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Hardly a day passes without the announcement of the discovery of a gene for heart disease or intelligence or eye colour or something else. But the discoverers know that if they are true to the complicated nature of DNA, they should add, "And the gene for a whole lot of other things too."
While the notion that each gene does only a single thing remains the stuff of many high-school biology texts, the rise of modern molecular biology has made it more and more apparent that most genes influence a multiplicity of activities in the body.
"When you knock out a single gene in an organism, you can today see that it affects the expression of something in the order of hundreds of other genes," says Sally Otto, a University of British Columbia professor of mathematical biology.
"But it is possible that if you had a very precise measure of all changes, you would find that all the genes in the genome have been affected to some degree by the operation of a single one."
The sorts of linkages that appear are often wildly non-intuitive. For example, a gene mutation that is known to be lethal in fruit flies also seems to affect their eye structure. Another mutation gives them protection from the cold while at the same time lessens their resistance to starvation.
On top of this, there are often sex-limited multigenic effects. The ability of the gene mutation that causes cystic fibrosis to make men sterile is a classic case.
Scientifically, the process is known as pleiotropy, from the Greek words pleion, meaning more, and tropism, meaning response. And while the variety of a gene's many faces has been discussed for the better part of 75 years, the implication of its entangled networking has only of late begun to dramatically affect the thinking of biologists who study how evolution works.
The emerging richness of pleiotropy means that any simple Darwinian notion of what is going on during natural selection has to be abandoned.
"You can't change selection on one thing without changing everything," says Prof. Otto, who published a mathematical formula that tries to explain the evolutionary interaction between positive and negative pleiotropic effects.
The issue is not just that many things change, but that the changes aren't neutral.
Allan Orr of the University of Rochester, who has co-written a book on speciation, says a gene mutation that might have a strong desirable trait -- let's say, making a person think faster -- is likely also to have so many significantly negative traits associated with it that getting into a population as a whole is extremely unlikely.
"How does the one positive win over the vast number of negatives? That is the great problem that evolution faces," Prof. Orr says.
The simplest answer is that nearly 150 years after Darwin first explained the theory of evolution, the richness of multiple effects from the same gene is such that existence itself seems problematic.
"If so many mutations are bad for you, how do we even manage to stay alive?" Prof. Otto says. "Right now, I am not sure people know what the answer to that is."
Faced with what amounts to a growing daily confusion of genetic effects, biologists are proposing new and more highly refined theories of evolution.
One theory suggests that there are some kinds of genes that are more generalist than others: They don't do any one thing particularly well, but on average do a number of things fairly well. Thus, if there is a mutation that improves one function a fair bit, the gene's middling status in affecting other things means that it can't do too much damage.
Nonetheless, it must still buck a negative trend in nature that seems designed to slow down the spread of a gene in a population.
Prof. Otto's mathematical model ascribes the relationship between the spread of a relatively strong positive effect with a nearly as strong negative effect as "two steps forward, one step back."
Another theory, put forward by Gunter Wagner of Yale University, suggests that certain genes are mainly modular in their operation. That is, genes that appear different actually operate in concert.
One thing that might happen is that a change in one linked gene might trigger a sort of cascade of other changes.
That would explain how Darwin's famous Galapagos finches, which theoretically all descended from a common ancestor, were able to evolve into one species with a beak specifically designed to eat insects, another to eat leaves and yet a third to eat fruit, Prof. Otto says.
Conversely, Prof. Orr argues that what pleiotropy might mean is that evolution selects against all big, single genetic changes.
"The analogy is what happens if you have at a television with a screwdriver, randomly changing things trying to make the whole thing better. Going that way, the possibility of improving things is almost zero. But if you do a very delicate change, it is not so unlikely you might slightly improve things," he says.
But perhaps the most interesting feature in the attempt to align pleiotropy with evolution is the notion that there may be some pattern of genes that control speciation itself.
As an example, a recent Japanese study of cichlid fish in Africa's Lake Victoria suggested that a change in an eye gene that allows the fish to perceive colours differently may have operated as an evolutionary trigger in the evolution of the lake's 300 species from a few common ancestors.
What appears to have happened is that the change in colour-sensitivity allowed females to accurately pick out males with different body stripes and in so doing make it easier to separate their kind from cousin fish nearby.
With modern genetics increasing the supply of data about the multiple functions of genes, evolutionary biologists are increasingly confident that they are going to be able to do what Darwin promised but couldn't quite delivery -- truly explain the origin of species.
"The important point is that we now have the genetic tools in place to figure out how evolution really works. It's now just a matter of hard work," Prof. Orr says.
Single genes have multiple effects
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Posted 17 January 2005 - 01:19 PM
Any simple Darwinian notion of natural selection has to be abandoned, and biologists are proposing more highly refined theories.
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