Upstream plasticity and downstream robustness in evolution of molecular networks

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omega

In developmental biology, and increasingly in evolutionary biology, one of the most important fields of study is deciphering the nature of regulatory networks of genes. Most people are familiar with the idea of a gene as stretch of DNA that encodes a protein in a sequence of As, Ts, Gs, and Cs, and that's still an important part of the story. Most people may also be comfortable with the idea that mutations are events that change the sequence of As, Ts, Gs, and Cs, which can lead to changes in the encoded protein, which then causes changes in the function of the protein. These are essential pieces in the story of evolution; we do accumulate variations in genes and gene products over time.

There's more to evolution than just that relatively straightforward pattern of change, however. Consider humans and chimpanzees. We're both made of mostly the same stuff: the keratin that makes up our hair and the organization of hair follicles is nearly identical, and our brains each contain the same structures. The differences are in regulation. We both have the same kinds of hair, but chimps have more of it turned on all over the place, while we've mostly down-regulated it everywhere except a few places. The differences in our brains may be mostly differences in select timing: our brains are switched on to grow for longer periods of time in development, and there are almost certainly specific regions and patterns of connectivity that are tweaked by adjusting different levels of different gene products in different places at different times.

Continue reading "Upstream plasticity and downstream robustness in evolution of molecular networks" (at Pharyngula)

33 Comments

Most people are familiar with the idea of a gene as stretch of DNA that encodes a protein in a sequence of As, Ts, Gs, and Cs…

Actually most people are not familiar with that.

— Anti-spam: replace “usenet” with “harlequin2”

Most people are familiar with the idea of a gene as stretch of DNA that encodes a protein in a sequence of As, Ts, Gs, and Cs…

Actually most people are not familiar with that.

Though it would be true for most readers of this site.

— Anti-spam: replace “usenet” with “harlequin2”

PZ Myers wrote:

You must understand that genes don’t stand alone, but every gene is an actor in a complex regulatory network. Each gene has a set of other genes that can influence whether that gene is off or on (these are called upstream elements.) A gene produces a protein product that affects multiple other genes (the downstream elements); this affect can be direct, if the gene is a regulatory gene itself, or indirect, if the gene product is part of a complex of cytoplasmic regulators. (I’m trying to keep this simple, or I’d go into greater detail on the fact that there are also multiple levels of regulatory interaction, that there is a great cloud of things called transcription factors that interact directly with DNA, and there is another great cloud of signal transduction factors and regulatory proteins working away in the cytoplasm.)

Indeed.…

My question to you is this: At what point does the organization and adaptation of process and structure to function observed in the interactions of genes with one another and with their associated RNA’s when they are expressed preclude a darwinian machanism of chance mutation and natural selection in their etiology?

In your mind, has that point been reached?

Don’t be silly. This doesn’t look designed at all, and the whole point of the paper is that there is a pattern of organization completely consistent with duplication and divergence…by entirely natural mechanisms. No pixies, fairies, sasquatches, aliens, time-travelers, or deities necessary.

I really wish people were able to read some of the cool stuff going on in biology without their minds shutting down as soon as they see some complexity, compelling them to reach for the sweet, sweet oblivion of the god-juice.

PZ Myers wrote:

I really wish people were able to read some of the cool stuff going on in biology without their minds shutting down as soon as they see some complexity, compelling them to reach for the sweet, sweet oblivion of the god-juice.

Funny you should mention it ;-) Sean Carroll’s latest paper is sitting here on my desk. Perhaps a taste would do:

Genome Biol. 2004;5(4):R25. Epub 2004 Mar 15.

The regulatory content of intergenic DNA shapes genome architecture.

Nelson CE, Hersh BM, Carroll SB.

Howard Hughes Medical Institute, University of Wisconsin-Madison, 1525 Linden Drive, Madison, WI 53703, USA. [Enable javascript to see this email address.]

BACKGROUND: Factors affecting the organization and spacing of functionally unrelated genes in metazoan genomes are not well understood. Because of the vast size of a typical metazoan genome compared to known regulatory and protein-coding regions, functional DNA is generally considered to have a negligible impact on gene spacing and genome organization. In particular, it has been impossible to estimate the global impact, if any, of regulatory elements on genome architecture. RESULTS: To investigate this, we examined the relationship between regulatory complexity and gene spacing in Caenorhabditis elegans and Drosophila melanogaster. We found that gene density directly reflects local regulatory complexity, such that the amount of noncoding DNA between a gene and its nearest neighbors correlates positively with that gene’s regulatory complexity. Genes with complex functions are flanked by significantly more noncoding DNA than genes with simple or housekeeping functions. Genes of low regulatory complexity are associated with approximately the same amount of noncoding DNA in D. melanogaster and C. elegans, while loci of high regulatory complexity are significantly larger in the more complex animal. Complex genes in C. elegans have larger 5’ than 3’ noncoding intervals, whereas those in D. melanogaster have roughly equivalent 5’ and 3’ noncoding intervals.

CONCLUSIONS: Intergenic distance, and hence genome architecture, is highly nonrandom. Rather, it is shaped by regulatory information contained in noncoding DNA. Our findings suggest that in compact genomes, the species-specific loss of nonfunctional DNA reveals a landscape of regulatory information by leaving a profile of functional DNA in its wake.

Our findings suggest that in compact genomes, the species-specific loss of nonfunctional DNA reveals a landscape of regulatory information by leaving a profile of functional DNA in its wake.

As a scientist who greatly admires Dr. Carroll’s work, I must say that this sentence makes no sense to me. The more I read it the more confused I get.

That said, Charlie, I think we’d all appreciate it if you ceased spamming the blog with molecular biology and genetics papers which impress you for whatever reason.

Why don’t you take a few weeks off to educate yourself all about selenocysteine metabolism? That’s about as good as an argument for the existence of God as you’re going to find in biology, IMHO.

Dr Roland Strickland wrote:

I think we’d all appreciate it if you ceased spamming the blog with molecular biology and genetics papers

I guess you’re right. The very last thing we need here are legitimate, peer-reviewed scientific research papers cluttering things up.

Chez Watt??

No, it’s not the science papers that are cluttering things up. It’s the essentially random posting of abstracts without any explanation of their presumed significance. You may think you are projecting biological erudition, but it truly doesn’t work here - it just shows you barely understand the subject.

For instance, what does that paper by Carroll say about gene regulatory networks, the topic of this thread? Very little if anything. It just says that in organisms in which a lot of non-functional DNA has been lost, it is easier to detect what extragenic DNA may have functional relevance. In these organisms, a correlation emerges that the more complex the regulatory pattern of a gene is, the higher the amount of DNA dedicated to its regulation seems to be. Interesting, but hardly earth-shattering. Also, I may add, it must be quite upsetting for those ID advocates who claim there can be no such thing as non-functional, “junk” DNA.

Andrea Bottaro wrote at: http://www.urmc.rochester.edu/gebs/[…]_bottaro.htm

Antibodies (also called immunoglobulins, or Ig) are B lymphocyte-derived serum proteins involved in the immune response to foreign substances and micro-organisms (antigens). To become fully productive, Ig-encoding genes have to undergo multiple rearrangements of their DNA sequences through unique recombination mechanisms. Early in B lymphocyte development, VDJ recombination originates the antigen-binding region of the antibody molecule; a second type of rearrangement, class switch recombination (CSR), is activated in mature B cells during an immune response and allows the generation of different classes of antibodies with specific effector functions. These processes are crucial for normal immune system function, and their alteration can lead to severe immunodeficiency.

You know Andrea, I’m old enough to remember the time when scientists believed that *all* specific antibodies were encoded in the egg and sperm cells. I even remember having arguments about this with die-hard selectionists who insisted on this kind of model. Now I’m not an immunologist, so feel free to correct me if I err, but it seems to be that while a certain amount of diversity is present in germlines, other local events are necessary to generate the enormous diversity required to respond to virtually any antigen, to mount an enhanced (memory) response to a second challenge and to maintain self-tolerance. Funny, no one ever called me up after Tonegawa’s seminal work in the late 70’s to say I was right. I guess they had other things to do in the 70’s ;-) Anyway, my point is this: if our bodies can “learn” to produce antibodies that they have never before encountered in nature, and to fight off invaders that may not have ever existed in their environment, then one would tend to describe this as a dynamic and responsive system that responds to new and previously unknown challenges and takes the steps, on it’s own initiative, to deal with these new threats, would they not? And so, the question occurs, why do we imagine that the genome itself is less capable, and does not have within its architecture the same kind of dynamic and responsive machinery that is possessed by the lesser immune system? Why would we imagine that evolutionary changes in the genome are somehow the result of random, accidental and haphazard mutations and natural selection, rather than the results of a carefully designed system that comes close to being a universal automaton, capable of making any other biochemical machine so long as it’s functional units are proteins, which because of their nearly infinite number of uses to which they can be put, gives the living genome an almost limitless potential? You ask me the significance of the papers that I’ve posted. They all point in one direction. And that direction is that the genome is not a static entity, subject only to random events such as mutation, recombination and drift, but is indeed a dynamic and responsive entity in which multiple structures and multiple processes are integrated in such a way so as to support each other and to support the overall function of the genome, that in most cases controls its own destiny.

  Funny, no one ever called me up after Tonegawa’s seminal work in the late 70’s to say I was right. I guess they had other things to do in the 70’s ;-)

Success has many parents; failure is an orphan.….….

You ask me the significance of the papers that I’ve posted. They all point in one direction. And that direction is that the genome is not a static entity, subject only to random events such as mutation, recombination and drift, but is indeed a dynamic and responsive entity in which multiple structures and multiple processes are integrated in such a way so as to support each other and to support the overall function of the genome, that in most cases controls its own destiny.

What is the function of the genome, and what is its destiny? How does the genome know what its destiny is?

Andy Groves wrote:

What is the function of the genome, and what is its destiny? How does the genome know what its destiny is?

The function of the genome is to keep the cell alive and to reproduce itself in the environment in which it finds itself and also possibly to “evolve” in new directions. IMHO, its destiny was written into its architecture when it was created. What that destiny ultimately is, one can only wonder. But I have no doubt that life in this universe is not a purposeless, accidental event and that we are here for a reason.

Charlie: But I have no doubt that life in this universe is not a purposeless, accidental event and that we are here for a reason.

I appreciate you sharing your faith with us but let’s not confuse this with science.

But let’s not confuse terms such as purpose and randomness as used here. (Darwinian) evolution may be ‘random’ but is also highly teleological in that it selects for ‘function’. In fact such form of evolution is very easily reconcilable with a Christian faith for instance or a faith based assumption that there is something called ‘purpose’. However such a stance, purpose in nature, should not automatically lead to a rejectance of scientific fact just because one interprets (incorrectly) natural processes with accidental. This false dichotomy found in Charlie’s writings is unfortunate

Examples

… such an organized system, with so many structures, processes and components, with such high level organization such as feedback and cascading processes could not have been the result of random, accidental processes, …

In this case Charlie seems to be presenting a false dichotomy of chance versus design but limits design to include only intelligence. The qustion of course is: Is intelligence required for such feedback processes to arise? The answer may be quite surprising. Of course when one is working from the presumption that intelligence is involved, the answer is simple but may be biased by one’s belief. Science has uncovered many fascinating aspects of DNA, protein networks, RNA which indicate that simple processes such as duplication and divergence may explain most of these structures. Combine this with the evidence that simple evolutionary processes can increase information and complexity in the genome and one has some fascinating hints as to how life was ‘designed’.

Charlie: But I have no doubt that life in this universe is not a purposeless, accidental event and that we are here for a reason.

I appreciate you sharing your faith with us but let’s not confuse this with science.

But let’s not confuse terms such as purpose and randomness as used here. (Darwinian) evolution may be ‘random’ but is also highly teleological in that it selects for ‘function’. In fact such form of evolution is very easily reconcilable with a Christian faith for instance or a faith based assumption that there is something called ‘purpose’. However such a stance, purpose in nature, should not automatically lead to a rejectance of scientific fact just because one interprets (incorrectly) natural processes with accidental. This false dichotomy found in Charlie’s writings is unfortunate

Examples

… such an organized system, with so many structures, processes and components, with such high level organization such as feedback and cascading processes could not have been the result of random, accidental processes, …

In this case Charlie seems to be presenting a false dichotomy of chance versus design but limits design to include only intelligence. The qustion of course is: Is intelligence required for such feedback processes to arise? The answer may be quite surprising. Of course when one is working from the presumption that intelligence is involved, the answer is simple but may be biased by one’s belief. Science has uncovered many fascinating aspects of DNA, protein networks, RNA which indicate that simple processes such as duplication and divergence may explain most of these structures. Combine this with the evidence that simple evolutionary processes can increase information and complexity in the genome and one has some fascinating hints as to how life was ‘designed’.

Pim wrote:

I appreciate you sharing your faith with us but let’s not confuse this with science.

This has nothing to do with faith and everything to do with science. Intelligent design is an interpretation of data. I keep hearing the claim all the time that there is no promising research being done on intelligent design. That’s simply not true. Research is being done on biological structures and systems all the time. Research is being done on the genome, on DNA, RNA (in all of it’s manifestations) and on molecular sequences. The authors of these papers often report the data and then, in addition to reporting the data, add an interpretation that attempts to explain the data. Since most of these researchers are darwinian evolutionists (some more so than others), most of the times known mechanisms such as selection, drift, etc are applied. But often these same data can be interpreted in other ways or not interpreted at all. Very rarely does a researcher provoke the wrath of the scientific establishment by proposing an ID interpretation for their work. Take for example a system like DNA repair. A lot of valuable work has been done to elucidate all of the mechanisms, structures and processes that are involved. My interpretation is that such an organized system, with so many structures, processes and components, with such high level organization such as feedback and cascading processes could not have been the result of random, accidental processes, but has the unmistakable signature of intelligent insight. Similar interpretations can be applied to the new discoveries in micro-RNA’s, RNA interference, etc. It doesn’t take a stretch of the imagination to suspect that intelligent guidance might have played a role in it’s etiology. There are hundreds of examples in the journal literature of the elucidation of processes, structures and functions by competent, gifted researchers, who then go on to explain their findings as the result of selective pressure or genetic drift simply because they are heavily invested in the paradigm that supports this interpretation. Were they to open their minds to other possibilities, they might begin to understand that what they’re seeing is beyond the capability of random chance and that intelligent guidance must be considered as a possibility.

Can I ask a stupid question about DNA?

Does the DNA of an organism change or mutate during the natural life of the organism?

I tend to think the answer is “No,” but, truthfully, I ain’t sure. I guess there are people like the survivors of Hiroshima who get their DNA mutated by all that radiation and tragically develop Leukemia and/or lymphoma later in life. So, technically, that would be a change in DNA (or in the DNA of some, but not all of the cells of the person)

I guess, the better question is, Does the DNA of an organism change or mutate so as to RESULT IN A BIOLOGICALLY ADVANTAGEOUS adaptation during the life of the organism?

Does that question make sense, or am I confused? Be gentle, I’m just a layman. Cheers.

Charlie: It’s unclear what my research has to do with the topic in question, but I guess it’s just another way for you to change the subject.

Ironically, the immune system is a perfect example of darwinian principles in action. Antibody genes are generated by a DNA recombination mechanism essentially randomly, by joining a few (two or three, depending on the chain) of hundreds of potential component gene segments, plus a sprinkle of completely random, non-genomically encoded nucleotides added to the joining sites. Billions of antibody-producing immune system cells, each one different from all the others, are produced every day, with no foresight about which cells are going to be useful and which will not (the overwhelming majority). It’s an enormously wasteful process, 50% of the cells fail to produce successful rearrangements, and many more are elminated becuase they end up recognizing “self” antigens. Almost all the cells that make it through will die after a few weeks, having done nothing at all. But, if even one in the billions of cells produced ends up recognizing the next pathogen that you will encounter, it will be worth it. That cell will become activated, and will begin to proliferate, while its antibody genes again undergo multiple rounds of random mutational changes. Most of these changes will inactivate the antibody, and those cells also will die, but a few mutations will improve binding to the pathogen, and those lucky cells will be selected for further expansion, based on their antibody’s chemical affinity to the target. Again, a terribly wasteful process. And yet, by sheer mass action, and the power of random mutation and selection to generate specific adaptations, your antibody system is capable of responding to pretty much any potential pathogen in existence, plus all other pathogen that will ever evolve.

Pretty impressive, isn’t it, for a “blind” system?

You ask me the significance of the papers that I’ve posted. They all point in one direction. And that direction is that the genome is not a static entity, subject only to random events such as mutation, recombination and drift, but is indeed a dynamic and responsive entity in which multiple structures and multiple processes are integrated in such a way so as to support each other and to support the overall function of the genome, that in most cases controls its own destiny.

That paper really says nothing of the sort. I can’t even imagine how you got that idea. I descibed above what the point of the paper is: organisms with reduced genomes allow to better track functional regulatory sequences in non-coding DNA, and the more complex the regulation of a gene, the larger the fraction of DNA involved in its regulation seems to be. No “destiny”, “dynamic responsive” mumbo-jumbo in there. None at all.

Navy Davy, besides the specific mechanisms that I described above for certain immune system cells, each cell in the body undergoes mutations as it divides and develops. Most mutations are either neutral or have negative effcts. As you say, cancer-causing mutations may allow a cell to proliferate more than its neighbors, which could be seen in a sense as “beneficial “ to the cell itself, but of course it’s bad for the organism. In large, multicellular organisms like us there is little chance that a mutation affecting one or some of our somatic cells will have beneficial effects, though I guess there may are scenarios in which it could (for instance, a mutation occurring very early during development may show up in many, even all cells in the organism). However, unless these mutations take place in germ cells (the lineage that gives rise to gamwetes, sperms and eggs), they will not be transmitted to the progeny. Also, somatic cell mutations are also random with regard to fitness, i.e. their occrrance is not influenced by the immediate needs of the organism.

Andrea Bottaro,

besides the specific mechanisms that I described above for certain immune system cells, each cell in the body undergoes mutations as it divides and develops.

Yes, and I thought your description of the immune system was very good. But, surely, each cell that divides (800 gazillion?) cannot undergo a “substantial” mutation, or else we’d be growing third eyes every once in a while. On the other hand, maybe they do mutate frequently and just die off.

Most mutations are either neutral or have negative effcts.

I agree. We’d see much faster evolution, if not.

As you say, cancer-causing mutations may allow a cell to proliferate more than its neighbors, which could be seen in a sense as “beneficial “ to the cell itself, but of course it’s bad for the organism.

I think that’s exactly right.

.…though I guess there may are scenarios in which it could (for instance, a mutation occurring very early during development may show up in many, even all cells in the organism).

I’d be interested in exploring this. It seems to me that such mutation (of the DNA) HAS to occur during the child-bearing years of the organism, so that it could be passed down thru subsequent generations.

However, unless these mutations take place in germ cells (the lineage that gives rise to gamwetes, sperms and eggs), they will not be transmitted to the progeny. Also, somatic cell mutations are also random with regard to fitness, i.e. their occrrance is not influenced by the immediate needs of the organism

Not sure I understand the significance between germ and somatic cells, but I very much enjoyed the ideas expressed in your post.

Charlie wrote:

Take for example a system like DNA repair. A lot of valuable work has been done to elucidate all of the mechanisms, structures and processes that are involved. My interpretation is that such an organized system, with so many structures, processes and components, with such high level organization such as feedback and cascading processes could not have been the result of random, accidental processes, but has the unmistakable signature of intelligent insight.

This is, however, another case where data apparently incompatible with the conventional interpretation of natural selection were presented in the literature. You may recall so-called “directed evolution” discovered by J. Cairns and associatees (esp. P. Foster). Briefly, the observation was that lactose-minus mutant E. coli gave rise to lactose-plus descendents only when presented with lactose in the media . This looked for all the world like a case of instructive (Lamarckian) adaptation. If this mutagenesis were truly instructive, it might have dealt a body blow to the modern synthesis. However, careful analysis of the phenomenon found that E. coli has an error-prone DNA polymerase which is induced by stress and is also closely linked to the lac operon. The induction of this polymerase form gave rise to the increased number of lac+ mutants in the cells. There are some E. coli arcana involved (J. Roth and coworkers), but the bottom line is that it works just like other cases of adaptation by selection of random variants in the population.

I am rather surprised that we in the scientific community don’t bring this up when confronted with the “Darwin can’t be/hasn’t been tested” shibboleth.

This is how science works: we start with a phenomenon that we can’t explain. Then we look for a way to study it, and a way to fit it in with natural phenomena. And we discover something cool along the way, like error-prone DNA synthesis. Much more fun than looking for a Designer who happens to be in our own image and likeness.

Andrea Bottaro wrote:

It’s unclear what my research has to do with the topic in question,…

I’m interested in all types of scientific work and I don’t often get to interact with people in the trenches. I found your work interesting and informative, as I’ve had a long-standing interest in immunology, as I mentioned. This discussion has served a useful purpose also because it forced me to “get current” with what’s been happening in your field. I tend to get outdated pretty fast these days. I’m sorry that you think so little of me that you would assume that I was trying to “change the subject”. I’ve gotten a lot of that in my travels ;-) Of course, I’m not going to try and challenge you on the topic of immunology since you have me at a distinct disadvantage. So let me say only that I’ve always had my suspicions about clonal selection and I’m noticing some new work coming out of Weitzman in Israel that seems pretty interesting. Care to comment? Anyway, WRT my post, you seem to have missed or chose not to comment on my main point, that connects your work to the discussion: if our bodies can “learn” to produce antibodies that they have never before encountered in nature, and to fight off invaders that may not have ever existed in their environment, then one would tend to describe this as a dynamic and responsive system that responds to new and previously unknown challenges and takes the steps, on it’s own initiative, to deal with these new threats, would they not? And so, the question occurs, why do we imagine that the genome itself is less capable, and does not have within its architecture the same kind of dynamic and responsive machinery that is possessed by the lesser immune system? Why would we imagine that evolutionary changes in the genome are somehow the result of random, accidental and haphazard mutations and natural selection, rather than the results of a carefully designed system that comes close to being a universal automaton, capable of making any other biochemical machine so long as it’s functional units are proteins, which because of their nearly infinite number of uses to which they can be put, gives the living genome an almost limitless potential? While you are perfectly correct in saying that the immune system is a “perfect example of darwinian principles in action”, you fail to differentiate between how the system works, and how it was created. It is clear that clonal “selection” is most likely at least partially correct, but this cannot be construed to mean that the immunological system itself is the product of darwinian selection.

Frank Schmidt wrote:

You may recall so-called “directed evolution” discovered by J. Cairns and associatees (esp. P. Foster). Briefly, the observation was that lactose-minus mutant E. coli gave rise to lactose-plus descendents only when presented with lactose in the media.

And don’t forget about Barry Hall.

Bioessays. 1990 Nov;12(11):551-8.

Directed evolution of a bacterial operon.

Hall BG.

Department of Biology, University of Rochester, NY 14627.

And after that, they just renamed it “adaptive evolution” and everyone lived happily ever after.

It is clear that clonal “selection” is most likely at least partially correct,

I assume you mean this without irony and that the Nobelists and others who worked it out can rest easy.

but this cannot be construed to mean that the immunological system itself is the product of darwinian selection.

Oh yes, it can, in conjunction with the other data that support the modern synthesis. While here are many things we don’t understand, there is no reason to postulate an ad hoc explanation instead of trying to do science. Science doesn’t admit untestable (among them ad hoc) hypotheses. It appears that Charlie and the ID True Believers are still stuck in the God of the Gaps conundrum.

Charlie: our bodies do not ““learn” to produce antibodies [to antigens] that they have never before encountered in nature”, our immune system works, frankly, by throwing everything and the kitchen sink at pathogens, hoping that something will work. Because immune systems have no foresight of what pathogens they will encounter (although they may have an evolutionary memory of past pathogens, but that’s another story), the best strategy is to randomly diversify as much as possible, and then select the rare useful solutions. This is a fully darwinian process. In that respect, the immune system is a good example of how genomes work on an evolutionary scale, but for reasons opposite to those you mention. Genomes, like the immune system, have no foresight of adaptive needs. The do not “learn”, do not “seek” a solution. They mutate, and selection does the rest.

ndrea Bottaro wrote:

our bodies do not ““learn” to produce antibodies [to antigens] that they have never before encountered in nature”, our immune system works, frankly, by throwing everything and the kitchen sink at pathogens, hoping that something will work.

I think this is, at the very least, an oversimplification of the process. While most diversity occurs *before* contact with an antigen, a significant amount of processing goes on afterward. The huge diversity of lymphocyte detectors produced pre-challenge have relatively low affinity thresholds. This is good, because it allows the immune system to detect almost any foreign antigen but the response time is rather slow and inefficient. I don’t believe that it’s incorrect to say that the immune system incorporates mechanisms that enable lymphocytes to *learn* the structures of specific foreign proteins and to produce lymphocytes that have a high affinity for specific antigens. I will agree that this mechanism is somewhat darwinian in that somatic hypermutation can result in clones, some of which have different receptors. Those of highest affinity will in turn be activated and cloned. I guess you could say (much as I despise the terminology) that some sort of “survival of the fittest” occurs when there is competition for pathogens. But again, I say that even though a darwinian mechanism might be operating, it doesn’t follow that since the system works that way, that it was created that way. I still hold the opinion that such a system, because of it’s multiple processes, multiple structures and multiple functions and their integration into a functional system could not have emerged by random chance.

More on what I said above:

I also do not believe that somatic hpermutation, whether it is occurring in the immune system or in the genome is a purely random event. Apparently neither do these folks:

Semin Immunol. 1996 Jun;8(3):159-68. The targeting of somatic hypermutation.

Jolly CJ, Wagner SD, Rada C, Klix N, Milstein C, Neuberger MS.

Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.

Somatic hypermutation does not occur randomly within immunoglobulin V genes but, rather, is preferentially targeted to certain nucleotide positions (hot spots) and away from others (cold spots). Cold spots often coincide with residues essential for V gene folding. Hotspots, which appear to be strategically located to favour affinity maturation, are most frequently located in the CDRs (particularly CDR1) though conserved hotspots are also found at the base of FR3. Hotspots are in part created by local DNA sequence and the strong biases of codon usage in V genes indicate that the genes have evolved such that somatic hypermutation is targeted to those parts of the V where it is likely to prove most useful. These features of mutational hotspots and biased codon usage are also evident in V genes of lower animals suggesting that diversification by strategic targeting of non-templated mutation may have evolved early in antigen receptor evolution.

The only part they got wrong:

…the genes have evolved such that somatic hypermutation is targeted to those parts of the V where it is likely to prove most useful.

IMHO somatic hypermutation is the result of directed mechanisms, most likely related to micro-RNA’s or some other such mechanism that carries information to the regions based on the needs of the system.

I think this is, at the very least, an oversimplification of the process. While most diversity occurs *before* contact with an antigen, a significant amount of processing goes on afterward. The huge diversity of lymphocyte detectors produced pre-challenge have relatively low affinity thresholds. This is good, because it allows the immune system to detect almost any foreign antigen but the response time is rather slow and inefficient. I don’t believe that it’s incorrect to say that the immune system incorporates mechanisms that enable lymphocytes to *learn* the structures of specific foreign proteins and to produce lymphocytes that have a high affinity for specific antigens. I will agree that this mechanism is somewhat darwinian in that somatic hypermutation can result in clones, some of which have different receptors. Those of highest affinity will in turn be activated and cloned. I guess you could say (much as I despise the terminology) that some sort of “survival of the fittest” occurs when there is competition for pathogens.

Yes, that’s exactly what happens (although it’s not “somewhat” darwinian - it is). As for “learning”, if one defines learning as including randomly generating an immense diversity of possible answers, and then letting non-teleological physical/chemical processes select which one is best, than the immune system “learns”. (I tend to consider learning an intelligent, purposefully-driven process, as opposed to, say, memory.)

But, mind you, even if you adopt that extended definition of “learning” (inclusive of random generation of answers, followed by selection of successful ones), that’s still exactly what happens during evolution, according to evolutionary theory.

So, if you agree, as it seems, that the adaptive immune system can indeed achieve remarkably high efficiency and specificity, as well as the (superficial) appearance of purposeful “learning”, by relying on random variation and selection strategies, why is it so inconceivable to you that evolutionary mechanisms based on the same principles can achieve the same outcome?

But again, I say that even though a darwinian mechanism might be operating, it doesn’t follow that since the system works that way, that it was created that way. I still hold the opinion that such a system, because of it’s multiple processes, multiple structures and multiple functions and their integration into a functional system could not have emerged by random chance.

As stated, that’s just an argument from personal incredulity, and so vague it can’t be addressed. A skeptic ignorant of modern immunology might equally say that they do not believe that the high antibody affinities and specificities observed during immune responses can emerge from random chance, but they do (coupled with selection).

What specific features of the immune system do you think could not possibly have evolved?

The term “hotspots” of somatic hypermutation just refers to lose preferences in the target sequences, due probably to the specificity of catalytic activity of the mutation-inducing enzyme itself. However, during an immune response the mutations are not “targeted” to sites that increase antibody affinity, i.e. are random wrt fitness. In the past few years the enzymology of the process has actually been worked out to a large extent, although many things are still unclear. Do a Pubmed search for “activation induced deaminase + hypermutation” if you mant to know more.

Andrea Bottaro wrote:

A skeptic ignorant of modern immunology might equally say that they do not believe that the high antibody affinities and specificities observed during immune responses can emerge from random chance, but they do (coupled with selection).

Yes, that would be about what I would say. ;-)

(gotta go do some work…I’ll answer the rest later)

Charlie. It seems to be that you seem to be using the term random or non-random in a manner not consistent with common usage.

Charlie:

I also do not believe that somatic hpermutation, whether it is occurring in the immune system or in the genome is a purely random event.

Versus

Somatic hypermutation does not occur randomly within immunoglobulin V genes but, rather, is preferentially targeted to certain nucleotide positions (hot spots) and away from others (cold spots).

What initially looked like adaptive or directed mutations was quickly found to be a hypermutation response quite in line with Darwinian explanations. Remember that in (Darwinian) evolutionary theory randomness refers to its immediate effect in a particular environment. This should not be confused with a non random distribution of mutations for instance.

“A skeptic ignorant of modern immunology might equally say that they do not believe that the high antibody affinities and specificities observed during immune responses can emerge from random chance, but they do (coupled with selection).” Yes, that would be about what I would say. ;-)

I see. I was under the impression that you had agreed that the immune system works by darwinian principles. You had said

While you are perfectly correct in saying that the immune system is a “perfect example of darwinian principles in action”, .… I will agree that this mechanism is somewhat darwinian … etc

I was just pointing out that, if darwinian mechanisms can indeed generate highly specific and targeted antibodies and the illusion of “intelligent learning” during immune responses, why can’t you accept that the same mechanisms can generate complex adaptations and the illusion of teleology in evolution?

But if you have changed your mind and are now claiming that the immune system does not after all work under darwinian principles, we’re back at square one. It’s going to be a long day, I know…

Andrea Bottaro wrote:

It’s going to be a long day, I know …

Indeed. It turned out to be a very long day. Twelve hours in the air, four hours on the tarmac in Oakland and a six hour jet lag. I’m too old for this!

I was under the impression that you had agreed that the immune system works by darwinian principles.

The operative word in my statement was “somewhat”. We live in a mostly digital world in which everything is viewed in terms of one or zero, on or off, black or white, evolution or creation. The human mind, however is an analog computer where there are infinite numbers of intermediate states. If I design a dozen prototypes using all of the basic principles of engineering and design and then I offer them to the public, they will select the one that is “best” and it will probably survive, leaving the less fit to the dustbin of engineering history. This example exhibits clearly darwinian principles of variation and selection, but the variety was not random, it was the clear result of intelligent design. In the immunology example, as I explained, there are clear evidences that some darwinian mechanisms are at work in “selecting” those lymphocytes that have the highest affinity for pathogen. I am not, however, ready to admit that affinity maturation, somatic hypermutation and C-region switching are purely darwinian processes. I don’t believe they are and I believe that information travels in two directions in both the genome and the immune system to tailor the output to the system’s needs. (I guess I shouldn’t even get into Ted Steele and Bob Blanden’s work with reverse transcriptase and their claim that immunities acquired by parents can be passed on to their offspring)

In the immunology example, as I explained, there are clear evidences that some darwinian mechanisms are at work in “selecting” those lymphocytes that have the highest affinity for pathogen. I am not, however, ready to admit that affinity maturation, somatic hypermutation and C-region switching are purely darwinian processes.

Class switching is an entirely different beast, it is the result of induction of specific genetic programs, not of variation + selection mechanisms. Affinity maturation, which is the result of somatic hypermutation and clonal selection, follows darwinian principles, whether you are ready to admit it or not.

I don’t believe they are and I believe that information travels in two directions in both the genome and the immune system to tailor the output to the system’s needs.

What you (or I) believe is irrelevant. There is no evidence of “information traveling in two directions to tailor the output to the system’s needs” as far as affinity maturation is concerned (or the genome, for that matter, but let’s stick to the topic). On the contrary, for the immune system we have enough evidence to indicate that our current models are sufficient to explain the observed phenomena to a very fine molecular detail. People even isolated single cells from germinal centers, and constructed genealogical trees of cell lineages following the accumulation of mutations. I’ll gladly eat my hat if in my lifetime this general model is overturned.

(I guess I shouldn’t even get into Ted Steele and Bob Blanden’s work with reverse transcriptase and their claim that immunities acquired by parents can be passed on to their offspring)

You are welcome to bring those up if you wish, but before you do, I suggest you read the relevant literature, and ask yourself why Steele himself has long ago abandoned his model that purportedly showed transgenerational transfer of immunological memory.

Andrea wrote:

I’ll gladly eat my hat if in my lifetime this general model is overturned.

No fair. I’m probably 20 years older than you ;-) I want to live to *see* that!

Anyway, I’m going to let you have the last word. You obviously aren’t seeing what I see and only time will tell which of us is right. I hope you find a cure for AIDS or cancer or something like that or win the Nobel Prize someday. Rest assured that I am 100% behind you insofar as your battle against religious creationists. This was *always* about science as far as I’m concerned and I wish you well in your research.

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This page contains a single entry by PZ Myers published on May 18, 2004 9:12 AM.

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