Alanis Morissette Doesn't Get Irony

 
Guy Kawasaki interviews Jon Winokur [Ten Questions with Jon Winokur: How to Heighten Your Sense of the Absurd]. In response to a question about what he's working on now (Q12) Winokur say he's writing a book called The Big Curmudgeon. Winokur then goes ont to say,

It drives me crazy when people say “ironic” when they mean “coincidental.” The classic example is Morissettian Irony, which I define in the book as “irony based on a misapprehension of irony, i.e., no irony at all.” It’s named for the pop singer Alanis Morissette, whose hit single, “Ironic” mislabels coincidence and inconvenience as irony.

In the song, situations purporting to be ironic are merely sad, random, or annoying (“It's a traffic jam when you're already late/It's a no-smoking sign on your cigarette break”). In other words, “Ironic” is an un-ironic song about irony. Which, of course, is ironic in itself. But wait, there’s more, a “bonus irony” if you will: “Ironic” has been cited as an example of how Americans don’t get irony, despite the fact that Alanis Morissette is Canadian!

I hate it when people don't get irony ... or sarcasm.

[To see the video, go to Alanis Morissette, click on "music" then on "ironic" at the bottom, third from the left.]

[Hat Tip: Jim Lippard]

[Photo Credit: Agência Brasil disponibiliza, gratuitamente, imagens e fotos. Para cumprir a legislação em vigor, solicitamos aos nossos usuários a gentileza de registrar os créditos como no exemplo: nome do fotógrafo—via Wikipedia.]

Basic Concepts: The Central Dogma of Molecular Biology

The demise of the Central Dogma of Molecular Biology is becoming an annual event. Most recently, it was killed by non-coding RNA (ncRNA) (Mattick, 2003; 2004). In previous years the suspects included alternative splicing, reverse transcriptase, introns, junk DNA, epigenetics, RNA viruses, trans-splicing, transposons, prions, epigenetics, and gene rearrangements. (I’m sure I’ve forgotten some.)

What’s going on? The Central Dogma sounds like the backbone of an entire discipline. If it’s really a “dogma” how come it gets refuted on a regular basis? If it’s really so “central” to the field of molecular biology then why hasn’t the field collapsed?

In order to answer these questions we need to understand what the Central Dogma actually means. It was first proposed by Francis Crick in a talk given in 1957 and published in1958 (Crick, 1958). In the original paper he described all possible directions of information flow between DNA, RNA, and protein. Crick concluded that once information was transferred from nucleic acid (DNA or RNA) to protein it could not flow back to nucleic acids. In other words, the final step in the flow of information from nucleic acids to proteins is irreversible.

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.

Crick restated the Central Dogma of Molecular Biology in a famous paper published in 1970 at a time when the premature slaying of the Central Dogma by reverse transcriptase was being announced (Crick, 1970). According to Crick, the correct, concise version of the Central Dogma is ...

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid. (F.H.C. Crick, 1970)

Announcing the (Premature) Death of the Central Dogma
The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from microbes to mammals. However, the latter may not be the case in complex organisms. A number of startling observations about the extent of non-protein coding RNA (ncRNA) transcription in the higher eukaryotes and the range of genetic and epigenetic phenomena that are RNA-directed suggests that the traditional view of genetic regulatory systems in animals and plants may be incorrect.

Mattick, J.S. (2003) Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. BioEssays 25:930-939.

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The central dogma, DNA makes RNA makes protein, has long been a staple of biology textbooks.... Technologies based on textbook biology will continue to generate opportunities in bioinformatics. However, more exciting prospects may come from new discoveries that extend or even violate the central dogma. Consider developmental biology. The central dogma says nothing about the differences between the cells in a human body, as each one has the same DNA. However, recent findings have begun to shed light on how these differences arise and are maintained, and the biochemical rules that govern these differences are only being worked out now. The emerging understanding of developmental inheritance follows a series of fundamental discoveries that have led to a realization that there is more to life than the central dogma.

Henikoff, S. (2002) Beyond the central dogma. Bioinformatics 18:223-225.

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It will take years, perhaps decades, to construct a detailed theory that explains how DNA, RNA and the epigenetic machinery all fit into an interlocking, self- regulating system. But there is no longer any doubt that a new theory is needed to replace the central dogma that has been the foundation of molecular genetics and biotechnology since the 1950s.

The central dogma, as usually stated, is quite simple: DNA makes RNA, RNA makes protein, and proteins do almost all of the work of biology.

Gibbs. W.W. (2003) The unseen genome: gems among the junk. Sci. Am. 289:26-33.

Unfortunately, there’s a second version of the Central Dogma that’s very popular even though it’s historically incorrect. This version is the simplistic DNA → RNA → protein pathway that was published by Jim Watson in the first edition of The Molecular Biology of the Gene (Watson, 1965). Watson’s version differs from Crick’s because Watson describes the two-step (DNA → RNA and RNA → protein) pathway as the Central Dogma. It has long been known that these conflicting versions have caused confusion among students and scientists (Darden and Tabery, 2005; Thieffry, 1998). I argue that as teachers we should teach the correct version, or, at the very least, acknowledge that there are conflicting versions of the Central Dogma of Molecular Biology.

The pathway version of the Central Dogma is the one that continues to get all the attention. It’s the version that is copied by almost all textbooks of biochemistry and molecular biology. For example, the 2004 edition of the Voet & Voet biochemistry textbook says,

In 1958, Crick neatly encapsulated the broad outlines of this process in a flow scheme he called the central dogma of molecular biology: DNA directs its own replication and its transcription to yield RNA, which, in turn, directs its translation to form proteins. (Voet and Voet, 2004)

If the Watson pathway version of the Central Dogma really was the one true version then it would have been discarded or modified long ago. In his original description, Watson drew single arrows from DNA to RNA and from RNA to protein and stated ....

The arrow encircling DNA signifies that it is the template for its self-replication; the arrow between DNA and RNA indicates that all cellular RNA molecules are made on DNA templates. Most importantly, both these latter arrows are unidirectional, that is, RNA sequences are never copied on protein templates; likewise, RNA never acts as a template for DNA.

Fig. 2. Watson’s version of the Central Dogma. This figure is taken from the first edition of The Molecular Biology of the Gene (p. 298).

Watson's statement is clearly untrue, as the discovery of reverse transcriptase demonstrated only a few years after his book was published. Furthermore, there are now dozens of examples of information flow pathways that are more complex than the simple scheme shown in Watson’s 1965 book. (Not to mention the fact that many information flow pathways terminate with functional RNA’s and never produce protein.)

Watson’s version of the Central Dogma is the one scientists most often refer to when they claim that the Central Dogma is dead. The reason it refuses to die is because it is not the correct Central Dogma. The correct version has not been refuted.

Crick was well aware of the difference between his (correct) version and the Watson version. In his original 1958 paper, Crick referred to the standard information flow pathway as the sequence hypothesis. In his 1970 paper he listed several common misunderstandings of the Central Dogma including ....

It is not the same, as is commonly assumed, as the sequence hypothesis, which was clearly distinguished from it in the same article (Crick, 1958). In particular, the sequence hypothesis was a positive statement, saying that the (overall) transfer nucleic acid → protein did exist, whereas the central dogma was a negative statement saying that transfers from protein did not exist.

The Sequence Hypothesis and the Central Dogma in 1957
My own thinking (and that of many of my colleagues) is based on two general principles, which I shall call the Sequence Hypothesis and the Central Dogma. The direct evidence for both of them is negligible, but I have found them to be of great help in getting to grips with these very complex problems. I present them here in the hope that others can make similar use of them. Their speculative nature is emphasized by their names. It is an instructive exercise to attempt to build a useful theory without using them. One generally ends in the wilderness.

The Sequence Hypothesis. This has already been referred to a number of times. In its simplest form it assumes that the specificity of a piece of nucleic acid is expressed solely by the sequence of its bases, and that this sequence is a (simple) code for the amino acid sequence of a particular protein.

This hypothesis appears to be rather widely held. Its virtue is that it unites several remarkable pairs of generalizations: the central biochemical importance of proteins and the dominating role of genes, and in particular of their nucleic acid; the linearity of protein molecules (considered covalently) and the genetic linearity within the functional gene, as shown by the work of Benzer and Pontecorvo; the simplicity of the composition of protein molecules and the simplicity of nucleic acids. Work is actively proceeding in several laboratories, including our own, in an attempt to provide more direct evidence for this hypothesis.

The Central Dogma. This states that once “information” has passed into protein it cannot get out again. In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.

Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163 quoted in Judson, H.F. The Eight Day of Creation, Expanded Edition (1979, 1996) p. 332.

So, how do we explain the current state of the Central Dogma? The Watson version is the one presented in almost every textbook, even though it is not the correct version according to Francis Crick. The Watson version has become the favorite whipping boy of any scientist who lays claim to a revolutionary discovery, even though a tiny bit of research would uncover the real meaning of the Central Dogma of Molecular Biology. The Watson version has been repeatedly refuted or shown to be incomplete, and yet it continues to be promoted as the true Central Dogma. This is very strange.

The Crick version is correct—it has never been seriously challenged—but few textbooks refer to it. One exception is Lewin’s GENES VIII (Lewin, 2004) (and earlier editions). Lewin defines the Central Dogma of Molecular Biology as,

The central dogma states that information in nucleic acid can be perpetuated or transferred but the transfer of information into protein is irreversible. (B. Lewin, 2004)

I recommend that all biochemistry and molecular biology teachers adopt this definition—or something very similar—and teach it in their classrooms.

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]

Darden, L. and Tabery, J. (2005) Molecular Biology

Lewin, B. (2004) GENES VIII Pearson/Prentice Hall

Mattick, J.S. (2003) Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. BioEssays 25:930-939

Mattick, J.S. (2004) The hidden genetic program of complex organisms. Sci. Am. 291:60-67.

Thieffry, D. (1998) Forty years under the central dogma. Trends Biochem. 23:312-316.

Watson, J.D. (1965) The Molecular Biology of the Gene. W.A. Benjamin. Inc. New York

Chapel Hill, North Carolina

I'm going to Chapel Hill next weekend. It's one of my favorite places in the world. My daughter lives there. (Hi Jane, are you ready?)

I'm going to meet some bloggers.

Monday's Molecule #9

 
Name this molecule. You must be specific. We need the exact chemical name and the common name. The common name will be much more familiar to you. We'll discuss how this molecule works after you've been given a chance to identify it.

Comments will be blocked for 24 hours. Comments are now open.

Even at a conference, you've got to eat!

 
Even at a conference, you've got to eat! I'm going to Mama Dip's for Bar-B-Que on Saturday night. Are you going too?

Chicken with Ribs
pork ribs and choice of fried or bar-b-que chicken
Chopped Bar-B-Que Pork with Chicken
choice of fried or bar-b-que chicken
Brunswick Stew & Chopped Bar-B-Que
served with coleslaw and cornbread only
Bar-B-Que Pork Ribs & Chopped Bar-B-Que Pork
for the true connoisseur
Chicken & Dumplings
broiled chicken seasoned and cooked with rolled dumplings
Chittlins
really "down home" served plain or pan fried
Chicken & Gravy
our 1/4 fried chicken smothered in gravy, white or dark meat
Salmon Biscuit
fried salmon patty sandwiched between a sliced buttermilk biscuit
Country Ham Biscuit
country ham sandwiched between a sliced buttermilk biscuit
Sausage Biscuit
pork sausage sandwiched between a sliced buttermilk biscuit
Chicken Tender Biscuit
chicken tenders smothered in gravy sandwiched between a sliced buttermilk biscuit
Sweet Potato Biscuit
Mama Dip's sweet potato biscuits served hot with butter

Safer than LSD and 'Shrooms

 
Would you take this drug if it made you dream you were climbing in the Himalayas with a duck, an ape, and a turtle? Kevin Beck would.

The duck wasn't a very good climber but it was turtles all the way up.

There's Some Kinda Test Going ON

 
The BBC reports that South Africa close in on victory. Here's an excerpt from the article,

Nazir was dropped by Pollock before the break off the luckless Ntini and could have been run out twice before thrashing the seamer over mid-wicket for six and seeing his stumps re-arranged attempting a repeat.

Naved, who survived a strong caught behind appeal off Pollock in the first over after tea, and Kaneria took over to launch a succession of meaty blows.

Three fours came in one over from Ntini and a startled Pollock was thrashed over long-off and mid-wicket for huge maximums.

Harris saw off Kaneria to bring the carnage to an end but the momentum had shifted back towards Pakistan.

Hmmm ... it looks like English but .....

Does anyone want to explain to this ignorant Canadian what's happening?

A Professor's Worst Nighmare

 
Has this ever happened to you? Read what happens when a Professor doesn't look in the mirror after putting on his pants [A classic professorial moment].

Time-shifting "Studio 60 on the Sunset Strip"

 
Freakonomics reports that my favorite TV show, Studio 60 on the Sunset Strip, is the show that people are most likely to record and watch at some other time [“Studio 60″: Tops in Time-Shifting]. I thought this might reflect the sophistication of the Studio 60 audience but then I read the rest of the top ten time-shifted shows .....

Massacre in Canada

 
The results of the latest grant competition in Canada are leaking out and the news is bad. Canadian health science research is being gutted.

The main funds for health science research come from the Canadian Institutes of Health Research (CIHR). This is the agency that funds basic science in biochemistry, molecular biology, immunology, human genetics etc. CIHR grants are the backbone of research in my department (Biochemistry) and many others.

The word from CIHR is that only 15% of the September applicants will be funded. Many of my colleagues have already received notice that they are below the cutoff. Their grants will be terminated.

These colleagues are not incompetent scientists. Many of them publish 3-5 papers a year in high quality journals. In most cases they have had continuous funding since they were first hired 10-20 years ago. Their groups consist of research assistants (lab technicians), several post-docs, and several graduate students. The lab techs and the post-docs will be terminated and the graduate students may not be able to finish their degrees.

This is a disaster. You cannot sustain high quality research if your chances of getting a grant are only 15%. What's happening is that excellent scientists are being kicked out of the system due to lack of funds at CIHR. This has got to change. The Conservative Government of Stephen Harper is ruining careers.

Already there's talk of a moratorium on hiring new faculty members. Why should we bring in new scientists if their chances of success are so small? (The funding rate for new grants is even lower than 15%.)

Stay tuned.

Birth-and-Death Evolution in Mammalian Gene Families

Once we recognize the accidental nature of evolution as described in birth-and-death evolution of gene families [The Evolution of Gene Families] we are better prepared to appreciate the significance of other studies.

In an earlier posting [Mammalian Gene Families: Humans and Chimps Differ by 6%] I described the results of Demuth et al. (2006) who looked at global expansion and contraction of gene families. They published this diagram to show the extent of gene loss and gain in mammalian lineages.

Figure 1. Distribution of gene gain and loss among mammalian lineages.

Creative Commons Attribution License

The Creationists made a big deal about this when the paper first came out but we can now see that the expansion and contraction of gene families is just part of the normal, ongoing, process of birth-and-death evolution.

Can Anyone Answer This Question?

 
Check out the new look of Uncommon Descent, the blog by Dembski, O'Leary, and friends. It almost looks as though someone intelligent designed it.

Isn't it interesting that the best they can come up with is a bacterial flagellum—a structure whose evolution is getting to be fairly well understood?

While you're there, read Every day biology is looking more and more designed and see if you can answer the question posed by the author,

I receive Nature E-Alerts in a number of biological research fields. Almost every time I read the abstracts and even the titles, or spend more time delving into the detail, I hear “Intelligent Design” silently screamed from the pages. Am I deluded ...?

Update: Joshua Rosenau has an answer at [Simple answers to stupid questions (now with bonus answer to bonus question!)].

The Evolution of Gene Families

The genes for olfactory receptors are part of a gene family. A gene family, by definition, means that there's two or more related genes in a genome. In the case of olfactory receptor genes there are hundreds of different genes spread out over many chromosomes. All the copies are closely related (homologous). They clearly descend from a common ancestor following a gene duplication event.

The evolution of gene families has been studied for over 50 years. We now recognize three different modes of evolution. The two simplest modes are shown below.

Imagine a gene duplication event occurring in a common ancestor at the left-hand side of these trees. Two genes, A and B, are now present in the genome of every species that descends from this common ancestor. In divergent evolution, each of the genes evolves independently after the duplication. Thus, we have two separate phylogenies: one for the A genes and one for the B genes. The two phylogenies will be identical. This is the most common mode of evolution for gene families, especially if the A gene and the B gene are separated in the genome (i.e., on different chromosomes). The classic example is evolution of the α- and β-globin genes in vertebrates.

In concerted evolution, the trees looks like the one on the right. If we assume that the gene duplication event occurred in the last common ancestor of fish, chickens, mice, and humans, then the pattern we see looks very strange. Instead of showing two independent phylogenies, the A and B genes in each species are much more closely related to each other than to family members in any other species. The prototypical example is the evolution of ribosomal RNA genes in all species.

This form of evolution is termed concerted evolution because the pair of genes (A and B) evolved in a concerted manner. They talk to each other. When a mutation occurs in one gene it is transferred to the other so that both genes change in the same direction. The only differences between family members within a species are those that have only become fixed in the very recent past.

The most important mechanism of concerted evolution is gene conversion. This is a form of recombination where the sequence of one gene "converts" the other. It explains how the two genes can communicate. Gene conversion can take place between any two homologous genes in the genome but it is much more common between two homologous genes that are adjacent to each other, especially if they are transcribed in the same direction as a result of a tandem duplication. Gene conversion has been well studied. It is known to produce the results shown in the figure.

There's another way to explain the result in the right-hand tree without invoking concerted evolution. It's possible that our initial assumption is wrong. Perhaps the common ancestor had only a single gene and gene duplications occurred independently within each lineage. This would give a result similar to the tree shown. While this is possible, it seems very unlikely that for a single pair of genes the same duplication would occur in every lineage. With larger genes families such multiple duplication events are more probable.

The third mode of gene family evolution is a combination of the patterns seen in divergent evolution and in concerted evolution. If duplications of family members occur frequently then this gives rise to the birth of new genes. Newborn genes will closely resemble one another, as in concerted evolution. The number of family members does not keep expanding because some of the genes become inactivated—they become pseudogenes and they die. The resulting pattern of evolution will look like a mixture of divergent and concerted evolution. The mode is called "birth-and-death."

The figure below is from a review by Nei and Rooney (2005). Masatoshi Nei is one of the discoverers of birth-and-death evolution (Nei and Hughes, 1992).

Note that in birth-and-death evolution some genes survive in a lineage and some genes are lost. The birth and death of genes can be random or it can be under selection. The point is that not all members of the gene family in the ancestor will show up in all species descending from the common ancestor, and that sometimes several members of the gene family will be much more closely related than you would expect from divergent evolution.

Niimura and Nei (2006) studied the evolution of olfactory receptor genes. In order to study the evolution of gene families you have to be sure you have included every copy of the gene in your study. If you're going to test birth-and-death hypotheses, you also have to include all the pseudognes.

Niimura and Nei (2006) were able to do this for the mouse and human olfactory receptor genes because the complete genomes have been published. By examining the sequences of all genes and pseudogenes, they were able to determine that the most recent common ancestor (MCRA) of mice and humans had 754 functional genes (see figure below). Of these ancestral genes, 691 are still functional in the mouse genome but only 326 remain functional in the human genome.

This study can now be extended because there are complete genome sequences of chickens, frogs, and fish. In addition, there is enough sequence information from lampreys to estimate the number of olfactory receptor genes in that species.

The result is shown above in (b). The ancestor of jawed and jawless fish had two olfactory receptor genes: one type 1 gene and one type 2 gene. Each of these genes gave rise to subfamilies in fish so that the MCRA between fish and tetrapods had six type 1 genes and three type 2 genes. Various members of these subfamilies expanded or contracted in number in the lineages leading to modern fish, amphibians, birds, and mammals. This is birth-and-death evolution.

The patterns produced by birth-and-death evolution look much more like random fluctuations than something produced by sustained directional selection. Niimura and Nei (2006) caution against adaptationist explanations of the differing numbers of genes in various species of mammals. For example, it is widely assumed that the reason mice have more functional olfactory receptor genes than humans is because mice have a better sense of smell. But Niimura and Nei (2006) point out that dogs are supposed to have an excellent sense of smell even though they have fewer OR genes than rodents. The number of genes could be due to chance and not selection. (Or, most likely, a combination of accident and selection.)

Nei, M. and Hughes, A.L. (1992) Balanced polymorphism and evolution by the birth-and-death process in the MHC loci. In 11th Histocompatibility Workshop and Conference, ed. K. Tsuji, M. Aizawa, and T. Sasazuki, pp. 27-28. Oxford, UK: Oxford Univ. Press

Nei, M. and Rooney, A. P. (2005) Concerted and Birth-and-Death Evolution in Multigene Families. Ann. Rev. Genet. 39: 121-152.

Niimura, Y. and Nei, M. (2006) Evolutionary dynamics of olfactory and other chemosensory receptor genes in vertebrates. J. Hum. Genet. 51: 505-517.

Evolution and Religion According to John West

 
John West, one of the leading IDiots at the Discovery Institute, continues his defense of religion (his version) with A Further Response to Larry Arnhart, pt. 4: Darwinism, Religion, and Intelligent Design. He says,

In the section of my book on religion, I make clear that “evolution” can be compatible with theism in general and Biblical theism in particular—depending on how one defines the term “evolution.” If all one means by “evolution” is “change over time,” or “microevolution” through natural selection, or even biological “common descent,” then evolution would seem perfectly compatible with most forms of theism. Only if one insists that evolution is an undirected Darwinian process of chance and necessity, with no particular end in view, does there seem to be a serious problem with traditional theism.

Personally, I wouldn't use the term "Darwinism." I would say. "According to science, evolution is an undirected process with no particular end in view." In a rare example of intelligent insight, West has recognized a truth that many evolutionists and appeasers overlook. The scientific version of evolution is not compatible with theism.

Basic Terms and Concepts

 
Coturnix over at Blog Around the Clock has proposed an explanation of Basic Terms and Concepts. This seems to be an idea hatched by the ScienceBlogs group, but I'm going to assume that anyone can play. John Wilkins has started it off with his expanation of CLADE.

The post below is my definition of Evolution and I'll follow up with The Central Dogma of Molecular Biology tomorrow Monday.