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Tuesday, December 22, 2015

Waiting for multiple mutations: Michael Lynch v. Michael Behe

Casey Luskin is trying to help out a university student by describing some important ID contributions to science [No ID Research? Let's Help Out This Iowa State Student].

One of those contributions is a paper by Michael Behe and David Snoke published eleven years ago in Protein Science (Behe and Snoke, 2004). I described the result in a previous post: Waiting for multiple mutations: Intelligent Design Creationism v. population genetics.

If Behe & Snoke are correct then modern evolutionary theory cannot explain the formation of new functions that require multiple mutations.

Cassey Luskin is aware of the fact that this result has not been widely accepted. He mentions one specific criticism:
In 2008, Behe and Snoke's would-be critics tried to refute them in the journal Genetics, but found that to obtain only two specific mutations via Darwinian evolution "for humans with a much smaller effective population size, this type of change would take > 100 million years." The critics admitted this was "very unlikely to occur on a reasonable timescale."
He's referring to a paper by Durrett and Schmidt (2008). Those authors examined the situation where one transcription factor binding site was disrupted by mutation and another one nearby is created by mutation. The event requires two prespecified coordinated mutations.

Waiting for multiple mutations: Intelligent Design Creationism v. population genetics

Casey Luskin is worried about university students. Apparently, they aren't getting enough correct information about intelligent design. Luskin uses the example of a student named Michael Heckle at Iowa State University. Mr. Heckel said; "So far, there has been no research done by intelligent design advocates that has led to any sort of scientific discovery."

This happens to be a true statement but Casey Luskin takes exception in a blog post that appeared the other day on Evolution News & Views (sic) [No ID Research? Let's Help Out This Iowa State Student].

Saturday, December 19, 2015

Here's why Alain Beaudet, President of the Canadian Institutes of Health Research, should resign

The Canadian Institutes of Health Research (CIHR) is the main source of research funding for Canadian health researchers, including those doing basic research like most of the researchers in my biochemistry department.

A few years ago, CIHR decided to revamp the process of applying for and obtaining research grants. They did this without taking into consideration the wishes of most applicants. (They did "consult," but consulting isn't the same as listening.)

The result has been a disaster. Most researchers are confused and discouraged by the new process and there's great fear that the results of the next competitions will be harmful to basic research and harmful to new investigators.

But even before the new rules came into play the funding of basic, curiosity-motivated, science was taking a major hit. Many mid-career basic researchers at the University of Toronto have lost their grants or are struggling to make do with a lot less money. This is partly due to a lack of money in the system but it's been exacerbated by a deliberate shift in priorities under the previous Conservative government of former Prime Minister Stephen Harper.

These are some of the reasons why Canadian researchers have been calling for Alain Beuadet to resign [Support basic research with new leaders at the Canadian Institutes of Health Research (CIHR)].

Thursday, December 17, 2015

Joe Hanson tells us about evolution

Joe Hanson Ph.D. (Biology) of It's Okay To Be Smart is posting a series of videos on evolution. They're called The 12 Days of Evolution.

The first one is "What Is Evolution Anyway?" You won't surprised to learn that Joe Hanson conflates "evolution" with "natural selection" and fails to mention the most important features of evolution [see What Is Evolution]. You WILL be surprised to learn that Jerry Coyne has the same objections I do! [Twelve Days of Evolution: #1: What’s evolution?]

We need to do a much better job of educating the general public about the meaning of evolution but first we need to educate the teachers. It's okay to be smart but it's not okay to just pretend to be smart.

Strolling around slopes and valleys in the adaptive landscape

Another article about evolution and the attainment of perfection has appeared. This one was published by Nathaniel Scharping on the Discover website [Could Evolution Ever Yield a ‘Perfect’ Organism?].

The article focuses on a recent paper from Richard Lenski's group at Michigan State University (Lenski et al., 2015). Lenski's group asked a different question. They wanted to know whether there was a limit to the increase in fitness in their evolving E. coli populations in the Long-Term Evolution Experiment (LTEE). It's a different question than whether evolution can select for a "perfect" organism because Lenski and his collaborators understand modern evolutionary theory. They know that mutations causing small fitness increases are beyond the reach of natural selection in their evolving populations and they know that deleterious mutations can be fixed by random genetic drift.

They know that real evolving populations can never reach the summit of an adaptive peak or, if they do, they can never stay there.

Intelligent design explanations and speculations have all been refuted, discredited, or shown to be unnecessary

Intelligent Design Creationism is a movement based on bad science. Every single one of their positive, science-like, claims about ID have been refuted, or discredited, or shown to be completely unnecessary in the face of robust evolutionary explanations. Some of them have the distinction of being unnecessary AND refuted AND discredited (e.g irreducible complexity).

In addition to a small number of claims in support of ID, the proponents of Intelligent Design Creationism also advance dozens and dozens of arguments against evolution. In fact, this is by far the main activity of most adherents to the movement. Some of their arguments focus on legitimate scientific controversies. They are legitimate criticisms of some aspects of evolution but, even then, ID proponents often misrepresent and/or misunderstand the science behind the controversy (e.g. junk DNA).

However, the vast majority of their attacks on evolution are just as bad as their attempts to build a positive case for intelligent design. A disturbingly large number of such attacks exhibit a profound ignorance of science and how it works. In particular—surprisingly—they are ignorant of evolution. The movement is full of kooks. It will never become a credible source of information unless it purges itself by getting rid of the kooks.

Speaking of kooks,1 Casey Luskin has been publishing a series of articles on the Kitzmiller v. Dover trial that was decided ten years ago. Some of the articles make valid points but the latest one is a joke: Ten Myths About Dover: #4, "The Dover Ruling Refuted Intelligent Design".

You should read the article. It's a remarkable example of apologetics and why lawyers shouldn't try and explain science. While it's true that Judge Jones said lots of things we could quibble about, the big-picture take-home lesson from the trial is correct. No ID explanation stood up to the scrutiny of science. They were all shown to be either irrelevant or wrong.

That's why none of them should be presented in science class except as examples of bad science and faulty scientific reasoning.2

1. Luskin won't even admit that Young Earth Creationism is absurd.

2. In my opinion, they SHOULD be discussed in class since it's important to teach critical thinking and that requires that you directly confront common misconceptions.

Tuesday, December 15, 2015

How many different proteins are made in a typical human cell?

There are about 20,000 protein-coding genes in the human genome. Protein products for about 18,000 of these genes have been detected in at least one human tissue (Kim et al, 2015; Wilhelm et al., 2015) [see How many proteins do humans make?].

About 10,000 of these proteins are present in all cells (Wilhelm et al., 2015) and somewhere between 1500 and 2000 are derived from genes that are essential in the average human cell (Blomen et al., 2015; Wang et al, 2015; Hart et al., 2015) [see How many human protein-coding genes are essential for cell survival?].

Let's assume there are about 10,000 protein-coding genes that are expressed in a typical human cell. Does this mean that there are only 10,000 different proteins in those cells? The answer is "no" but the differences are often subtle. The activities of some proteins, for example, are regulated by covalent modification so a typical cell will contain different versions of the protein: some are modified and some are not (e.g. phosphorylated and non-phosphorylated). These would be genuine versions of different proteins although you probably wouldn't want to make a fuss about it.

In some cases, there are various intermediates produced during protein synthesis. For example, some proteins destined for the mitochondria have an N-terminal tag that's cleaved when the proteins reach their destination. There are two different versions of the protein but, again, this isn't really a big deal. We should really only count the steady-state, terminal, stage of processing and modification.

Similarly, there are proteins that are glycosylated in various ways and cells will always contain intermediates including non-glycosylated versions that have just entered the ER. These don't count as different versions of the protein.

Some genes are alternatively spliced to give proteins that have different internal amino acid sequences. These are genuinely different proteins produced from the same gene.

If you add up all the genuinely different versions of proteins produced from 10,000 protein-coding genes, how many proteins are present in a typical human cell?

Here's a standard answer given in a recent news article in Nature (Savage, 2015)
The human body contains roughly 20,000 genes that are capable of producing proteins. Each gene can produce multiple forms of a protein, and these in turn can be decorated with several post-translational modifications: they can have phosphate or methyl groups attached, or be joined to lipids or carbohydrates, all of which affect their function. “The number of potential molecules you can make from one gene is huge,” says Bernhard Küster, who studies proteomics at the Technical University of Munich in Germany. “It's very hard to estimate, but I wouldn't be surprised to have in one cell type 100,000 or more different proteins.”
I suspect that Küster is one of those scientists who think that almost all human protein-coding genes are alternatively spliced to yield several different proteins in each cell. He has to imagine that there are, on average, ten different versions of a protein produced from each gene that's expressed in a typical cell.

That means ten different versions of each of the subunits of pyruvate dehydrogenase and RNA polymerase. It means ten different versions of triose phosphate isomerase and each of the ribosomal proteins. There should be ten different versions of actin and ten different versions of cytochrome c.

This seems very unlikely to me.


(There may be a few genes that have thousands of different variants, although I'm skeptical. In that case there may be 100,000 different proteins in a human cell but surely this is misleading even if it's accurate?)

Blomen, V.A., Májek, P., Jae, L.T., Bigenzahn, J.W., Nieuwenhuis, J., Staring, J., Sacco, R., van Diemen, F.R., Olk, N., and Stukalov, A. (2015) Gene essentiality and synthetic lethality in haploid human cells. Science, 350:1092-1096. [doi: 10.1126/science.aac7557 ]

Hart, T., Chandrashekhar, M., Aregger, M., Steinhart, Z., Brown, K.R., MacLeod, G., Mis, M., Zimmermann, M., Fradet-Turcotte, A., and Sun, S. (2015) High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 163:1515-1526. [doi: 10.1016/j.cell.2015.11.015]

Kim, M.-S., Pinto, S.M., Getnet, D., Nirujogi, R.S., Manda, S.S., Chaerkady, R., Madugundu, A.K., Kelkar, D.S., Isserlin, R., Jain, S., Thomas, J.K., Muthusamy, B., Leal-Rojas, P., Kumar, P., Sahasrabuddhe, N.A., Balakrishnan, L., Advani, J., George, B., Renuse, S., Selvan, L.D.N., Patil, A.H., Nanjappa, V., Radhakrishnan, A., Prasad, S., Subbannayya, T., Raju, R., Kumar, M., Sreenivasamurthy, S.K., Marimuthu, A., Sathe, G.J., Chavan, S., Datta, K.K., Subbannayya, Y., Sahu, A., Yelamanchi, S.D., Jayaram, S., Rajagopalan, P., Sharma, J., Murthy, K.R., Syed, N., Goel, R., Khan, A.A., Ahmad, S., Dey, G., Mudgal, K., Chatterjee, A., Huang, T.-C., Zhong, J., Wu, X., Shaw, P.G., Freed, D., Zahari, M.S., Mukherjee, K.K., Shankar, S., Mahadevan, A., Lam, H., Mitchell, C.J., Shankar, S.K., Satishchandra, P., Schroeder, J.T., Sirdeshmukh, R., Maitra, A., Leach, S.D., Drake, C.G., Halushka, M.K., Prasad, T.S.K., Hruban, R.H., Kerr, C.L., Bader, G.D., Iacobuzio-Donahue, C.A., Gowda, H., and Pandey, A. (2014) A draft map of the human proteome. Nature, 509:575-581. [doi: 10.1038/nature13302]

Savage, N. (2015) High-protein research. Nature 527:S6-S7. [doi: 10.1038/527S6a]

Wang, T., Birsoy, K., Hughes, N.W., Krupczak, K.M., Post, Y., Wei, J.J., Lander, E. S., and Sabatini, D.M. (2015) Identification and characterization of essential genes in the human genome. Science, 350:1096-1101. [doi: 10.1126/science.aac7041]

Wilhelm, M., Schlegl, J., Hahne, H., Gholami, A.M., Lieberenz, M., Savitski, M.M., Ziegler, E., Butzmann, L., Gessulat, S., Marx, H., Mathieson, T., Lemeer, S., Schnatbaum, K., Reimer, U., Wenschuh, H., Mollenhauer, M., Slotta-Huspenina, J., Boese, J.-H., Bantscheff, M., Gerstmair, A., Faerber, F., and Kuster, B. (2014) Mass-spectrometry-based draft of the human proteome. Nature, 509:582-587. [doi: 10.1038/nature13319]

Monday, December 14, 2015

Did Michael Behe say that astrology was scientific in Kitzmiller v. Dover?

Yes he did. But it doesn't mean what you think it means according to Casey Luskin [Ten Myths About Dover: #8, "Michael Behe Admitted that ID Is No More Scientific than Astrology"

I agree with Casey Luskin. During the trial, Behe was asked to define scientific theory and of course he adopted the broad view of science. He said, "Under my definition, a scientific theory is a proposed explanation which focuses or points to physical, observable data and logical inferences."

Here's the exchange that took place during the trial [Dover: Day 11].
Q In any event, in your expert report, and in your testimony over the last two days, you used a looser definition of "theory," correct?
A I think I used a broader definition, which is more reflective of how the word is actually used in the scientific community.
Q But the way you define scientific theory, you said it's just based on your own experience; it's not a dictionary definition, it's not one issued by a scientific organization.
A It is based on my experience of how the word is used in the scientific community.
Q And as you said, your definition is a lot broader than the NAS definition?
A That's right, intentionally broader to encompass the way that the word is used in the scientific community.
Q Sweeps in a lot more propositions.
A It recognizes that the word is used a lot more broadly than the National Academy of Sciences defined it.
Q In fact, your definition of scientific theory is synonymous with hypothesis, correct?
A Partly -- it can be synonymous with hypothesis, it can also include the National Academy's definition. But in fact, the scientific community uses the word "theory" in many times as synonymous with the word "hypothesis," other times it uses the word as a synonym for the definition reached by the National Academy, and at other times it uses it in other ways.
Q But the way you are using it is synonymous with the definition of hypothesis?
A No, I would disagree. It can be used to cover hypotheses, but it can also include ideas that are in fact well substantiated and so on. So while it does include ideas that are synonymous or in fact are hypotheses, it also includes stronger senses of that term.
Q And using your definition, intelligent design is a scientific theory, correct?
A Yes.
Q Under that same definition astrology is a scientific theory under your definition, correct?
A Under my definition, a scientific theory is a proposed explanation which focuses or points to physical, observable data and logical inferences. There are many things throughout the history of science which we now think to be incorrect which nonetheless would fit that -- which would fit that definition. Yes, astrology is in fact one, and so is the ether theory of the propagation of light, and many other -- many other theories as well.
Q The ether theory of light has been discarded, correct?
A That is correct.
Q But you are clear, under your definition, the definition that sweeps in intelligent design, astrology is also a scientific theory, correct?
A Yes, that's correct. And let me explain under my definition of the word "theory," it is -- a sense of the word "theory" does not include the theory being true, it means a proposition based on physical evidence to explain some facts by logical inferences. There have been many theories throughout the history of science which looked good at the time which further progress has shown to be incorrect. Nonetheless, we can't go back and say that because they were incorrect they were not theories. So many many things that we now realized to be incorrect, incorrect theories, are nonetheless theories.
Q Has there ever been a time when astrology has been accepted as a correct or valid scientific theory, Professor Behe?
A Well, I am not a historian of science. And certainly nobody -- well, not nobody, but certainly the educated community has not accepted astrology as a science for a long long time. But if you go back, you know, Middle Ages and before that, when people were struggling to describe the natural world, some people might indeed think that it is not a priori -- a priori ruled out that what we -- that motions in the earth could affect things on the earth, or motions in the sky could affect things on the earth.
I mostly agree with Behe.1 Astrology was an attempt to explain human behaviors by relating them to the position of the Earth on the day you were born. There is no connection. So today we think of astrology as bad science. It's not true that the stars determine your behavior and whenever we make this claim to an astologist we make sure to point out that the evidence is against it.

What we don't do is tell astrologers that they are entitled to believe whatever they want because astrology is not science and therefore we can't make a scientific statement about whether it's correct or not.

Intelligent Design Creationism is bad science. So is most of evolutionary psychology and some of genomics. So is the attempt to find god in a football helmet [The God Helmet: Your Brain on Religion].

It's disingenuous to make fun of Behe's testimony without understanding that the real issue is epistemology and the demarcation problem. Behe's view of science is perfectly legitimate but it didn't jibe with what the plaintiffs were trying to establish during the trial. They wanted to prove that ID isn't science and the best way to do that was to show that something can't be science unless it's true. In other words, science isn't a "way of knowing," it's the end result.

What does this mean? It means that every discredited attempt to explain something using science as a way of knowing becomes "not science" with hindsight. All those people who tried to show that genes were proteins were wrong so it means that what they were doing is not science. It means that of the two sides arguing about junk DNA, one of them will be wrong so, at some time in the future, their current activities will be seen as "not science."

Isn't that bizarre?

1. He should have been defining "science" not "scientific theory." That's the fault of his lawyers who failed to make this point during his direct testimony.

Did Kitzmiller v. Dover kill Intelligent Design Creationism?

The 10th anniversary of Judge Jone's decision in Kitzmiller v. Dover is coming up on Dec. 20, 2015. See the post at Panda's Thumb: Kitzmas is Coming!.

ID proponents are also marking the event in various ways. If you are interested in the discussion, you should read the posts on Evolution News & Views covering the Ten Myths about Dover. The first one (#10) is Ten Myths About Dover: #10, "The Intelligent Design Movement Died After the Dover Decision".

Of course the ID movement didn't die after Kitzmiller v. Dover. From the outside (i.e. not in the USA) it seems to be as strong as ever. State legislatures all over America are still trying to suppress the teaching of evolution and promote creationist perspectives. The movement has captured the attention of many (most?) prominent politicians and much of the American public still believes that scientists are wrong about evolution.

Friday, December 11, 2015

A "synthetic" view of the Modern Synthesis

I just re-read a 1997 paper by Francis Ayala and Walter Fitch (Ayala and Fitch, 1997). The opening two paragraphs describe the Modern Synthesis of Evolution in a very interesting way. The emphasis is on the history and the contributions of Theodosius Dobzhansky (1900-1975) but it makes another point that I'd like to mention.
Theodosius Dobzhansky (1900–1975) was a key author of the Synthetic Theory of Evolution, also known as the Modern Synthesis of Evolutionary Theory, which embodies a complex array of biological knowledge centered around Darwin’s theory of evolution by natural selection couched in genetic terms. The epithet ‘‘synthetic’’ primarily alludes to the artful combination of Darwin’s natural selection with Mendelian genetics, but also to the incorporation of relevant knowledge from biological disciplines. In the 1920s and 1930s several theorists had developed mathematical accounts of natural selection as a genetic process. Dobzhansky’s Genetics and the Origin of Species, published in 1937 (1), refashioned their formulations in language that biologists could understand, dressed the equations with natural history and experimental population genetics, and extended the synthesis to speciation and other cardinal problems omitted by the mathematicians.

The current Synthetic Theory has grown around that original synthesis. It is not just one single hypothesis (or theory) with its corroborating evidence, but a multidisciplinary body of knowledge bearing on biological evolution, an amalgam of well-established theories and working hypotheses, together with the observations and experiments that support accepted hypotheses (and falsify rejected ones), which jointly seek to explain the evolutionary process and its outcomes. These hypotheses, observations, and experiments often originate in disciplines such as genetics, embryology, zoology, botany, paleontology, and molecular biology. Currently, the ‘‘synthetic’’ epithet is often omitted and the compilation of relevant knowledge is simply known as the Theory of Evolution. This is still expanding, just like one of those ‘‘holding’’ business corporations that have grown around an original enterprise, but continue incorporating new profitable enterprises and discarding unprofitable ones.
The important point here is that evolutionary theory is a complex synthesis of sub-theories, hypotheses, and observations. While it may be convenient to refer to this synthetic version as the "Theory of Evolution," it's also very misleading.

I strongly recommend that we abandon that term and use "evolutionary theory" instead. Furthermore, we should be careful about using the term "Modern Synthesis" unless we are specifically referring to the version of evolutionary theory that was popular in the 1950s.

It's true that Ayala and Fitch would like to retain the term "Synthetic Theory" to refer to the expanded version of the Modern Synthesis. They want to emphasize that there have been important extensions to the original Modern Synthesis but these are merely add-ons. Darwin's basic idea of evolution by natural selection remains at the core of their version of the "Theory of Evolution."

That seems like a very pluralistic view but I'd like to note several things about this paper.
  1. The word "drift" appears only once and it's in the form "neutral drift." There's no mention of random genetic drift as a mechanism of evolution that's been incorporated into the synthetic version of evolutionary theory.
  2. The word "neutral" appears five times but "Neutral Theory" is not mentioned. The authors do concede that "the neutral-selection controversy rages on."
  3. There are 50 references but not a single paper by Mootoo Kimura is mentioned. They do, however, discuss molecular clocks and discuss whether amino acid substitutions are really of "no adaptive consequence."
  4. There's a fairly well-known paper by Gould and Lewontin that might be relevant in a discussion about the synthetic version modern evolutionary theory. They neglected to mention it.

Ayala, F.J., and Fitch, W.M. (1997) Genetics and the origin of species: an introduction. Proc. Natl. Acad. Sci. (USA) 94:7691-7697. [PDF]

Gould, S.J., and Lewontin, R.C. (1979) The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proc. Roy. Soc. (London) Series B. Biological Sciences 205:581-598. [doi: 10.1098/rspb.1979.0086]

Thursday, December 10, 2015

How many human protein-coding genes are essential for cell survival?

The human genome contains about 20,000 protein-coding genes and about 5,000 genes that specify functional RNAs. We would like to know how many of those genes are essential for the survival of an individual and for long-term survival of the species.

It would be almost as interesting to know how many are required for just survival of a particular cell. This set is the group of so-called "housekeeping genes." They are necessary for basic metabolic activity and basic cell structure. Some of these genes are the genes for ribosomal RNA, tRNAs, the RNAs involved in splicing, and many other types of RNA. Some of them are the protein-coding genes for RNA polymerase subunits, ribosomal proteins, enzymes of lipid metabolism, and many other enzymes.

The ability to knock out human genes using CRISPR technology has opened to door to testing for essential genes in tissue culture cells. The idea is to disrupt every gene and screen to see if it's required for cell viability in culture.

Three papers using this approach have appeared recently:
Blomen, V.A., Májek, P., Jae, L.T., Bigenzahn, J.W., Nieuwenhuis, J., Staring, J., Sacco, R., van Diemen, F.R., Olk, N., and Stukalov, A. (2015) Gene essentiality and synthetic lethality in haploid human cells. Science, 350:1092-1096. [doi: 10.1126/science.aac7557 ]

Wang, T., Birsoy, K., Hughes, N.W., Krupczak, K.M., Post, Y., Wei, J.J., Lander, E. S., and Sabatini, D.M. (2015) Identification and characterization of essential genes in the human genome. Science, 350:1096-1101. [doi: 10.1126/science.aac7041]

Hart, T., Chandrashekhar, M., Aregger, M., Steinhart, Z., Brown, K.R., MacLeod, G., Mis, M., Zimmermann, M., Fradet-Turcotte, A., and Sun, S. (2015) High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 163:1515-1526. [doi: 10.1016/j.cell.2015.11.015]
Each group identified between 1500 and 2000 protein-coding genes that are essential in their chosen cell lines.

One of the annoying things about all three papers is that they use the words "gene" and "protein-coding gene" as synonyms. The only genes they screened were protein-coding genes but the authors act as though that covers ALL genes. I hope they don't really believe that. I hope it's just sloppy thinking when they say that their 1800 essential "genes" represent 9.2% of all genes in the genome (Wang et al. 2015). What they meant is that they represent 9.2% of protein-coding genes.

By looking only at genes that are essential for cell survival, they are ignoring all those genes that are specifically required in other cell types. For example, they will not identify any of the genes for olfactory receptors or any of the genes for keratin or collagen. They won't detect any of the genes required for spermatogenesis or embryonic development.

What they should detect is all of the genes required in core metabolism.

The numbers seen too low to me so I looked for some specific examples.

The HSP70 gene family encodes the major heat shock protein of molecular weight 70,000. The protein functions as a chaperone to help fold other proteins. They are among the most highly conserved genes in all of biology and they are essential. The three genes for the normal cellular proteins are HSPA5 (Bip, the ER protein); HSPA8 (the cytoplasmic version); and HSPA9 (mitochondrial version). All three are essential in the Blomen et al. paper. Only HSPA5 and HSPA9 are essential in Hunt et al. (This is an error.) (I can't figure out how to identify essential genes in the Wang et al. paper.)

There are two inducible genes, HSPA1A and HSPA1B. These are the genes activated by heat shock and other forms of stress and they churn out a lot of HSP70 chaperone in order to save the cells. There are not essential genes in the Blomen et al. paper and they weren't tested in the Hunt et al. paper. This is an example of the kind of gene that will be missed in the screen because the cells were not stressed during the screening.

I really don't like these genomics papers because all they do is summarize the results in broad terms. I want to know about specific genes so I can see if the results conform to expectations.

I looked first at the genes encoding the enzymes for gluconeogenesis and glycolysis. The results are from the Blomen et al. paper. In the figure below, the genes names in RED are essential and the ones in blue are not.

As you can see, at least one of the genes for the six core enzymes is essential. But none of the other genes is essential. This is a surprise since I expect both pathways (gluconeogenesis and glycolysis) to be active and essential in those cells. Perhaps the cells can survive for a few days without making these enzymes. It means they can't take up glucose because one of the hexokinase enzymes should be essential.

These result suggest that the Blomen et al. study is overlooking some important essential genes.

Now let's look at the citric acid cycle. All of the enzymes should be essential.

That's very strange. It's hard to imagine that cells in culture can survive without any of the genes for the subunits of the pyruvate dehydrogenase complex or the subunits of the succinyl C0A synthetase complex. Or malate dehydrogenase, for that matter.

Something is wrong here. The study must be missing some important essential genes. I wish the authors had looked at some specific sets of genes and told us the results for well-known genes. That would allow us to evaluate the results. Perhaps this sort of thing isn't done when you are in "genomics" mode?

The "core fitness" protein-coding genes that were identified are more highly conserved than the other genes and they tend to be more highly expressed. They also show lower levels of variation within the human population. This is consistent with basic housekeeping features.

Each group identified several hundred unannotated genes in their core sample. These are genes with no known function (yet).

The results of the three studies do not overlap precisely but most of the essential genes were common to all three analyses.

Wednesday, December 09, 2015

Why doesn't natural selection reduce the mutation rate to zero?

All living organisms have developed highly accurate DNA replication complexes and sophisticated mechanisms for repairing DNA damage. The combination results in DNA replication errors that are about 1 per 10 billion base pairs (10-10 per bp). DNA damage due to other factors is effectively repaired with an error rate of 1 in 100 per base pair (10-2 per bp).

Mutations can be beneficial, deleterious, or neutral. In organisms with large genomes there are many more neutral mutations than the other two classes but in organisms with smaller genomes a higher percentage of mutations are either beneficial or deleterious. In all cases, there are more deleterious mutations than beneficial ones.

If deleterious mutations are harmful to the individual then natural selection should favor a low mutation rate in order to minimize that effect. This is especially true in large multicellular organisms where somatic cell mutations cause cancer and other problems. It seems logical that the optimal mutation rate should be zero in order to maximize the survival of the individual and its offspring.

Nothing in biology makes sense except in the light of population genetics.

Michael Lynch
But even though the number of beneficial mutations is low compared to those that are deleterious, this is the stuff of adaptive evolution. In the long run the population will become more fit if beneficial mutations occur and become fixed by natural selection. Eliminating mutations might provide a short-term advantage but eventually the population will go extinct if it can't adapt to new environments. (Neutral and deleterious mutations can also contribute to adaptation over the long term.)

The simplest explanation for this apparent paradox is that there's a trade-off between selection to minimize deleterious mutations and selection for long-term evolutionary advantage. The problem with that explanation is that it is very difficult to show how you can select for the future benefit of mutations to the species (population). It seems as though you have to invoke two bogeymen; group selection and teleology.

Maybe there's a better explanation?

Jerry Coyne recently thought about this problem and posted his analysis under the provocative title: The irony of natural selection. He concludes that there's some constraint that limits the ability of natural selection to achieve a zero mutation rate.
The most probable explanation is that evolution does not produce perfect adaptations. In the case of mutations, though natural selection favors individuals most able to repair any changes in DNA (although a small percentage of these might be adaptive), this level of perfection cannot be achieved because of constraints: the cost of achieving perfection, the fact that all errors are impossible to detect or remove, or that some cells (i.e., sperm or eggs) may not even have DNA-repair mechanisms because of genetic or physiological constraints.
I used to think that this was the best explanation. I taught my students that the accuracy of DNA replication, for example, comes at the cost of speed. The more accurate the polymerization process, the slower it takes. This makes a lot of sense and there's experimental support for the claim. Slowing down the time it takes to replicate the genome will affect the time it takes for cell divisions and that could be harmful ... or so the argument goes.

Unfortunately, I ran into Michael Lynch at an evolution meeting and he quickly destroyed that argument. There's no evidence that the speed of DNA replication is limiting the rate of cell divisions and, besides, there are easy ways for selection to get around such a limitation if it ever occurred. (This is a photo of Michael Lynch looking at me right after setting me straight. He's wondering how I could have been so stupid.)

When you think about it, there doesn't seem to be any biochemical or physiological constraints that could prevent the mutation rate from getting to zero ... or at least a lot closer than it is now.

Michael Lynch has a better answer and he explains it in a paper titled: "The Lower Bound to the Evolution of Mutation Rates" (Lynch, 2011).
As the mutation rate is driven to lower and lower levels by selection, a point must eventually be reached where the advantage of any further increase in replication fidelity is smaller than the power of random genetic drift (Lynch 2008, 2010). The goal here is to evaluate the extent to which such an intrinsic barrier can provide an adequate explanation for the patterns of mutation rates known to have evolved in natural populations.
The main "constraint" is the limited power of natural selection in the presence of random genetic drift. This will depend to some extent of the size of the population.

This idea is called the "drift-barrier hypothesis. It is described in Sung et al. (2012):
... the drift-barrier hypothesis predicts that the level of refinement of molecular attributes, including DNA replication fidelity and repair, that can be accomplished by natural selection will be negatively correlated with the effective population size (Ne) of a species. Under this hypothesis, as natural selection pushes a trait toward perfection, further improvements are expected to have diminishing fitness advantages. Once the point is reached beyond which the effects of subsequent beneficial mutations are unlikely to be large enough to overcome the power of random genetic drift, adaptive progress is expected to come to a standstill. Because selection is generally expected to favor lower mutation rates as a result of the associated load of deleterious mutations, and because the power of drift is inversely proportional to Ne, lower mutation rates are expected in species with larger Ne.
The Lynch lab has produced lots of evidence in support of the hypothesis although there may be some confounding factors in some populations.

The bottom line is that the real irony of natural selection is that it's just not powerful enough to reduce the error rate of replication and repair below the values we currently see.

In a sense, it's the "error rate" of fixation by natural selection in the face of random genetic drift that allows evolution to occur.

The more we learn about biology the more we learn that it's messy and sloppy at every level. Evolution is not a watchmaker and it's not even a blind watchmaker. It's a tinkerer1 and the "watch" barely keeps time.

Image Credit: The Mendel's traits image is from Wikispaces Classroom.

1. Jacob, F. (1977) Evolution and tinkering. Science (New York, NY), 196:1161. [PDF]

Lynch, M. (2011) The lower bound to the evolution of mutation rates. Genome Biology and Evolution, 3:1107. [doi: 10.1093/gbe/evr066]

Sung, W., Ackerman, M.S., Miller, S.F., Doak, T.G., and Lynch, M. (2012) Drift-barrier hypothesis and mutation-rate evolution. Proc. Natl. Acad. Sci. (USA) 109:18488-18492. [doi: 10.1073/pnas.1216223109]

Thursday, December 03, 2015

Facts and theories of evolution according to Dawkins and Coyne

Sometime back in the pre-Cambrian (before blogs) there was a newsgroup called—it still exists. In 1993 I wrote a little essay that tried to convince creationists1 of the difference between facts of evolution and evolutionary theory [Evolution is a Fact and a Theory]. I relied heavily on Stephen Jay Gould's essay on "Evolution as Fact and Theory" originally published in Discover magazine in 1981 and re-printed in Hen's Teeth and Horse's Toes.

I updated my thoughts on Gould's essay in 2007 [Evolution Is a Fact and a Theory] and added some more comment on the 30th anniversary [Evolution Is a Fact and a Theory].

Lot's of other people have presented their take on the facts and theories of evolution. Here's one from Richard Lenski and another from Ryan Gregory.