centered bias about the role of genes? Who were your teachers?

Didn't anyone teach you who won the Nobel Prize in 1989? Didn't you learn about snRNAs? What did you think RNA polymerases I and III were doing in the cell?


Ling, H., Vincent, K., Pichler, M., Fodde, R., Berindan-Neagoe, I., Slack, F.J., and Calin, G.A. (2015) Junk DNA and the long non-coding RNA twist in cancer genetics. Oncogene (published online January 26, 2015) [PDF]

Palazzo, A.F. and Lee, E.S. (2015) Non-coding RNA: what is functional and what is junk? Frontiers in genetics 6: 2 (published online January 26, 2015 [Abstract]

Friday, July 24, 2015

John Parrington talks about The Deeper Genome

Here's a video from Oxford Press where you can hear John Parrington describe some of the ideas in his book: The Deeper Genome: Why there is more to the human genome than meets the eye.



John Parrington discusses genome sequence conservation

John Parrington has written a book called, The Deeper Genome: Why there is more to the human genome than meets the eye. He claims that most of our genome is functional, not junk. I'm looking at how his arguments compare with Five Things You Should Know if You Want to Participate in the Junk DNA Debate

There's one post for each of the five issues that informed scientists need to address if they are going to write about the amount of junk in you genome. This is the last one.

1. Genetic load
John Parrington and the genetic load argument
2. C-Value paradox
John Parrington and the c-value paradox
3. Modern evolutionary theory
John Parrington and modern evolutionary theory
4. Pseudogenes and broken genes are junk
John Parrington discusses pseudogenes and broken genes
5. Most of the genome is not conserved (this post)
John Parrington discusses genome sequence conservation

5. Most of the genome is not conserved

There are several places in the book where Parrington address the issue of sequence conservation. The most detailed discussion is on pages 92-95 where he discusses the criticisms leveled by Dan Graur against ENCODE workers. Parrington notes that 9% of the human genome is conserved and recognizes that this is a strong argument for function. It implies that >90% of our genome is junk.

Here's how Parrington dismisses this argument ...
John Mattick and Marcel Dinger ... wrote an article for the HUGO Jounral, official journal of the Human Genome Organisation, entitled "The extent of functionality in the human genome." ... In response to the accusation that the apparent lack of sequence conservation of 90 per cent of the genome means that it has no function, Mattick and Dinger argued that regulatory elements and noncoding RNAs are much more relaxed in their link between structure and function, and therefore much harder to detect by standard measures of function. This could mean that 'conservation is relative', depending on the type of genomic structure being analyzed.
In other words, a large part of our genome (~70%?) could be producing functional regulatory RNAs whose sequence is irrelevant to their biological function. Parrington then writes a full page on Mattick's idea that the genome is full of genes for regulatory RNAs.

The idea that 90% of our genome is not conserved deserves far more serious treatment. In the next chapter (Chapter 7), Parrington discusses the role of RNA in forming a "scaffold" to organize DNA in three dimensions. He notes that ...
That such RNAs, by virtue of their sequence but also their 3D shape, can bind DNA, RNA, and proteins, makes them ideal candidates for such a role.
But if the genes for these RNAs make up a significant part of the genome then that means that some of their sequences are important for function. That has genetic load implications and also implications about conservation.

If it's not a "significant" fraction of the genome then Parrington should make that clear to his readers. He knows that 90% of our genome is not conserved, even between individuals (page 142), and he should know that this is consistent with genetic load arguments. However, almost all of his main arguments against junk DNA require that the extra DNA have a sequence-specific function. Those facts are not compatible. Here's how he justifies his position ...
Those proposing a higher figure [for functional DNA] believe that conservation is an imperfect measure of function for a number of reasons. One is that since many non-coding RNAs act as 3D structures, and because regulatory DNA elements are quite flexible in their sequence constraints, their easy detection by sequence conservation methods will be much more difficult than for protein-coding regions. Using such criteria, John Mattick and colleagues have come up with much higher figures for the amount of functionality in the genome. In addition, many epigenetic mechanisms that may be central for genome function will not be detectable through a DNA sequence comparison since they are mediated by chemical modifications of the DNA and its associated proteins that do not involve changes in DNA sequence. Finally, if genomes operate as 3D entities, then this may not be easily detectable in terms of sequence conservation.
This book would have been much better if Parrington had put some numbers behind his speculations. How much of the genome is responsible for making functional non-coding RNAs and how much of that should be conserved in one way of another? How much of the genome is devoted to regulatory sequences and what kind of sequence conservation is required for functionality? How much of the genome is required for "epigenetic mechanisms" and how do they work if the DNA sequence is irrelevant?

You can't argue this way. More than 90% of our genomes is not conserved—not even between individuals. If a good bit of that DNA is, nevertheless, functional, then those functions must not have anything to do with the sequence of the genome at those specific sites. Thus, regions that specify non-coding RNAs, for example, must perform their function even though all the base pairs can be mutated. Same for regulatory sequences—the actual sequence of these regulatory sequences isn't conserved according to John Parrington. This requires a bit more explanation since it flies on the face of what we know about function and regulation.

Finally, if you are going to use bulk DNA arguments to get around the conflict then tell us how much of the genome you are attributing to formation of "3D entities." Is it 90%? 70%? 50%?