Image: Jon Krause
In Brief
- Scientists long assumed that any DNA mutation that does not change the final protein encoded by a gene is effectively “silent.”
- Mysterious exceptions to the rule, in which silent changes seemed to be exerting a powerful effect on proteins, have revealed that such mutations can affect health through a variety of mechanisms.
- Understanding the subtler dynamics of how genes work and evolve may reveal further insights into causes and cures for disease.
Biologists long thought they understood how genetic mutations cause disease. But recent work has revealed an important twist in the tale and uncovered surprising—even counterintuitive—ways that alterations in DNA can make people sick. The classic view assumed that what are termed “silent” mutations were inconsequential to health, because such changes in DNA would not alter the composition of the proteins encoded by genes. Proteins function in virtually every process carried out by cells, from catalyzing biochemical reactions to recognizing foreign invaders. Hence, the thinking went, if a protein’s makeup ends up being correct, any small glitches in the process leading to its construction could not do a body harm.
Yet detective work occasionally traced a disorder to a silent mutation, even though researchers presumed that it could not possibly be the culprit. Similar mysteries popped up in studies of genome evolution, where patterns of changes in the DNA of various species indicated that many silent mutations were preserved over time—a sign that they were useful to the organisms possessing them. In many species, these changes seemed to help cells make proteins more efficiently, but not in people.
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13 Comments
Add CommentAll of this illustrates the difficulty of a single mutation (say one caused by a high-speed inter-galactic proton zipping thought our body) ending up causing a different protein to be expressed which in turn causes an organism to be functionally different from its predecessors. Then, Darwinism tells us, superior adaptation to the environment by the mutated form would cause it to become the new mainstream blueprint for the species.
Reply | Report Abuse | Link to thisAt the cellular level things are much too complicated already for that to happen. For one thing, mutating DNA with cosmic rays is like trying to sculpt Mt. Rushmore by shooting cannons at a granite mountain. Most of the time DNA is coiled up so only the outside surface is likely to be hit. Secondly, a projectile particle would ricochet through the structure, likely causing multiple random mutations, not a surgically precise single mutations.
But highly energetic cosmic rays are still the best suspect we have for a mutation producer. Chemical agents tend to produce one-generation mutants, by messing with the proteins. Very few chemicals are subtle enough to get inside DNA and change it without doing a lot of other damage first.
When we have just one "new" protein being produced by a mutation we have to keep in mind that this protein is likely going to be involved in a lot of things other than just creating a new trait for the organism that is beneficial for survival in some way. Proteins are famous multi-taskers. Any newcomer has to fill all the niche roles that its predecessor managed.
It kinda looks like a "shadow" prototype of a new, mutated version of an organism has to be built up in the DNA, with probably much of this "shadow" hiding in what used to be called junk DNA. In some way this shadow evolves and readies itself by working out all its own bugs until one fine day the outside environmental circumstances are such that it is time for the shadow plan to step out inthe the daylight.
An interesting post. You spend the majority of it describing how this new finding makes mutation by radiation a most unlikely engine for evolution, then throw all that overboard with a clever phrasing of the hopeful monster theory.
Reply | Report Abuse | Link to thisWith great relief to me there was no mention in the article of Anfinsen's dogma, which was unquestioned in 1989 and held that the amino acid sequence was the only determinant of protein structure. I got contradictory results in 1989 correlating the local shape around an amino acid with the codon representing it in the DNA encoding the protein, but was not believed, because my results contradicted a Nobel prize winner. It's good to see science corrects its mistakes fairly quickly.
Reply | Report Abuse | Link to thisIn polycythemia disorders, a nonsense mutation truncates one of the hemoglobin proteins, or a hemoglobin alpha/beta subunit? Just wondering...
Reply | Report Abuse | Link to thisdeus ex machina, everywhere
Reply | Report Abuse | Link to this@Michael Cook: an excellent dissertation of how you don't understand mutation and evolution
Reply | Report Abuse | Link to this"All of this illustrates the difficulty of a single mutation (say one caused by a high-speed inter-galactic proton zipping thought our body) ending up causing a different protein to be expressed which in turn causes an organism to be functionally different from its predecessors. "
I think you're confusing Marvel Comics with science. We're not talking Reed Richards and his friends going up in a rocket ship and coming down as the Fantastic Four. We're talking a subtle and potentially tiny change that may or may not be a beneficial advantage to the organism. It may even be detrimental. If, however, the change is beneficial, it increases that organism's chance of surviving, procreating and thus passing on that new gene to its descendants. If, however, it provides neither a positive or negative it still has a chance of being passed on.
"Then, Darwinism tells us, superior adaptation to the environment by the mutated form would cause it to become the new mainstream blueprint for the species."
Darwinism? Why are you still reading Darwin? You do realize Darwin's breakthroughs occurred 150 years ago, and like the organisms he discussed it has gone through extensive evolution. Portions of his theories have been found to be completely wrong, others have gained more detail. You should probably read a modern biology book. "Origin of the Species" is a great nostalgia read, but it's got very little to do with modern evolutionary science. It's like reading Jules Vernes "First Men in the Moon" and trying to extrapolate the technology of the space shuttle.
"For one thing, mutating DNA with cosmic rays is like trying to sculpt Mt. Rushmore by shooting cannons at a granite mountain."
No, it's not. It's like shooting cannons at a granite mountain and hitting it occasionally. Your Rushmore analogy assumes there's a final design in mind to your actions which is not the case. A random gamma ray hitting a random base pair on a randome chromosome of a random animal that may or may not produce a mutation that may or may not be beneficial or detrimental doesn't fit your analogy in any way at all.
"Secondly, a projectile particle would ricochet through the structure, likely causing multiple random mutations, not a surgically precise single mutations."
Potentially, assuming the energy from the ray wasn't absorbed by the first structure it hit, thus producing a mutation. To quote Seinfeld "that's one magic loogie".
"When we have just one "new" protein being produced by a mutation we have to keep in mind that this protein is likely going to be involved in a lot of things other than just creating a new trait for the organism that is beneficial for survival in some way."
Again, the assumption is NOT that a mutation will lead to a benefit survival. A mutation that causes a detrimental effect can still be passed on, the animal merely needs to breed*. Some mutations cause beneficial detriments. Sickle-cell anemia, for example, can be deadly to the person, but it provides a level of immunity to malaria. Seeing as it's much more likely that a person will die from malaria before being old enough to breed than to die from sickle-cell we have a negative that provides a better chance of being passed on.
(*Or, in the case of single-cells, divide.)
"Proteins are famous multi-taskers. Any newcomer has to fill all the niche roles that its predecessor managed."
Not necessarily at all. What if it fails to fill one or two of the roles, and that's not enough to limit the viability of the animal, thus allowing it to pass on the gene? What if it produces new functionality that doesn't replace the functionality lost but provides something new? The common example of evolutionary biologists is "a mousetrap without a retention bar is no longer useful as a mousetrap, but it can now be used as a tie clip".
"It kinda looks like a "shadow" prototype of a new, mutated version of an organism has to be built up in the DNA, with probably much of this "shadow" hiding in what used to be called junk DNA. In some way this shadow evolves and readies itself by working out all its own bugs until one fine day the outside environmental circumstances are such that it is time for the shadow plan to step out inthe the daylight."
The changes are subtle, yes, and occur over many generations. I think the problem you're having isn't with evolution, but simply grasping the scale of time it takes for it to work. Life arose on this planet about 500,000,000 years after the planet was formed 4.5 billion years ago. That means, from our meager beginnings, it's taken US 4 billion years to get here. That's a lot of mutations in a lot of generations of a lot of species in a lot of differing environments. Each minor change, no matter how small, in the aggregate works out to some tremendous differences.
Well, over three billion of all that time was spent getting to the simplest multi-cellular organisms. Granted, by that time DNA is established and the important metabolic pathways are going, plus every species of anything is constantly fighting off a tremendous urge to de-evolve into something much simpler, ESPECIALLY WHEN LIFE IS EASY.
Reply | Report Abuse | Link to thisMy cat, for instance. The domestic feline brain has been shrinking for thousands of years. Why does a house cat need a brain? All Fluffy has to do is wait around listening for the sound of the electric can opener in the kitchen, Brains take a lot of energy. But all organisms are like that, even long self-replicating chains of molecules. Given the choice, simpler is better and an organism will simplify.
And how about that last billion years when higher organisms really get in gear? There seem to be long periods of not much happening, and then "bursts" of evolution happen, usually (I claim) because in the extra, apparently useless, DNA of a species a pattern, shadow, or ghost of a higher, more complex organism suddenly becomes realizable. Yes, this makes all the possible combinations in a really messy bunch of DNA kind of like Plato's ideal world, and what gets expressed on the wall of our cave won't be perfect either.
The picture of evolution being the triumphal march of a myriad incremental, minor changes that happenstantially and totally unintentionally build up beings capable of creating the Internet and wasting their time posting on it is preposterously optimistic bull-kaka. Life evolved the way it did because it had to, the game was strongly fixed from the start.
They claim it is now proven that a million supercomputers generating totally random sequences of letters will eventually produce Hamlet. But the supercomputers have no idea what they have written, do not know how to stop the algorithm that compels them to write, and worst of all do not know how to forget all the plays written about Gamlet, Hamler, or West Side Story. Their storage gets full and they die.
Shakespeare not only had no choice but to eventually appear as a product of directed evolution, the bard had to write Hamlet exactly like he did.
Damfino who directed that Shakespeare, or myself, or Susan Boyle, or any other suffering genius come into existence. But something made irrational numbers exist and then made not only innumerable books but movies about numbers like pi exist so that we non-accidental types can ponder and wonder in awe. Prove anything is "random" if you can. . .
I agree that all life is totally programmed.All events are controlled, manufactured to create a link in an ongoing chain of events that we call life on earth. Every event having the effect it was meant to have.
Reply | Report Abuse | Link to thisEverything happens for a reason--not only is that the fundamental principle of all religion, it is a consolation to those who grieve this week because the tail tends to fall off Airbus airplanes whenever they get into severe turbulence or even go a little too fast. Yes, I do live near Seattle and have a certain economic interest here. Priests and engineers tend to think alike.
Reply | Report Abuse | Link to thisHey, new stuff on the Science channel last night, from the world of paleoentology. Jack Horner and others at Montana State University (my alma mater) are claiming that dinosaurs are a lot closer to modern birds than anyone would have thunk. Chickens actually do have dinosaur type teeth at one stage of embryo development. Catepillars use the same gene for building a 100 little feet that they later use for putting spots on the butterfly wings.
Reply | Report Abuse | Link to thisWhat this really all means is that there is some type of hidden genetic code that enables as few as 1000 genes to make a human by familiar genes turning off and on at PRECISE times. This also means we don't have to look for our missing link ancestor anymore. By manipulating a human embryo that ancestor would pop out.
This all emplies that evolution is a vastly different process than imagined in recent decades. The older idea that philogeny recapitulates ontogeny is vastly empowered and the evolution of today's species is less a random walk than it is the product of some type of busy, powerful, plan.
Ahh, the happy buzz of creationalist speach.
Reply | Report Abuse | Link to thisAfter reading the article on the apparent importance of introns, I (a liberal arts educated dabbling generalist) was feeling pretty smug about the below forum post I made 3 years earlier on www.cr4.globalspec.com:
Reply | Report Abuse | Link to this"Re: Darwin Still Rules, but Some Biologists Dream of a Paradigm Shift
06/29/2007 10:58 AM
Yes, rather than finding that there is "junk DNA" that is redundant or ineffective, I suspect that science will find that typical DNA segments are more like the mayor of a small town who also serves as the judge, town comptroller, local master of ceremonies, purveyor of hardware and household goods, dabbles in real estate, has a family, and raises little dogs as a hobby."
Texlex
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2br02b
Actually, I intended to make the prior comment a year from now, when it WILL THEN BE three years earlier than the article...I made the error because I've been forcing myself to use the Mayan calendar, but the learning curve is rather steep...I expect to master it by 2013...
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