Investigations
And now for news from the genetic twilight zone
>> What is the genetic basis of evolutionary change? What forces cause different species to evolve?

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We all know how evolution occurs: during the multitudinous molecular busywork of dividing and splicing, somewhere some random genetic blip crops up. The mutation most likely has no effect, or it may provide an advantage and even become the point at which a new species splits off.

Evolutionary biologist Chung-i Wu has found that competitive pressures actively shape as much as 25 percent of fruit fly genes - mainly those involved in sex and immunity.

Random chance is how biologists, or those who study genotypes at least, explain evolution. But Chung-i Wu, chair and professor of ecology & evolution and himself a student of genotypes-that is, a group's genetic makeup-doesn't see it that way. Nor, he points out, is that the view of evolution embraced by biologists who study phenotypes-the visible properties of groups that are produced by the genotype's interaction with the environment. Their observations, like Darwin's before them, prove that natural selection plays a much more active role than the word random implies.

"There's a discrepancy between molecules and morphology," says Wu. "On one hand, we can see by looking at breeds of dogs and even humans the difference in morphology. But when we measure the differences among groups in the same species at the genetic level, the differences vanish."

Wu would like to reconcile these views. He believes natural selection plays a major role even at the genic level and, in competitive environments, actually speeds up.

Take sex genes, which evolve much faster than other genes, as Wu, postdoctoral fellow Wen Wang, and Gerald Wyckoff, PhD'00, noted in a January 2000 Nature study. Genes that resist diseases evolve at a faster pace too. The gene that fights malaria, according to preliminary findings by one of Wu's graduate students, is the fastest evolving gene in the human body. In this year's February 28 Nature Wu, Justin Fay, PhD'01, and Wyckoff reported that as many as one in four fruit-fly genes show evidence of ongoing, rapid evolution. And most of those rapidly evolving genes are involved in fighting diseases or reproducing the species, areas where, says Wu, there is "continually room for improvement."

So why do most molecular evolutionists still espouse the random-chance, or "neutral" view of evolution? The theory, conceived in the 1960s and still dominant in the genomic era, states that, of the many small genetic changes that randomly occur, the vast majority simply do not matter, and less than 1 percent make enough difference to be embraced by natural selection.

The theory dominates partly "because it's elegant and aesthetically appealing," says Wu, who trained as a neutralist under geneticist Mastoshi Nei at the University of Texas and whose down-to-earth manner reflects his pragmatic view of molecular evolution. During the 1930s heyday of neo-Darwinism, he explains, biologists intuited that "probably every piece of DNA was subjected to natural selection." But by the 1960s scientists were able to study DNA directly, and the genome's sheer size-thousands of teeny tiny molecules laid bare to the forces of natural selection-overwhelmed them.

"We knew from artificial selection and the domestication of animals that you cannot improve a stock rapidly; there's a limit to how much selection can be tolerated by a species," Wu continues. But direct observations showed that the genome was undergoing many changes at many points. If they were all the product of natural selection, evolution would move too quickly for a species to digest it. So a Japanese geneticist named Motoo Kimura proposed neutral theory, placing the power of evolution in the hands of random "genetic drift," with the rare occurrence of "good" mutations. "It's survival of the unscathed," says Wu, "preservation of the status quo."

Wu's research team takes an approach that he says the neutral theory all but killed: "screening populations for good mutations and finding out why they're good," that is, pinpointing the exact locations along the genetic code where advantageous mutations led to a new species. The easiest way to do this is to study fruit flies, which are genetically simple creatures, relatively speaking. For the most recent Nature study, the team did a blanket survey, tallying the minute variations within each of 45 genes among flies of one species (Drosophila melanogaster) and contrasted those with the same genes from a different species (Drosophila simulans).

They found that competitive pressures were actively shaping 11 genes-mainly those involved in sex and immunity-while 34 genes, or about 75 percent, showed no sign of natural selection. Next Wu's team turned to the recently completed map of the human genome and extrapolated their results to see if humans evolved at similar genetic locations. By studying variation within human genes and comparing them with genes from old-world monkeys, the researchers found that survival of the fittest is just as active in humans as in fruit flies. Comparing variation within the human genome and divergence from ape ancestors, they determined that about 35 percent of the accumulated changes in humans were "good," that is, provided humans with advantages that contributed to speciation. That's a "shockingly high" proportion, says Wu. It means one advantageous substitution has entered the human genome every two centuries since humans separated from monkeys.

Each study the team publishes advances Wu's molecular adaptation theory-his cure for the vertigo molecular evolutionists experience when confronted by the sheer size of the genome and the possibilities for natural selection to wreak havoc on it. "Just because the stock market goes up 10 percent in one week, doesn't mean it will go up 520 percent over a year's time," says Wu. In other words, the most commonly made mistake is to extrapolate an observation made over a short time period to the vast expanse of evolutionary time.

Wu, who also has appointments in molecular genetics & cell biology, the Committees on Genetics and Evolutionary Biology, and the College, doesn't have that luxury. He deals with both morphology and molecules-two worlds that "generally agree to be separate and equal. But true biologists," he says, "ought to be able to traverse the two. I have seen the vicissitudes of life in the lab. The theory isn't adequate to explain what we see."

Since completion of the Human Genome Project, Wu's team has been racing toward a genomic approach: where before it could only study three genes at a time, now it is studying 150 and soon will be able to study 1,000. "The scale itself makes our work qualitatively different," he says. The more genes he's able to study, the more he's able to hammer his molecular adaptation theory into the pages of peer-reviewed journals-which paves the way for his work on speciation.

One unfortunate result of neutral theory, he notes, is that molecular evolutionists have failed to study how speciation occurs-that is, where and why those "good" mutations happen. Their focus tends to be on differences that occur within species and similarities that occur across species. Little has been done to explain how species differ from their closest relatives. "There are 30 to 40 million differences in the human and the chimp genetic sequences," notes Wu, "but we cannot identify a single one and say, That is the one that makes humans smarter or chimps hairier or the jaw protrude."

A gene that both humans and mice share, says Wu, "is simply not interesting to me. I admit it may be important-but in a physical sciences kind of way. Physical scientists look for the general principles that explain life: an apple falling from a tree, sound from a violin. But if there's a way to define what this department does as opposed to what they do on the other side of Ellis, it's our interest in the differences between species. The end of population genetics," he continues. "is the be- ginning of speciation. That's the twilight zone no one wants to touch. That is where the neutral theory's limits become clear."

What Wu really needs is to take a genomic approach to monkeys too: so that he can measure human variations directly against those of our closest relatives. The problem is, the next genome scheduled to be completed is the mouse. "That's not useful. Mice are too different from humans!" he grumbles. So he's assembling an international consortium of universities in Japan and Taiwan and the U of C. Its goal, if the National Institutes of Health agrees to fund Chicago's portion, is to sequence the protein-coding portion of the genome of the Asian macaque, and begin demonstrating more precisely just how unrandomly natural selection has driven the monkeys and humans apart.

Reflecting on his neutralist training, Wu calls the theory "very efficient. But life is very messy, not elegant at all." Neutralism and molecular adaptation, he says, are like Hemingway and Faulkner. "Hemingway's prose is simple and beautiful, but Faulkner is probably more true to life."
-S.A.S.

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