Vitamin K

 
Vitamin K (phylloquinone) is a lipid vitamin found in plants as K₁, or phytylmenaquinone, and in bacteria as K₂, or multiprenylmenaquinone. Vitamin K is related to ubiquinone [Monday's Molecule #10]. Ubiquinone serves as an electron carrier in reactions such as membrane-associated electron transport [Ubiquinone and the Proton Pump]. Related cofactors in plants (plastoquinone) and bacteria (menaquinone) can be absorbed in the intestine and converted to vitamin K.


Although we can't synthesize vitamin K ourselves, we usually get enough of it from intestinal bacteria. Vitamin K deficiency is not common for this reason. The most common symptom of vitamin K deficiency is hemorraging due to a defect in blood clotting. The symptoms are frequently seen in newborn babies, especially those born prematurely because they lack intestinal bacteria. This is why premature babies are given vitamin K.

Vitamin K is a cofactor in reactions required for the synthesis of some of the proteins involved in blood coagulation. It is the coenzyme for a mammalian carboxylase that catalyzes the conversion of specific glutamate residues to γ-carboxyglutamate residues. The reduced (hydroquinone) form of vitamin K participates in the carboxylation as a reducing agent.

Silent Mutations and Neutral Theory

 
This is a post about the quality of science writing and what can be done about it. I'm picking on an article in SEED magazine here but it's not because SEED is any worse than the competition. It's partly because SEED makes claims about raising the quality of science writing and science education. For example, this statement from a SEED press release seems to indicate that they aspire to better science writing than the competition [Seed Media Group Adds Scientific and Political Pundits to Editorial Team] and certainly their commitment to science bloggers suggests the same aspiration.

As part of its growth strategy, Seed Media Group will develop original science content aimed at a general audience for distribution across a number of media channels, including magazines, books, newspapers, online, topical blogs, digital, film and television. Seed Media Group's endeavors will present science in the same culturally articulate and accessible style that earned Seed a prestigious UTNE Independent Press Award in 2004 and the support of leading advertisers.

It's reasonable, in my opinion, to expect that SEED will live up to this billing. They've certainly made a major step in that direction by hiring PZ Myers to write a monthly science column. The science in his first two contributions is impeccable. As we will see, it raises the question of whether you need to be a scientist in order to get the science right. I hope that's not true.

I'm not going to criticize PZ's articles. Instead, I want to examine another article published in the March 2007 issue of SEED. (That's the one with the "TRUTH" prominently displayed on the cover!) The article in question is titled The Sound of Silence and it's written by Lindsay Bothwick, an experienced science writer with a M.Sc. from McGill and a Masters degree in journalism from Ryerson University here in Toronto. She's a senior editor at SEED so I'm assuming she can take criticism.

The article talks about silent mutations in protein-coding regions. The focus is on a recent Science paper showing that some silent mutations affect the activity of a protein. The point I will make is that the SEED article is very misleading and misrepresents the state of knowledge in this field.

Before getting into the article, let me give you some background.

The most common kinds of mutations are those where one nucleotide is substituted for another. For example, a G or an A or a T replaces a C. This substitution usually results from an error during DNA replication.

If the mutation (allele) persists in a population, it's called a single nucleotide polymorphism or SNP (pronounced snip). The term polymorphism means that there are at least two different alleles segregating in the population. Often these are the original "wild-type" allele and the new mutant allele.

We now recognize that genomes within a population are very heterogeneous. Polymorphism is common. This level of variation was discovered in studies during the 1960's and it's much higher than most scientists thought prior to 1960.

There are three explanations that can, in theory, account for this high level of polymorphism

First, if we think about SNP's, they can represent a transient phase of fixation by natural selection. In this case, one of the alleles is rapidly replacing the other and we just happen to catch it in the act. Back in the days when natural selection was the only game in town it was thought that this transient stage would be rare so populations were not expected to show much variation.

Polymorphism can also be explained by balancing selection. This is when the population has to maintain several different alleles because there is selection for heterogeneity. The classic example is the mutation for sickle cell anemia. When a person is homozygous for the mutant allele they exhibit the symptoms of anemia but when heterozygous they are resistant to malaria. Balancing selection is not common and it can't explain the variation that was discovered in the 1960's.

The third explanation was that the variation is mostly neutral. The idea here is that the majority of mutations are not being acted upon by natural selection. They are not being removed by purifying selection; they are not being maintained by balancing selection; and they are not rising to fixation under positive selection. It was the discovery of significant polymorphism in populations that gave rise to Neutral Theory in the first place ((Kimura, 1968, King and Jukes, 1969).

Neutral mutations will eventually become fixed or be eliminated from the population and the change in frequency is due entirely to random genetic drift. Drift is a much slower process than natural selection so there will always be large numbers of neutral alleles in the process of becoming fixed or extinct.

Neutral Theory and random genetic drift explains variation and it also explains molecular evolution and the (approximate) molecular clock. There are no other explanations that make sense and nobody has offered a competing explanation since Motoo Kimura (1968) or Jack King and Thomas Jukes (1969) published their papers almost fifty years ago. (Aside from occasional nitpicks, of course. There are always scientists who like to show that some mutations that were thought to be neutral are actually beneficial or deleterious. None of them have mounted a serious claim that most variation or most of molecular evolution can be explained by natural selection.)

The history of variation and the competing explanations were well covered by Lewontin in his 1974 book The Genetic Basis of Evolutionary Change. (Lewontin published the classic 1960's papers that revealed extensive within population variation.)

Long-held assumptions about "silent" genetic mutations have been torn down, challenging a fundamental evolutionary theory.

Lindsay Borthwick
SEED
March 2007This brings me to the article in the March issue of SEED [The Sound of Silence]. It begins with a conclusion that's all too common in popular science writing these days,

Scattered throughout the human genome are thousands of mutations that biologists have treated mostly as footnotes. They're hardly few in number—in coding regions of the genome, there are as many as 15,000—but biologists regard them as mutations that simply don't change the way a cell functions. Both in name and effect, they have been accepted as "silent." Now, however, new discoveries are showing that silent mutations appear to play an important role in dozens of human genetic diseases, a fact that is forcing biologists to discard a long-held evolutionary theory and to reexamine the very rules governing the transfer of information from DNA to proteins.

What's going on here? Has there been some extraordinary new discovery that's about to overthrow evolutionary theory and the "rules" of information flow? I will attempt to show that this rhetoric is completely unjustified. It presents a misleading picture of the state of modern science.

The author is talking about silent mutations. These are mutations in the coding region of a gene that alter a codon without changing the amino acid. The genetic code is redundant because there are 64 possible codons and only 20 amino acids. This means that several amino acids have multiple codons. For example, there are six codons for leucine (Leu): TTA, TTG, CTT, CTC, CTA, and CTG. If an original TTA codon is mutated to CTA then it still specifies leucine and this is a silent mutation.

The concept of codon bias has been known for almost forty years and it's an important part of all university courses in molecular biology. Some codons are more efficient than others during translation because the levels of various tRNAs in a cell are not identical. A rare codon will be translated less efficiently because the tRNA that binds to it will not be recognized as frequently as the codon for more abundant tRNAs. There are published codon usage tables for most species showing the preferred codons in that species. Highly expressed genes will preferentially use the codons recognized by the abundant tRNA species. All students know what these tables mean. It means that not all silent mutations are neutral. (It's on the exam!)

This is only one possible reason for silent mutations not being neutral. The various possibilites were discussed by Jukes back in 1980 when he revisited the evidence for neutral changes (Jukes, 1980)) . He gave some specific examples and then addressed the theoretical problem,

The question arises, are these silent changes actually neutral, or have they taken place for adaptive reasons, such as the requirement for a specific secondary structure in mRNA, or a preferential use for certain transfer RNAs in regulating the rate of synthesis of a protein?

For some results the answer is that the silent changes really are neutral, although in a few cases there is evidence of adaptation. The point is that these issues have been recognized and dealt with for decades.

The existence of a few exceptions to a rule does not invalidate the generality. That's an important point. It's one that all science journalists need to grasp. There are no absolute, inviolate, rules in biology. The generalities are all about relative frequencies. Are most silent mutations neutral or are most subject to natural selection?

As Jukes put it 27 years ago,

The neutral approach to molecular evolution is a proposal to prove a negative, which is something like trying to show that a given substance is not a carcinogen. The counterrresponse to the publications by Kimura (1968) and King & Jukes (1969) has been quite strong. Any exceptions to neutrality are usually taken as disproof of it, and many authors have cited such exceptions for this purpose. We have, indeed, developed evidence for such exceptions ourselves, because a theory should be challenged by those who have postulated it.

For example, the finding that synonymous codons for each amino acid are not use in equal amounts in β-hemoglobin mRNA has been cited as disproof of the neutral model, as if such a departure from randomness in a single gene were pertinent.

As the old expression goes, "those who are ignorant of history are doomed to repeat it." It helps a lot to be aware of the history of biology and the contributions of those who developed our current understanding. Modern science writers often fail to understand that there's not much that's new in biology these days. In this case, it's just not true that biologists were too stupid to recognize that some silent mutations weren't neutral. There was no "orthodoxy" that all silent mutations were neutral and, therefore, no orthodoxy has been overturned.

Silent mutations have no impact on the amino acid sequence of proteins and, therefore, were not expected to change their function.

Lindsay Borthwick
SEED
March 2007The SEED article goes on to describe the results of experiments done by Kimchi-Safaty et al. (2007). They presented evidence that a cluster of three silent mutations in the MDR1 gene led to a slow down in translation and subsequent misfolding of the protein. Lindasy Bortwick then writes, "Through a series of elegant experiments, the team put to rest the idea that silent mutations were neutral." Of course, they did no such thing. They merely added one more data point to something that we already knew; namely, not all silent mutations are neutral.

Borthwick closes with,

Most fundamentally, the involvement of silent mutations in disease undermines the neutral theory of molecular evolution. This theory, posited by Motoo Kimura in the late 1960s and a powerful influence ever since, asserted that the vast majority of mutations were neutral, having no effect on the fitness of an organism, and spread through a population by chance. The fact that silent mutations are not harmless anomalies of nature means that they are not neutral. In contrast, some, if not all, silent sites must be subject to the forces of Darwinian natural selection.

The theme of the article is that neutral theory is in big trouble. This point is emphasized in the highlighted quotations that are prominently displayed on page 35 (see the two boxes above). That's totally wrong and it distorts the modern consensus among knowledgeable scientists. Neutral Theory is alive and well, thank-you very much. It can easily accommodate one more example of a non-neutral mutation.

I believe that science writers have an obligation to get the concepts right and I believe they shouldn't misrepresent the science they're supposed to be presenting in a "culturally articulate and accessible style" to a general audience. A layperson reading this article would go away with the impression that a decades old concept has just been overthrown by a single paper published in Science. That's irresponsible journalism.

Jukes, T.H. (1980) Neutral Changes Revisited. In The Evolution of Protein Structure and Function, pp. 203-219.
.
Lewontin, R.C. (1974) The Paradox of Variation. in Evolution Mark Ridley ed., Oxfrod University Press, Oxford UK.

Kimchi-Sarfaty, C., Oh, J.M., Kim, I.W., Sauna, Z.E., Calcagno, A.M., Ambudkar, S.V., and Gottesman, M.M. (2007) A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 315, 525-528.

Kimura, M. (1968) Evolutionary rate at the molecular level. Nature 217, 624-626.

King,J.L. and Jukes,T.H. (1969) Non-Darwinian evolution. Science 164, 788-798.

The Taxonomy Song

 
Pop on over to Evolving Thoughts where John Wilkins has posted a YouTube video of kids singing The Taxonomy Song. Do you recognize the accent? I think they're Australian, no?

Problem is, they get the highest levels wrong (the rest is okay). How many people can correctly name the FIVE KINGDOMS of life? How many people can come up with a better classification scheme?

While you're over on John's blog, read Microbial Species - postlude. It's a discussion about how to identify bacteria species. Remember that the biological species concept doesn't work very well with bacteria because they don't have sex in the same that eukaryotes do. John has some important insights into this problem but it hurts my brain when I try and understand them.

Homer Jay Simpson Evolves

 
Everyone's going to be posting this but here it is anyway, ... just in case you don't see it elsewhere. As far as cartoon versions of evolution go, it's not bad. Just remember that individuals don't evolve, populations evolve. And don't forget that there's no direction to evolution and humans are not the only living mammal that evolved.

Internet Connection Speeds

 
Here are the results of a test for internet connection speed from InternetFrog.com. This is the speed I get at the university.

Now, here's some questions for all you technical experts out there. The download speed varies from a low of 2 Mbps to a high of close to 9Mbps. Why? Does anyone have faster connections on a regular basis?

The upload speed varies from a low of about 150 Kbps to a high of 1.7 Mbps. Why? And why is the upload speed so much slower than the download speed? Does that depend on the speed of my processor?



[Hat Tip: Kevin Black]

Happy 66th Birthday Richard Dawkins

 
Today is Richard Dawkins' birthday [RichardDawkins.net]. Go [here] to enter your own birthday message.

I may disagree with Dawkins on some parts of evolutionary theory but I think he's done a wonderful job of focusing attention on evolution as a scientific fact. I'm also a strong supporter of his attacks on superstition and support for rationality (e.g., The God Delusion).

Dawkins is just one of many intelligent men and women whose brains did not shut down when they turned 50 or 60. We need to point this out because there are, unfortunately, too many people who think that you can only make a contribution to science when you're under 40.

Monday's Molecule #19

 
Name this molecule. You must be specific but we don't need the full correct scientific name. (If you know it then please post it.)

As usual, there's a connection between Monday's molecule and this Wednesday's Nobel Laureate. This one's easy once you know the molecule and make the connection. There'll be a few extra bonus points for guessing Wednesday's Nobel Laureate(s).

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

RNA Polymerase Genes in the Human Genome

 
The structure of yeast RNA polymerase II was solved by Roger Kornberg [Nobel Laureate: Roger Kornberg]. There are many different polypeptide subunits labelled Rpb1 to Rpb12 in the nomenclature used by yeast workers. The mammalian enzyme is very similar. Most of the same subunits are present but they have different names.

The core of RNA polymerase is composed of two very large subunits called Rpb1 and Rpb2 in yeast. In mammals they are called subunits A (220 KDa) and B (140 KDa). These subunits are homologous to the β and β′ subunits in bacterial RNA polymerases. The genes for these polypeptides in humans are called POLR2A and POLR2B. They are located on chromosomes 17p13.1 and 4q12 respectively.

The Online Mendelian Inheritance in Man database has entries for both genes but there are no genetic diseases associated with mutations in either gene [OMIM POLR2A and OMIM POLR2B]. This should not be a surprise since it is rare for genetic diseases to be associated with important essential genes.

Recall that mammals have four different RNA polymerases [Eukaryotic RNA Polymerases]. Both RNA polymerase I and RNA polymerase III have homologous large A and B subunits. The genes for these polypeptides are called POLR1A (194 KDa, chromosome 2p11.2), POLR1B (128 KDa, chromosome 2q13), POLR3A (155 KDa, chromosome 10q22-q23), and POLR3B (~120 KDa, chromosome 12q23.3). As is the case with the large subunits of RNA polymerase II, none of these genes are associated with metabolic diseases because they are essential, important housekeeping genes.

These genes make up a typical eukaryotic gene family. It's important to remember that a gene family refers to homologous genes within the same genome and not to a group of homologous genes from different species. Gene families arise from gene duplication events.

The "A" genes evolved from a common ancestral RNA polymerase β gene several billion years ago and the "B" genes evolved from an ancestral β′ gene. The β and β′ genes, in turn, evolved from a common ancestor near the time life began about 3.5 billion years ago.

The "A" and "B" genes have evolved independently by divergence. In such cases the family members are often on different chromosomes and the intron-exon organization of each member is very different in spite of the fact that the genes are still closely related in amino acid sequence.

In addition to the "A" and "B" genes for each RNA polymerase, there are genes for three different subunits of RNA polymerase I (POL1C, POL1D, POL1E), 12 different subunits of RNA polymerase II (SURB7 and POL2C - POL2L), and 9 different subunits of RNA polymerase III. There are also dozens of genes for the general transcription factors required for initiation, elongation, and termination. Altogether, there are at least 80 different genes required for transcription and that's not counting any gene-specific regulatory genes.

The fourth RNA polymerase in humans is the mitochondrial version. Its gene is POLRMT located on chromosome 19p13.3. The large subunit of the mitochondrial RNA polymerase is only distantly related to the others. There are no metabolic defects associated with mutations in POLRMT [OMIM POLRMT].

Happy Birthday Elton John!

 
Elton John is 6o years old today.

The Salem Conjecture

 
The Salem Conjecture was popularized by Bruce Salem on the newsgroup talk.origins. It dates to before my time on that newsgroup (1990) and I haven't been able to find archives to research the exact origin. The conjecture was explained by Bruce on numerous occasions, here's a statement from Sept, 5, 1996.

My position is not that most creationists are engineers or even that engineering predisposes one to Creationism. In fact, most engineers are not Creationists and more well-educated people are less predisposed to Creationism, the points the statistics in the study bear out. My position was that of those Creationists who presented themselves with professional credentials, or with training that they wished to represent as giving them competence to be critics of Evolution while offering Creationism as the alternative, a significant number turned out to be engineers.

This is the so-called "soft" version of the conjecture. The "hard" version is that there is something about being an engineer that leads one to become a creationist. That's not what Bruce said,

For a long the so-called "soft" hypothesis is the one I have been putting forth, not the one earlier attributed to me. I have also further qualified it by saying numerous times that religious belief was the most significant factor. The reason I prefer to call my idea a "conjecture" is that I have had only anecdotal data to support it.

The Salem Hypothesis has its own entry on Wikipedia [Salem Hypothesis]. Both versions of the Salem Conjecture are listed there. The talk.origins Jargon File is incorrect because it only lists the hard version and attributes it to Bruce Salem.

We all know that scientists overwhelmingly reject creationism so it doesn't come as a surprise that there are so few scientists in the creationists movement. Ironically, the creationists long for scientific validity while, at the same time, they attack all the basic principles of science. The few so-called scientists who subscribe to superstition get very prominent play among the creationists.

Engineers are not scientists and they did not have much scientific training in school. They are technologists (i.e., engineers) and that's not the same thing. I don't think engineers spend much time studying evolutionary theory in university. (It's probably too difficult for them.)

Among the general public the distinction between scientists and technologists is lost so whenever an engineer comes out in favor of superstition (s)he is counted as a scientist. This is what the Salem Conjecture says. Whenever you see a common run-of-the-mill creationist who claims to have scientific knowledge, chances are they're an engineer and not a scientist.

Here's how Bruce explained it on talk.origins on May 10, 1996 in response to an engineer who was objecting to the conjecture.

By your own admission you are running the risk of becoming yet another data point for something called the "Salem Hypothesis" or "Salem Conjecture" in which I noticed some time ago the number of people publically supporting Creationism whether in Creationist publications or this group claiming to be "scientists" were mostly engineers. Most of them had little knowledge of the scientific disciplines that relate to the scientific acceptance of evolution and an old earth. Many people have noticed subsequently that while engineers as a group seem more inclined as a majority to believe Darwin, those with a background in certain religions and those concerned with intelligent design seemed predisposed to accept
Creationism or the arguments that support it.

This morning Larry Faraman, the author of the blog I'm From Missouri, posted this message [The Salem Hypothesis].

I have been aware for a long time that engineers have an especially strong tendency to be skeptical of Darwinism, but I just now learned that this tendency has a name: the "Salem hypothesis." I am especially interested in this tendency because I am an engineer myself ....

I feel that the reason why we engineers tend to be skeptical of Darwinism is that we are a logical, practical, no bullshit, cut the malarkey, "I'm from Missouri," "show me" kind of people.

The irony is palpable. Mr. Faraman, an engineer, is skeptical of evolutionary biology and, by implication, most of the rest of science. On the other hand, he's not the least bit skeptical of creationism. Another solid data point for the Salem Conjecture. In this case, it's the "hard" version that Mr. Faraman is supporting. He claims that training in technology predisposes one to believe in superstitious nonsense. Maybe he's right. I look forward to hearing from other engineers on this point.

BTW, Missouri must be a very strange state. These days when someone begins a conversation with "I'm from Missouri" it's usually following by something irrational.

Dennis Kucinich on Universal Health Care

 
This is why I would vote for Dennis Kucinich ... if only I could vote. Why don't you vote for him?



[Hat Tip: Corpus Callosum]

Gene Genie #3

 
Hsien Hsien Lei has just posted Gene Genie #3 at Genetics and Health. There are >26,000 genes in the human genome and we hope to cover them in a finite amount of time. At this rate we'll be done sometime in the Spring of 2207! Let's pick up the pace, fellow bloggers.

The next Gene Genie (#4) will be hosted right here on Sandwalk. Send me your articles by email or submit them at blogcarnival [gene genie]. You ain't never had a friend like Gene Genie!

Summary of Genes on Human Chromosomes

 
I've prepared a table of the number and types of gene on each human chromosome based on the data at the Ensembl site managed by the Wellcome Trust Sanger Institute in Cambridge UK.

The total number of genes comes to 26,290.

The different categories of gene are:

Known: The "known" protein-encoding genes are those for which there is solid full-length cDNA evidence that they are actually expressed.

Novel: The "novel" class is reserved for genes that are predicted but lack confirming evidence.

miRNA: Micro RNAs are short single-stranded RNAs that are thought to play a role in regulating gene expression.

snRNA: Small nuclear RNAs are required for a number of cellular processes such as RNA processing. Those required for splicing associate with proteins in the nucleus to form small nuclear ribonuleoprotein particles or "snurps."

rRNA: Ribosomal RNA forms the core of the ribosome.

snoRNA: Small nucleolar RNAs are required for proper processing of ribosomal RNA. The are located in the nucleolar region of the nucleus because that's where ribosomal RNA is made.

other RNA: The "other" category includes transfer RNA (tRNA) and some specialized RNAs such as 7SL RNA and P1 RNA.

Chr.	Size (kb)	Protein known	Protein novel	Pseudo- genes	miRNA	rRNA	snRNA	snoRNA	other RNA	Total     Genes
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y	247,249,719 242,951,149 199,501,827 191,273,063 180,857,866 170,899,992 158,821,424 146,274,826 140,273,252 135,374,737 134,452,384 132,349,534 114,142,980 106,368,585 100,338,915 88,827,254 78,774,742 76,117,153 63,811,651 62,435,964 46,944,323 49,691,432 154,913,754 57,772,954	2,146 1,375 1,111 828 922 1,103 984 736 921 819 1,390 1,088 358 661 657 915 1,232 293 1,428 612 271 509 878 86	54 84 47 59 63 29 68 32 38 35 52 51 10 28 65 49 60 20 49 15 23 26 37 27	159 40 45 32 23 81 48 19 66 52 61 38 41 25 34 25 56 8 45 29 9 39 80 2	43 23 24 21 19 17 31 17 26 16 19 21 14 51 15 14 32 5 71 16 7 15 58 6	42 24 21 13 22 16 14 14 11 17 19 15 9 14 6 13 10 42 6 8 10 2 19 6	178 116 89 81 74 82 64 61 43 64 51 77 29 42 43 39 47 12 14 32 5 18 64 14	60 37 30 16 18 25 27 21 15 8 40 21 12 56 95 14 29 12 12 16 5 11 25 3	93 74 66 58 67 56 62 39 47 42 47 65 34 38 35 31 52 21 18 34 6 20 48 2	2,616 1,733 1,388 1,076 1,185 1,328 1,250 920 1,101 1,001 1,618 1,338 466 890 916 1,075 1,462 401 1,598 733 325 601 1,129 140

Daisy, the Canada Goose

 
From KARE 11 News in Minneapolis, St. Paul, Minnesota (USA) [Daisy the Goose]. Why would evolution favor behaviors where a beagle, a Canada goose, and a human could get along in a boat? The video on the TV station's website is much, much better than the YouTube video. It's worth watching.

PZ's Hooked a Live One!

 
Hop on over to Pharyngula where PZ Myers is pointing out the deficiencies of an IDiot school teacher in Colorado [What's the matter with Colorado?].

This guy, Ken Poppe, has actually written a book exposing his ignorance. Look at the cover—that's supposed to be DNA but the structure is so wrong it makes you wonder if Poppe knows anything about science at all.

But here's the fun part. Ken Poppe has popped into Pharyngula to comment on PZ's post. Poppe's first comment is "I'm not afraid of your witchhunt. Bring it on, secularists. Bring it on." It goes downhill from there.