Upstream plasticity and downstream robustness in evolution of molecular networks

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...

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...

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.)

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.

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.

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. craignelson@wisc.edu 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.

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

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.

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.

  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 ;-)

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?

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'.

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

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.

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.

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.

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.

It's unclear what my research has to do with the topic in question,...

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.

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.

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.

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.

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

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.

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.

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).

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.

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).

"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. ;-)

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

It's going to be a long day, I know . . .

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

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)

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