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Wednesday, November 25, 2015

In defense of curiosity-motivated research

I was prompted to write this post by three recent events. First, I read an article by Angelika Amon who made A case for more curiosity-driven basic research. She is the recipient of the 2015 ASCB [American Society for Cell Biology] Women in Cell Biology Sandra K. Masur Senior Leadership Award.

She says,
While conducting research to improve the lives of others is certainly a worthy motivation, it is not the main reason why I get up very early in the morning to go to the lab. To me, gaining an understanding of a basic principle in the purest Faustian terms is what I find most rewarding and exciting.

... For me, having a career in curiosity-driven basic research has been immensely rewarding. It is my hope that basic research remains one of the pillars of the American scientific enterprise, attracting the brightest young minds for generations to come. We as a community can help to make this a reality by telling people what we do and highlighting the importance of our work to their lives.
I agree wholeheartedly with this sentiment although I would emphasize that the general public needs to understand that the important result of basic research is knowledge, and knowledge for its own sake is important. It's certainly far better than ignorance.

This kind of scholarly activity—curiosity motivated research—is the backbone of activity in the universities. At least it used to be. I still think that universities should stand up and defend the search for knowledge.

The second stimulus was an acknowledgement I recently stumbled across at the end of a paper by Ford Doolittle from 1982 (Doolittle, 1982).
And I' m most grateful to the Medical Research Council and the Natural Sciences and Engineering Research Council of Canada for providing us with the funds to pursue our sometimes arcane interests without hindrance.
The old MRC has become CIHR. It's hard to imagine any scientist writing such an acknowledgement today since CIHR is notorious for hindering basic curiosity-motivated research [see Support basic research with new leaders at the Canadian Institutes of Health Research (CIHR)].

Not only have the funding agencies abandoned curiosity-motivated research, so have the universities and that brings me to the third event. My university, the University of Toronto, has been trying to direct health research for several decades. It does this by preferentially funding and supporting research in designated areas that are likely to become the beneficiaries of substantial donations and/or support from the private sector. This emphasis often goes hand-in-hand with government wishes and the subverted goals of the funding agencies they control.

The latest example is a new research facility across the street from the main campus in a brand-new, expensive, building that's part of MaRS [U of T expands research facilities in new partnership with MaRS].
The first U of T groups to move over to the new MaRS tower are the Medicine by Design initiative, the Ted Rogers Centre for Heart Research, the Centre for Commercialization of Regenerative Medicine, and the ARCNet advanced research computing and data analytics centre. Other research groups from the Faculty of Medicine will move to MaRS to enhance existing networks in regenerative medicine, drug discovery and infectious disease.
The idea here is to take successful, well-funded, research groups from different campus-based basic science departments and group them together in units that focus on, for example, drug discovery and infectious diseases. They will get all the perks of a new building and new research facilities and enhanced prestige and recognition.

Meanwhile, those researchers working on basic curiosity-motivated projects like Drosophila development, the targeting of cellular RNAs, the survival of mitochondria, theoretical investigations of protein folding, the structure of glycoproteins, and protein turnover in yeast and bacteria—to name just a few—will remain in a 50 year old building that looks more like a prison than a modern research facility. The message is loud and clear. Curiosity-motivated basic researchers are second class scientists unless they just happen to be working on projects that Faculty administrators think are important

That's not how universities should behave. I expect university leaders and administrators to stand up for the search for knowledge and promote the rights of researchers to go where curiosity takes them. That's what academic freedom is all about.

I think you can make a case that grouping like-minded researchers together in specific goal-oriented research groups may not be the most successful strategy in a university environment even if you concede that it's up to universities to pick and choose research priorities. It reminds me of a discussion I had with Janet Stemwedel a few years ago. The discussion started off on the topic of ethics then changed to the difference between "science" and "technology." It applies also to the difference between curiosity-motivated research and goal-oriented research.

Is ‘what is this good for?’ a question to be discouraged?
Teaching Ethics in Science: Science v Technology
A worker in basic scientific research is motivated by a driving curiosity about the unknown. When his explorations yield new knowledge, he experiences the satisfaction of those who first attain the summit of a mountain or the upper reaches of a river flowing through unmapped territory. Discovery of truth and understanding of nature are his objectives. His professional standing among his fellows depends upon the originality and soundness of his work. Creativeness in science is of a cloth with that of the poet or painter.
National Science Foundation (USA) Annual Report 1953
I'm not arguing that scientists who are interested in drug discovery or infectious diseases aren't motivated by curiosity just like the rest of us. What I'm arguing is that it should not be the university's business to reward those whose curiosity leads them in one direction and penalize those who are curious about something else. That's sending a strong message and the message is "go in this direction" if you want the perks. That's not compatible with supporting curiosity-motivated research and the quest for knowledge in its purest form.

Maybe the university needs to stop supporting curiosity-motivated research? That's worth debating but in my experience debate is not what university administrators want to hear. It's rare that professors and researchers are invited to discuss the decisions made in the President's Office or the Dean's Office even though those decisions will seriously affect their lives and their careers.

Why can't we at least discuss these issues rather than read about them in the newspaper?


Doolittle, W.F. (1982) Evolutionary molecular biology: where is it going? Canadian Journal of Biochemistry, 60:83-90.

Support basic research with new leaders at the Canadian Institutes of Health Research (CIHR)

An important article in the Ottawa Citizen calls for the resignation of Alain Beaudet, recently reappointed President of the Canadian Institutes of Health Research (CIHR) ['Demoralized' scientists demand changes at $1B health research agency]. Criticism comes from Michael Rudnicki but he is merely voicing what lots of other researchers feel.
“He has rammed through what he calls reforms which have radically altered the grant delivery system and the system for evaluating grants has been done in a way that distorts the entire process,” said Rudnicki of changes brought in by Beaudet.

Top research scientists from across the country, in interviews with the Citizen, described their mood as demoralized and deeply disturbed by what has been going on at the CIHR. “There is a lot of scorched earth out there,” said one.

According to researchers, the malaise cannot be fixed by simply unmuzzling government scientists. The federal government needs to support basic scientific research, they say, with more money and with a system that is transparent and designed to reward the country’s best and brightest researchers. Instead, researchers say, a series of recent changes at the agency that funds a billion dollars of research each year, notably to the peer review system, have done the opposite.

“The entire research community is very upset and extremely concerned about these changes,” said Rudnicki.

Among concerns are that basic research is getting an ever-smaller share of flatlined funding, in favour of applied or targeted research. Some independent scientists working in labs — doing the kind of work that has led to discoveries such as stem cells — are finding it increasingly difficult to keep going.
The President of CIHR is essentially a government appointee and he or she is not beholding to the researchers (clients) in any legal way. However, I have long advocated that the leadership of CIHR, and the other government funding agencies, should deserve the confidence of the Canadian Research Community and they should resign if they do not have that confidence.

That time has come. Not only has CIHR discouraged basic curiosity-motivated research but the effect of their policies has encouraged university administrators to do the same. We see more and more university resources going into directed research on specific applied targets and the few remaining basic researchers are treated as second class citizens left in the oldest, out-dated, facilities with the fewest university resources.

I will gladly sign any petition calling for the resignation of the CIHR leaders and anyone else who supports their disastrous policies.


Intelligent design creationism and intellectual laziness

I stumbled upon this 2005 letter to Nature by Michael Lynch and I thought I'd share it with you since it emphasizes one of my main pet peeves about intelligent design creationists. I've highlighted the relevant sentences. Check out the video.
Intelligent design or intellectual laziness?

SIR – Much of the concern over ID (Nature 434, 1053 and 1062–1065; 2005) has focused on veiled attempts to inject religion into public education. Sheltered within the confines of academia, most biologists find it hard to believe that the slain need to be slain again. Those in the trenches—school boards, school biology teachers and their national representatives—often don’t know how to respond, in part because they themselves never really achieved a deep understanding of evolutionary biology at college.

However, there is a related and equally disturbing issue: the legitimization of intellectual laziness. Have a problem explaining something? Forget about it: the Designer made it that way. Any place for diversity of opinion as to who/what the Designer is/was? The ID literature makes it very clear that there is no room for scientific discourse on that. Think I’m exaggerating? To get a good idea of what IDers would have the face of science look like, check out the journal Perspectives on Science and Christian Faith (www.asa3.org/ASA/PSCF.html).

Two factors have facilitated the promotion of ID. First, IDers like to portray evolution as being built entirely on an edifice of darwinian natural selection. This caricature of evolutionary biology is not too surprising. Most molecular, cell and developmental biologists subscribe to the same creed, as do many popular science writers. However, it has long been known that purely selective arguments are inadequate to explain many aspects of biological diversity. Building a straw man based on natural selection alone makes it easy for opponents to poke holes in evolution. But features of the genome, such as genomic parasites or non-coding introns, which aren’t so evolutionarily favourable (nor obviously ‘intelligent’ innovations), can be more readily explained by models that include random genetic drift and mutation as substantial evolutionary forces.

Second, IDers like to portray evolution as a mere theory. But after a century of close scrutiny, evolutionary theory has passed so many litmus tests of validation that evolution is as much a fact as respiration and digestion.

Less widely appreciated is that evolution has long been the most quantitative field of biology, well grounded in the general principles of transmission genetics. Yet few students at university, and almost none at high school, are exposed to the mathematical underpinnings of evolutionary theory. The teaching of evolution purely as history, with little consideration given to the underlying mechanisms, reinforces the false view that evolution is one of the softer areas of science.

Here is a missed opportunity. Our failure to provide students with the mathematical skills necessary to compete in a technical world is a major concern in the United States. Mathematics becomes more digestible, and even attractive, when students see its immediate application. What better place to start than with the population-genetic theory of evolution, much of which is couched in algebraic terms accessible to school students?

Michael Lynch
Department of Biology, Indiana University,
Bloomington, Indiana 47405, USA



Selfish genes and transposons

Back in 1980, the idea that large fractions of animal and plant genomes could be junk was quite controversial. Although the idea was consistent with the latest developments in population genetics, most scientists were unaware of these developments. They were looking for adaptive ways of explaining all the excess DNA in these genomes.

Some scientists were experts in modern evolutionary theory but still wanted to explain "junk DNA." Doolittle & Sapienza, and Orgel & Crick, published back-to-back papers in the April 17, 1980 issue of Nature. They explained junk DNA by claiming that most of it was due to the presence of "selfish" transposons that were being selected and preserved because they benefited their own replication and transmission to future generations. They have no effect on the fitness of the organism they inhabit. This is natural selection at a different level.

This prompted some responses in later editions of the journal and then responses to the responses.

Here's the complete series ...

Sunday, November 22, 2015

What do pseudogenes teach us about intelligent design?

The human genome has about 14,000 pseudogenes that are derived from protein-coding genes and an unknown number derived from genes that specify functional noncoding RNAs. There is abundant evidence that the vast majority of these pseudogenes are nonfunctional by all measurable criteria.
It would be perverse to deny the existence of pseudogenes. Almost all of them are junk DNA with no known function. Anyone who claims otherwise can be dismissed as a kook and it's not worth debating those people.

The presence of a single well-characterized pseudogene at the same locus in the genomes of different species is powerful evidence of common descent. For example, Ken Miller has long argued that the existence of common pseudogenes in chimpanzees and humans is solid evidence that the two species share a common ancestor. He uses the β-globin pseudogene and the gene for making vitamin C as examples in Only a Theory: Evolution and the Battle for America's Soul.

Friday, November 20, 2015

The truth about ENCODE

A few months ago I highlighted a paper by Casane et al. (2015) where they said ...
In September 2012, a batch of more than 30 articles presenting the results of the ENCODE (Encyclopaedia of DNA Elements) project was released. Many of these articles appeared in Nature and Science, the two most prestigious interdisciplinary scientific journals. Since that time, hundreds of other articles dedicated to the further analyses of the Encode data have been published. The time of hundreds of scientists and hundreds of millions of dollars were not invested in vain since this project had led to an apparent paradigm shift: contrary to the classical view, 80% of the human genome is not junk DNA, but is functional. This hypothesis has been criticized by evolutionary biologists, sometimes eagerly, and detailed refutations have been published in specialized journals with impact factors far below those that published the main contribution of the Encode project to our understanding of genome architecture. In 2014, the Encode consortium released a new batch of articles that neither suggested that 80% of the genome is functional nor commented on the disappearance of their 2012 scientific breakthrough. Unfortunately, by that time many biologists had accepted the idea that 80% of the genome is functional, or at least, that this idea is a valid alternative to the long held evolutionary genetic view that it is not. In order to understand the dynamics of the genome, it is necessary to re-examine the basics of evolutionary genetics because, not only are they well established, they also will allow us to avoid the pitfall of a panglossian interpretation of Encode. Actually, the architecture of the genome and its dynamics are the product of trade-offs between various evolutionary forces, and many structural features are not related to functional properties. In other words, evolution does not produce the best of all worlds, not even the best of all possible worlds, but only one possible world.
How did we get to this stage where the most publicized result of papers published by leading scientists in the best journals turns out to be wrong, but hardly anyone knows it?

Back in September 2012, the ENCODE Consortium was preparing to publish dozens of papers on their analysis of the human genome. Most of the results were quite boring but that doesn't mean they were useless. The leaders of the Consortium must have been worried that science journalists would not give them the publicity they craved so they came up with a strategy and a publicity campaign to promote their work.

Their leader was Ewan Birney, a scientist with valuable skills as a herder of cats but little experience in evolutionary biology and the history of the junk DNA debate.

The ENCODE Consortium decided to add up all the transcription factor binding sites—spurious or not—and all the chromatin makers—whether or not they meant anything—and all the transcripts—even if they were junk. With a little judicious juggling of numbers they came up with the following summary of their results (Birney et al., 2012) ..
The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
See What did the ENCODE Consortium say in 2012? for more details on what the ENCODE Consortium leaders said, and did, when their papers came out.

The bottom line is that these leaders knew exactly what they were doing and why. By saying they have assigned biochemical functions for 80% of the genome they knew that this would be the headline. They knew that journalists and publicists would interpret this to mean the end of junk DNA. Most of ENCODE leaders actually believed it.

That's exactly what happened ... aided and abetted by the ENCODE Consortium, the journals Nature and Science, and gullible science journalists all over the world. (Ryan Gregory has published a list of articles that appeared in the popular press: The ENCODE media hype machine..)

Almost immediately the knowledgeable scientists and science writers tried to expose this publicity campaign hype. The first criticisms appeared on various science blogs and this was followed by a series of papers in the published scientific literature. Ed Yong, an experienced science journalist, interviewed Ewan Birney and blogged about ENCODE on the first day. Yong reported the standard publicity hype that most of our genome is functional and this interpretation is confirmed by Ewan Birney and other senior scientists. Two days later, Ed Yong started adding updates to his blog posting after reading the blogs of many scientists including some who were well-recognized experts on genomes and evolution [ENCODE: the rough guide to the human genome].

Within a few days of publishing their results the ENCODE Consortium was coming under intense criticism from all sides. A few journalists, like John Timmer, recongized right away what the problem was ...
Yet the third sentence of the lead ENCODE paper contains an eye-catching figure that ended up being reported widely: "These data enabled us to assign biochemical functions for 80 percent of the genome." Unfortunately, the significance of that statement hinged on a much less widely reported item: the definition of "biochemical function" used by the authors.

This was more than a matter of semantics. Many press reports that resulted painted an entirely fictitious history of biology's past, along with a misleading picture of its present. As a result, the public that relied on those press reports now has a completely mistaken view of our current state of knowledge (this happens to be the exact opposite of what journalism is intended to accomplish). But you can't entirely blame the press in this case. They were egged on by the journals and university press offices that promoted the work—and, in some cases, the scientists themselves.


[Most of what you read was wrong: how press releases rewrote scientific history]
Nature may have begun to realize that it made a mistake in promoting the idea that most of our genome was functional. Two days after the papers appeared, Brendan Maher, a Feature Editor for Nature, tried to get the journal off the hook but only succeeded in making matters worse [see Brendan Maher Writes About the ENCODE/Junk DNA Publicity Fiasco].

Meanwhile, two private for-profit companies, illumina and Nature, team up to promote the ENCODE results. They even hire Tim Minchin to narrate it. This is what hype looks like ...


Soon articles began to appear in the scientific literature challenging the ENCODE Consortium's interpretation of function and explaining the difference between an effect—such as the binding of a transcription factor to a random piece of DNA—and a true biological function.

Eddy, S.R. (2012) The C-value paradox, junk DNA and ENCODE. Current Biology, 22:R898. [doi: 10.1016/j.cub.2012.10.002]

Niu, D. K., and Jiang, L. (2012) Can ENCODE tell us how much junk DNA we carry in our genome?. Biochemical and biophysical research communications 430:1340-1343. [doi: 10.1016/j.bbrc.2012.12.074]

Doolittle, W.F. (2013) Is junk DNA bunk? A critique of ENCODE. Proc. Natl. Acad. Sci. (USA) published online March 11, 2013. [PubMed] [doi: 10.1073/pnas.1221376110]

Graur, D., Zheng, Y., Price, N., Azevedo, R. B., Zufall, R. A., and Elhaik, E. (2013) On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biology and Evolution published online: February 20, 2013 [doi: 10.1093/gbe/evt028

Eddy, S.R. (2013) The ENCODE project: missteps overshadowing a success. Current Biology, 23:R259-R261. [10.1016/j.cub.2013.03.023]

Hurst, L.D. (2013) Open questions: A logic (or lack thereof) of genome organization. BMC biology, 11:58. [doi:10.1186/1741-7007-11-58]

Morange, M. (2014) Genome as a Multipurpose Structure Built by Evolution. Perspectives in biology and medicine, 57:162-171. [doi: 10.1353/pbm.2014.000]

Palazzo, A.F., and Gregory, T.R. (2014) The Case for Junk DNA. PLoS Genetics, 10:e1004351. [doi: 10.1371/journal.pgen.1004351]

By March 2013—six months after publication of the ENCODE papers—some editors at Nature decided that they had better say something else [see Anonymous Nature Editors Respond to ENCODE Criticism]. Here's the closest thing to an apology that they have ever written ....
The debate over ENCODE’s definition of function retreads some old battles, dating back perhaps to geneticist Susumu Ohno’s coinage of the term junk DNA in the 1970s. The phrase has had a polarizing effect on the life-sciences community ever since, despite several revisions of its meaning. Indeed, many news reports and press releases describing ENCODE’s work claimed that by showing that most of the genome was ‘functional’, the project had killed the concept of junk DNA. This claim annoyed both those who thought it a premature obituary and those who considered it old news.

There is a valuable and genuine debate here. To define what, if anything, the billions of non-protein-coding base pairs in the human genome do, and how they affect cellular and system-level processes, remains an important, open and debatable question. Ironically, it is a question that the language of the current debate may detract from. As Ewan Birney, co-director of the ENCODE project, noted on his blog: “Hindsight is a cruel and wonderful thing, and probably we could have achieved the same thing without generating this unneeded, confusing discussion on what we meant and how we said it”.
Oops! The importance of junk DNA is still an "important, open and debatable question" in spite of what the video sponsored by Nature might imply.

(To this day, neither Nature nor Science have actually apologized for misleading the public about the ENCODE results. [see Science still doesn't get it ])

The ENCODE Consortium leaders responded in April 2014—eighteen months after their original papers were published.

Kellis, M., Wold, B., Snyder, M.P., Bernstein, B.E., Kundaje, A., Marinov, G.K., Ward, L.D., Birney, E., Crawford, G. E., and Dekker, J. (2014) Defining functional DNA elements in the human genome. Proc. Natl. Acad. Sci. (USA) 111:6131-6138. [doi: 10.1073/pnas.1318948111]

In that paper they acknowledge that there are multiple meanings of the word function and their choice of "biochemical" function may not have been the best choice ....
However, biochemical signatures are often a consequence of function, rather than causal. They are also not always deterministic evidence of function, but can occur stochastically.
This is exactly what many scientists have been telling them. Apparently they did not know this in September 2012.

They also include in their paper a section on "Case for Abundant Junk DNA." It summarizes the evidence for junk DNA, evidence that the ENCODE Consortium did not acknowledge in 2012 and certainly didn't refute.

In answer to the question, "What Fraction of the Human Genome Is Functional?" they now conclude that ENCODE hasn't answered that question and more work is needed. They now claim that the real value of ENCODE is to provide "high-resolution, highly-reproducible maps of DNA segments with biochemical signatures associate with diverse molecular functions."
We believe that this public resource is far more important than any interim estimate of the fraction of the human genome that is functional.
There you have it, straight from the horse's mouth. The ENCODE Consortium now believes that you should NOT interpret their results to mean that 80% of the genome is functional and therefore not junk DNA. There is good evidence for abundant junk DNA and the issue is still debatable.

I hope everyone pays attention and stops referring to the promotional hype saying that ENCODE has refuted junk DNA. That's not what the ENCODE Consortium leaders now say about their results.


Casane, D., Fumey, J., et Laurenti, P. (2015) L’apophénie d’ENCODE ou Pangloss examine le génome humain. Med. Sci. (Paris) 31: 680-686. [doi: 10.1051/medsci/20153106023]

Different kinds of pseudogenes: Polymorphic pseudogenes

There are three main kinds of pseudogenes: processed pseudogenes, duplicated pseudogenes, and unitary pseudogenes [Different kinds of pseudogenes - are they really pseudogenes?].

There's one sub-category of pseudogenes that deserves mentioning. It's called "polymorphic pseudogenes." These are pseudogenes that have not become fixed in the genome so they exist as an allele along with the functional gene at the same locus. Some defective genes might be detrimental, representing loss-of-function alleles that compromise the survival of the organism. Lots of genes for genetic diseases fall into this category. That's not what we mean by polymorphism. The term usually applies to alleles that have reached substantial frequency in the population so that there's good reason to believe that all alleles are about equal with respect to natural selection.

Polymorphic pseudogenes can be examples of pseudogenes that are caught in the act of replacing the functional gene. This indicates that the functional gene is not under strong selection. For example, a newly formed processed pseudogene can be polymorphic at the insertion site and newly duplicated loci may have some alleles that are still functional and others that are inactive. The fixation of a pseudogene takes a long time.

Different kinds of pseudogenes: Unitary pseudogenes

The most common types of pseudogenes are processed pseudogenes and those derived from gene duplication events [duplicated pseudogenes].

The third type of pseudogene is the "unitary" pseudogene. Unitary pseudogenes are genes that have no parent gene. There is no functional gene in the genome that's related to the pseudogene.

Unitary psedogenes arise when a normally functional gene becomes inactivated by mutation and the loss of function is not detrimental to the organism. Thus, the mutated, inactive, gene can become fixed in the population by random genetic drift.

The classic example is the gene for L-glucono-γ-lactone oxidase (GULO), a key enzyme in the synthesis of vitamin C (L-ascorbate, ascorbic acid). This gene is functional in most vertebrate species because vitamin C is required as a cofactor in several metabolic reactions; notably, the processing of collagen [Vitamin C]. This gene has become inactive in primates so primates cannot synthesize Vitamin C and must obtain it from the food they eat.

A pseudogene can be found at the locus for the L-glucono-γ-lactone oxidase gene[GULOP = GULO Pseudogene]. It is a highly degenerative pseudogene with multiple mutations and deletions [Human GULOP Pseudogene]


This is a unitary pseudogene. Unitary pseudogenes are rare compared to processed pseudogenes and duplicated pseudogenes but they are distinct because they are not derived from an existing, functional, parent gene.

Note: Intelligent design creationists will go to great lengths to discredit junk DNA. They will even attempt to prove that the GULO pseudogene is actually functional. Jonathan Wells devoted an entire chapter in The Myth of Junk DNA to challenging the idea that the GULO pseudogene is actually a pseudogene. A few years ago, Jonathan McLatchie proposed a mechanism for creating a functional enzyme from the bits and pieces of the human GULOP pseudogene but that proved embarrasing and he retracted [How IDiots Would Activate the GULO Pseudogene] Although some scientists are skeptical about the functionality of some pseudogenes, they all accept the evidence showing that most psuedogenes are nonfunctional.


Different kinds of pseudgogenes: Duplicated pseudogenes

Of the three different kinds of pseudogenes, the easiest kind of pseudogene formation to understand is simple gene duplication followed by inactivation of one copy. [see: Processed pseudogenes for another type]

I've assumed, in the example shown below, that the gene duplication event happens by recombination between sister chromosomes when they are aligned during meiosis. That's not the only possibility but it's easy to understand.

These sorts of gene duplication events appear to be quite common judging from the frequency of copy number variations in complex genomes (Redon et al., 2006; MacDonald et al., 2013).


Wednesday, November 18, 2015

Different kinds of pseudogenes: Processed pseudogenes

Let's look at the formation of a "processed" pseudogene. They are called "processed" because they are derived from the mature RNA produced by the functional gene. These mature RNAs have been post-transcriptionally processed so the pseudogene resembles the RNA more closely than it resembles the parent gene.

This is most obvious in the case of processed pseudogenes derived from eukaryotic protein-coding genes so that's the example I'll describe first.

In the example below, I start with a simple, hypothetical, protein-coding gene consisting of two exons and a single intron. The gene is transcribed from a promoter (P) to produce the primary transcript containing the intron. This primary transcript is processed by splicing to remove the intron sequence and join up the exons into a single contiguous open reading frame that can be translated by the protein synthesis machinery (ribosomes plus factors etc.).1 [See RNA Splicing: Introns and Exons.]

Different kinds of pseudogenes - are they really pseudogenes?

I define a gene as "DNA sequence that is transcribed to produce a functional product" [What Is a Gene? ]. Genes can encode proteins or the final product can be a functional RNA other than mRNA.

A pseudogene is a broken gene that cannot produce a functional RNA. They are called "pseudogenes" because they resemble active genes but carry mutations that have rendered them nonfunctional. The human genome contains about 14,000 pseudogenes related to protein-coding genes according to the latest Ensembl Genome Reference Consortium Human Genome build [GRCh38.p3]. There's some controversy over the exact number but it's certainly in that ballpark.1

The GENCODE Pseudogene Resource is the annotated database used by Ensembl and ENCODE (Pei et al. 2012).

There are an unknown number of pseudogenes derived from genes for noncoding functional RNAs. These pseudogenes are more difficult to recognize but some of them are present in huge numbers of copies. The Alu elements in the human genome are derived from 7SL RNA and there are similar elements in the mouse genome that are derived from tRNA genes.

There are three main classes of pseudogenes and one important subclass. The categories apply to pseudogenes derived from protein-coding genes and to those derived from genes that specify functional noncoding RNAs. I'm going to describe each of the categories in separate posts. I'll mostly describe them using a protein-coding gene as the parent.

1. Processed pseudogenes [Processed pseudogenes ]
2. Duplicated pseudogenes [Duplicated pseudogenes ]
3. Unitary pseudogenes [Unitary Pseudogenes]
4. subclass: Polymorphic pseudogenes [Polymorphic Pseudogenes]

Saturday, November 14, 2015

Which animals have barely evolved according to National Geographic?

Liz Langley of National Geographic has posted an article on their website: Which Animals Have Barely Evolved?.

The answers are the platypus and the opossum. The overall impression she conveys to the general public is that these species have not evolved for millions and millions of years.

I don't agree. I think it's important to teach the general public that such statements flatly contradict modern evolutionary theory. If, in fact, we discovered modern species that showed no signs of having evolved for millions of years, this would refute modern evolutionary theory.

The accepted minimal definition of evolution is ... [What Is Evolution?]
Evolution is a process that results in heritable changes in a population spread over many generations.
... or something similar like "change in the frequency of alleles in a population."

The main accepted mechanisms of evolution are natural selection and random genetic drift.

The only way positive natural selection1 can stop is if an organism is so perfectly adapted to its current environment (external and internal) that every possible mutation is either deleterious or neutral. That includes all metabolic processes and every structure in the cell.

Nobody could rationally advocate such a claim.

The only way to stop random genetic drift is if there's no such thing as a new neutral or nearly neutral mutation and all such variation in the population has been eliminated.

No evolutionary biologist could possibly make such a claim with a straight face.

It's easy to test such ridiculous claims by looking at the genomes of the opossum and the platypus. The evidence shows that they have evolved at the same rate as all other species.

The article actually mentions this problem ...
“'Unchanged' is a tricky word,” Nizar Ibrahim, a paleontologist at the University of Chicago and 2014 National Geographic Explorer, says via email.

With only fossils to go by, scientists can examine an ancient animal's skeletal structure, but it's not the whole story. Physiology and DNA change somewhat over time, he says, both through the basic process of evolution as well as random genetic changes.

That said, two mammals that have undergone the fewest evolutionary shifts are the platypus and the opossum, says Samantha Hopkins, associate professor of geology at the University of Oregon.
Liz Langley did not pick up on this comment so she missed a wonderful teaching moment.

It's possible that Liz Langley isn't aware of modern evolutionary theory and that she actually believes that evolution comes to a halt as long as species live in a relatively constant environment. It's possible that she disagrees with the minimal definition of evolution and prefers a definition that only counts significant changes in external phenotype. Or, it's possible that she thinks that National Geographic readers can't handle modern evolutionary theory. If it's the latter, I disagree.


1. You can't stop negative natural selection unless there are no new deleterious mutations. That's also impossible.

Friday, November 13, 2015

Cornelius Hunter predicts that there's going to be function found for the vast majority of the genome according to the intelligent design paradigm

Listen to this Podcast where Casey Luskin interviews Dr. Cornelius Hunter.1 It's only 9 minutes long.

Dr. Cornelius Hunter on ENCODE and "Junk" DNA, Part 2

Here's part of the transcript.
Casey Luskin: ... and, as we all know, or many ID the Future listeners probably know, for years Darwinian theorists and evolutionary scientists have said that our genomes ought to be full of junk if evolution is true

.....

Casey Luskin: So, Dr. Hunter, you think, just for the record, that in the long term there is going to be function found for probably the vast majority of the genome and so, maybe, you might call it a prediction you would make coming out of an intelligent design paradigm. Is that correct?

Cornelius Hunter: Yes, that's correct Casey, I'll definitely go on the record on that. Not to say I have a hundred percent confidence and also I wanna be clear that from a metaphysical perspective, from my personal belief, I don't have a problem wherever it lands. It doesn't matter to me whether it's 10% or 90% or any where in between or 100% ... just from the scientific perspective and just from the history of science and the history of what we've found in biology, it really does look like it's gonna be closer to 100 than zero.

Casey Luskin: Okay, great, I always like it when people put clear and concrete predictions out there and and I think that's very helpful.

I predict that about 90% of our genome will turn out to be junk DNA—DNA with no function. I base my prediction on the scientific perspective and the history of what we've found in biology. That's interesting because Cornelius Hunter and I are apparently reaching opposite conclusions based on the same data.

I also love it when people make predictions. Will the intelligent design paradigm be falsified if I turn out to be right?

Does it sound to you that Cornelius Hunter personally doesn't care if the prediction coming out of the intelligent design paradigm is correct or not?


1. How come in the podcast they never refer to Dan Graur as Dr. Graur? Isn't that strange?

The 2015 Nobel Prize in Chemistry: was the history of the discovery of DNA repair correct?

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

Stephen Jay Gould
Ontogeny and Phylogeny (1977)
Back when the Nobel Prize in Chemistry was announced I was surprised to learn that it was for DNA repair but Phil Hanawalt wasn't a winner. I blogged about it on the first day [Nobel Prize for DNA repair ].

I understand how difficult it is to choose Nobel Laureates in a big field where a great many people make a contribution. That doesn't mean that the others should be ignored but that's exactly what happened with the Nobel Prize announcement [The Nobel Prize in Chemsitry for 2015].
In the early 1970s, scientists believed that DNA was an extremely stable molecule, but Tomas Lindahl demonstrated that DNA decays at a rate that ought to have made the development of life on Earth impossible. This insight led him to discover a molecular machinery, base excision repair, which constantly counteracts the collapse of our DNA.
Maybe it's okay to ignore people like Phil Hanawalt and others who worked out mechanisms of DNA repair in the early 1960s but this description pretends that DNA repair wasn't even discovered until ten years later.

I published links to all the papers from the 1960s in a follow-up post [Nature publishes a misleading history of the discovery of DNA repair ].

By that time I was in touch with David Kroll who was working on an article about the slight to early researchers. He had already spoken to Phil Hanawalt and discovered that he (Hanawalt) wasn't too upset. Phil is a really, really nice guy. It would be shocking if he expressed disappointment or bitterness about being ignored. I'll do that for him!

The article has now been published: This Year’s Nobel Prize In Chemistry Sparks Questions About How Winners Are Selected.

Read it. It's very good.


Wednesday, November 11, 2015

Pwned by lawyers (not)

A few days ago I mentioned a post by Barry Arrington where he said, "You Should Know the Basics of a Theory Before You Attack It. I pointed out the irony in my post.

Barry Arringotn took exception and challenged me in: Larry Moran's Irony Meter.
OK, Larry. I assume you mean to say that I do not understand the basics of Darwinism. I challenge you, therefore, to demonstrate your claim.
This was the kind of challenge that's like shooting fish in a barrel but I thought I'd do it anyway in case it could serve as a teaching moment. Boy, was I wrong! Turns out that ID proponents are unteachable.

I decided to concentrate on Arrington's published statements about junk DNA where he said ...