Monday, July 13, 2009

Rules of nature

Genes and DNA sequences that are crucial to survival are preserved by natural selection, so looking for sequences conserved among many species or phyla will clue you in to which genes or regulatory regions have been important in evolution. Or at least that's the conventional wisdom. A News Focus in last week's Science , however, ("Genomic Clues to DNA Treasure Sometimes Lead Nowhere", by Don Monroe) suggests that it's not that that simple.

For a number of years researchers have been trolling the genomes of numerous species, looking for conserved or 'ultraconserved' DNA sequences (ultraconserved sequences are stretches of DNA that are the same in mice, rats, and humans and perhaps other species, and often similar in fish), assuming that they represent regions with important regulatory or coding functions which is why they've been maintained by natural selection. The idea is that these stretches of DNA are so crucial that without them, the organism would die. However, often when these regions are knocked out (experimentally deactivated), there is no effect on the animal. This has surprised many people, given the well-accepted equation of conservation=importance.

From an evolutionary perspective, the problem is that mutations are always occurring and no bit of DNA is invulnerable. Given that, over time every nucleotide will experience mutational hits; most of the new alleles may disappear by drift, but not all of them will. Eventually, there will be no recognizable sequence left (that is, if the corresponding sequence in distant descendants could be identified, they would bear no similarity). Selection can maintain sequence if it is functional, and if therefore most mutational changes are harmful. But otherwise, other than by unlikely aspects of chance, how can deep conservation occur?

The conservation=importance equation thus makes sense and fits evolutionary theory well--but unfortunately for evolutionary biologists, nature doesn't always follow the rules. There are several possible explanations for this. Linear DNA sequence is less important in many contexts than the three dimensional conformation a stretch of DNA folds up into in the cell. It's this three dimensional shape that determines what other stretches of DNA or proteins can bind to it, and thus its function(s), and there might be multiple ways to attain the same shape.

And, sometimes it's not the shape of the molecule that's so important but some other characteristic such as, for example, its acidity, which is determined by amino acid composition, and acidity determines what that stretch of DNA can bind to. There are many nucleotide and amino acid combinations that will produce the same acidity. That means that the specific DNA sequence may not be conserved, but other characteristics of that stretch of DNA may be.

Many gene knock-out experiments in mice, even if the gene isn't one that is ultraconserved, have shown no effect on the mouse. Even large regions with presumably essential genes or regulatory sites have been knocked out and the mice seem none the worse for wear. This is perplexing, except that the mice are only observed in ideal conditions in a laboratory setting, while the missing DNA may be important when the mice are in other contexts.

Finally, whatever works is what nature does, and whatever works in a given context can and does vary widely. There are no steadfast rules for how to get from here to there, and there are exceptions to every generalization. Natural selection isn't always the explanation, nor do specific genes and their evolutionary histories work the same way in every situation, and so on.

To us, this story is a reminder that any rule an evolutionary biologist can come up with, nature can break.

8 comments:

gnomon said...

When an evolution theory or rule is incomplete, as we do now with the existing paradigm, it is certain that it will have exceptions or contradictions. But not when we have a complete theory, such as the newly proposed MGD hypothesis here,
http://precedings.nature.com/documents/1751/version/2

Ken Weiss said...

When a new theory comes along, such as MGD, it has to be proven with a lot of evidence. There is clearly more to life, and to changes in life over time. The clock hypothesis does not say that the clock is perfect or uniform. But the general applicability of the clock has been supported by a lot of evidence that fits molecular divergence to geological data and the like.

It will be interesting and exciting if another hypothesis that is very different can show that mutational divergence does not accumulate as we think it does, because of epigenetic factors. That would, perhaps, mean that epigenetic factors impose a kind of selection on mutation changes (but epigenetic changes often are affected by mutational changes, since the former require DNA recognition sequences, etc.).

So it is not clear whether MGD is a reflection of nonuniformity in mutational accumulation, of forms that we'll need to learn to take account of, or is something more important.

gnomon said...

My standard of a theory is really a minimum for a physicist but is one no biologist has dare to apply in his work: a theory must explain all relevant facts and must not allow a single contradiction. The MGD easily passes this standard and explains more facts than any existing evolution theory. If you read the paper carefully, you will find every major fact of evolution supports the MGD. You are welcome to point out a single contradiction to the MGD.

Evolution has essentially two types of factual evidence, fossils and DNAs, that we can try to explain with our theory. For the fossil, any theory must explain both the continuous stability of species and the discontinuous instability, namely the PuncEq phenomenon. For the DNA, a theory must explain the most remarkable result of molecular evolution, the genetic equidistance result of Margoliash in 1963, which directly provoked the molecular clock idea.

To my knowledge, no existing theory of any kind, except the MGD, has explained any of the above two main facts of evolution. Darwinism is contradicted by the PuncEq as well as molecular data. I The clock/neutral theory is supposed to explain molecular evolution, in particular the equidistance result. But in fact, it has explained nothing. A newly appreciated feature of the equidistance result, the overlap feature, that has been completely overlooked for 46 years, fully contradicts the clock idea. visit this site here for a brief discussion.

http://thegoldengnomon.blogspot.com/2009/04/molecular-clock-at-best-explains-half.html

http://thegoldengnomon.blogspot.com/2009/05/molecular-clock-should-never-have-been.html

The molecular clock should never have been invented in the first place for macroevolution if people had known about the overlap feature of the equidistance result in the beginning. Yes, it sometimes works but not the other half of the time. And it works for the wrong reason, as explained by the MGD.

The genetic equidistance result (sister species are equidistant to a simpler outgroup) has been interpreted by a tautology, the molecular clock hypothesis, which says that vastly different lineages have very similar mutation rates. The neutral theory was invented to explain the molecular clock by postulating that the vast majority of residue differences between species are neutral mutations.

On surface, the similar mutation rate idea seems to explain the equidistance result in terms of percent identity. But another important feature of the equidistance result is: most of the residue positions differing between one sister lineage and the outgroup are also different between another sister lineage and the outgroup. In other words, suppose that sister species A and B are equidistant to the simpler outgroup C, where A and B has separated for much longer time than the time of separation between C and the common ancestor of A and B. We would observe that most of the residue positions that differ between A and C are also different between B and C. For example, yeast is approximately equidistant to drosophila (67/104 identity) and to human (66/102 identity). If one carefully compares the alignments, one would find that among those 36 residue differences between yeast and human, 31 are also different between yeast and drosophila.

This nearly complete overlap in mutated residue positions in two separate sister lineages is one of the two fundamental features of the genetic equidistance phenomenon (the other is of course the equidistance in terms of percent identity). However, it, dubbed the overlap feature, has been completely ignored or overlooked in the past 46 years. The molecular clock interpretation and the neutral theory were invented based on a complete ignorance of this feature. They would not have been invented in the first place if people had paid attention to the overlap feature because they are clearly contradicted by this feature.

gnomon said...

Darwin followers never said that their theory has no exceptions. Here are a few typical claims:

“Unlike the case in physics, the predictive power of a model in biology is quite low. It seems to us that if the prediction (e.g., a phylogenetic tree reconstructed) of a model is correct in 80% of the cases, it is a good model at least at the present time.”

Masatoshi Nei and Sudhir Kumar, 2000, Molecular Evolution and Phylogenetics, p85.


“any rule an evolutionary biologist can come up with, nature can break.”

From Professor Ken Weiss’s Blog page of July 13, 2009, http://ecodevoevo.blogspot.com/2009/07/rules-of-nature.html

A common sense and logical view of mine on why any theory must not allow a single contradiction in order to qualify as scientific or testable:

In mathematics or physics, one exception is sufficient to doom any theory. The science of biology or any scientific discipline for that matter should not be held to a lower standard. When one allows exceptions, one has effectively and automatically rendered the theory non-testable and non-scientific. Think about it: if a test turns out to be against the theory, would the theory still stand as correct? Yes, if one allows exceptions. Thus, such a theory can never be falsified by the scientific method. That theory would be no different from a false theory that happens to explain a fraction of nature while being contradicted by the rest. The only way to distinguish a true theory from a false or incomplete one is to see if it has not a single factual exception within its domain of application or relevance.

The worst theory possible would still be able to explain at least one factual observation, namely, the fact itself that directly provoked the theory or the tautology. For example, apple falls because it is the intrinsic nature of apple to fall. Thus, to be able to explain a small fraction of all relevant facts while being contradicted by the rest is not evidence of a true theory but is evidence of an incomplete or false theory.

I have no patience with such typical self-serving and self-deceiving claims that you don’t expect a theory of evolution to have no contradictions since most things are chance. The one thing that all genuine science like mathematics and physics have taught us is that it would take a miracle for an incomplete theory to have no contradictions and it would equally take a miracle for a complete theory to encounter a single contradiction in nature. The difference between truth and falsehood is not quantitative or measured by the difference in the number of contradictions but is qualitative.
There can be countless incomplete or false theories with each accounting for a few facts but there can only be one unique true theory that accounts for all facts within its domain of application. Until evolutionary biology has such a theory that has not a single contradiction, it is not real science. But I still view the daily work of biologists as scientific even if being misguided by an incomplete theory because the facts that they collect will be useful for looking for the true theory and fact collection rather than theory building is what they do for a living. In this sense, the taxpayers’ money is well spent indeed.
Newton physics does not work in the microworld and Newton followers have no trouble admitting it. Darwinism would not have a single exception if it is limited to microevolution such as drug resistance in bacteria. It only encounters exceptions when being applied to domains such as macroevolution where it is irrelevant and false. Darwinists could easily meet the no contradiction standard if they could just be honest and specific about where their theory works and where it does not.

Ken Weiss said...

This could go on forever. You're not the first to claim that biology wasn't a 'real' science because it has exceptions. A lot has to do with definitions. Biology is a science! Our knowledge is incomplete, and the main point of 'exceptions' in your quotes is (based on current admittedly incomplete knowldge) the hierarchical nature of stochasticities. They are not like measurement error, or perhaps even Heisenberg uncertainties or distributions of electron fields, which do in a sense 'even out'.

In life, once gone, gone forever, and in many other ways chance effects that are heritable become unpredictable except probabilistically, and we are far from understanding those probabilities adequately. Yet, many biologists argue as if we knew more than we do and as if, as Darwin also basically believed, everything that's here today is here because of a deterministic, force-like natural selection.

One can argue about that til the cows come home, but this is the place for it.

Physics has many exceptions or uncertainties due, at best, to probabiilistic aspects. Heisenberg, anomalies in 'laws' in the vicinity of black holes, scale-based differences between Newton and Einstein, wave-particle duality, untestable string theory, the exception due to 'dark matter', particles after splitting experiments that know about each other at a distance, the nature of gravity. Wolfram's argument that the universe is pulsed rather than continuous. The three or multibody problem that is, as far as I know, theoretically insoluble. Recent arguments that physical constants are perhaps variable or universe-specific. There's chaos and self-organizing complexity. And then there's Godel.

I'm not a physicist, and one can dismiss whichever of these things one doesn't happen to like. A theory is perfect if you only accept the perfect parts of it, of course, and deny views you don't like.

In any case, we're not denying that, if we knew everything we could understand everything. But we might not be able to _predict_ everything. That would depend on whether there is true stochasticity in the world, or whether, if there is, it has distributional properties.

Most sciences, and certainly biology, are currently underdetermined--many alternatives currently are comparably good explanations of the existing data, and there can always be unknown theories that would be better. That's the real world that we have to accept. It makes us (all!) fallible, but it doesn't make our field unscientific.

As to your MGD theory, we don't really understand it. We would be very surprised if you can show that it is not tautological and yet is universal. We and others would love to know of that if it's true. But we would have to see an organized paper, with data, to show what the argument is. From your messages, we simply can't understand it well enough (maybe that's our limitation, but it's why we can't respond to it).

Finally, in biology as in any other field, the burden of proof lies on anyone who claims a truly new view, especially a perfect one. Most such claims are wrong. Occasionally they transform human thought. The latter have a hard time being accepted, in any field at any time, against prevailing views. I'm sure your ideas have the same challenge. But if they are right they need to be understood.

If you have a paper that presents, and documents, the theory and its universality, please provide a reference so we can go see for ourselves.

gnomon said...

Here is the reference for the MGD paper again that you can find on the internet: Huang, S. Inverse relationship between genetic diversity and epigenetic complexity, submitted.
http://precedings.nature.com/documents/1751/version/2

The main idea of this paper, i.e. the inverse relationship between genetic diversity and epigenetic complexity, has been published as a peer reviewed book chapter. Citation: Huang, S. (2008) Histone methylation and the initiation of cancer. Cancer Epigenetics, Ed. Tollefsbol, T., CRC Books.

A new theory, as you well know and well put by Max Planck, never converts the old minds who, perhaps due to aging, can always conveniently claim that they dont understand. A young mind who knows no dogma would find it much easier to understand. So I am counting on your students to understand the MGD better than you ever will.

Your silence to my charge that the molecular clock should never have been invented for macroevolution suggest that you understood my point and have nothing to say to refute my charge.

If you and the entire field can be fooled for 46 years by the grossly mistaken molecular clock interpretation of the genetic equidistance result, could one has any confidence in whatever negative opinion you may have on a new theory? At least we need to hear your stance on the shortcomings of the old theory, which I have pointed out to you in plain English in my earlier post, before we would value you as an honest and competent scientist who is open to new ideas. So if you would, please defend the molecular clock against my charges. If you cannot and agree with my charges, then you may have a bit of chance of understanding the MGD.

It is funny that you would charge the MGD to be a tautology. Do you know what a tautology means? If you know, you would know that the molecular clock is the most deceiving tautology in the history of science. see this peer reviewed paper of mine for more discussion on the clock tautology.

http://omicsonline.com/ArchiveJCSB/Ab01/JCSB1.092.html (Peer Reviewed) Published as 'Huang, S. (2008) The genetic equidistance result of molecular evolution is independent of mutation rates. J. Comp. Sci. Syst. Biol., 1: 92-102.'

gnomon said...

Darwinists self destruct when self defend

Let us do a few necessary/inevitable logical deductions from the typical claims of a Darwinist like Ken Weiss and others and see where they may lead us. Ken Weiss: “Any rule an evolutionary biologist can come up with, nature can break.”

The rules/hypotheses of Darwinists include a few like the following:

1. The very rule itself that ‘any rule an evolutionary biologist can come up with, nature can break.”

2. Variations are random/chance.

3. There is no God doing any selection. There is no artificial/mind selection and only natural selection, at least before the appearance of human mind.


The following are the exceptions to each of the above. They must be true if Darwinists are right that “any rule an evolutionary biologist can come up with, nature can break”:

1. There is such a rule that has no exceptions.

2. Some variations are due to intention or not random.

3. There is a God doing artificial selection during evolution.


These logical exercises are meant to illustrate the absurdity of the position of no absolute truth/certainty/rule in evolution. It is a self defeating position and a double edged sword. Darwinists cannot escape self-destruction when they use it for self-defence of their contradiction-laiden theory.

A person caring only about the disinterested search for truth can only have one possible position. There must be a law of evolution that has no exceptions. Nothing can break it. Not accidents, not mother nature, and not God.

"Only a disinterested search can result in Truth, for every form of self-interest will lead only to a creation which will serve that self-interest." by N. Sri Ram

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