Descended from Darwin

How does one species become two, and what keeps them that way? Why isn't there just one good, all-purpose fruit fly? Despite the promise of his masterwork's title, On the Origin of Species, Charles Darwin really didn't know the details. Biology professor Mohamed Noor has a few ideas.

It's hopeless. Try as he might, the eager young suitor with the brick-red eyes simply cannot inspire the beautiful female's affections.

He stands beside her, waving one iridescent wing over her as if making a blessing and producing what sounds like the drumming of a very small grouse. But she couldn't care less. His song and dance are not her style. And, he smells funny. He's literally not her type. In fact, he's another species entirely. She informs him of this with a little ditty of her own, call it the "buzz-off song," that sounds like a raspberry blown on a tiny kazoo.

This failed pickup between two closely related North American fruit flies offers a glimpse of the power of biodiversity, the thing that made humans different from chimps and allowed DNA-based life to establish its sweeping power over the oceans, the forests, and the air. Her genes and his genes, though remarkably similar, are forever kept separate by being carried in different species. So the subtle differences between the way each of them metabolizes sugars or tolerates toxins, as well as their scents, songs, and dances, are preserved and protected rather than melded into some intermediate version.

Noor builds on Darwin: discovering the process at chromosomal level whereby one species of fruit fly becomes two. During the cell division that creates eggs and sperm, chromosomes normally swap versions of the same gene (A for a, b for B, and so on). But sometimes, a section of chromosome comes out completely and is then reinstalled upside down. The genes within that section can no longer trade places with their complements on another chromosome. Tom Dunne/Courtesy of Duke Research.

Charles Darwin understood diversity as a good thing—nature's way of hedging its bets. He postulated that the formation of species is one mechanism by which life adapts to new opportunities like larger seeds or plentiful but poisonous prey, and how it weathers dramatic challenges like droughts, ice ages, and the occasional cataclysmic meteor. Species are also the way to pack the most life into a given area. "The same spot will support more life if occupied by very diverse forms," Darwin wrote 150 years ago.

It is this ability to form discrete species that makes this planet more than a giant monoculture of some single-celled slime. Biodiversity is what makes DNA-based life resilient in a changing environment, and it's something we probably need to understand better.  

But where is the specific breakpoint: How does one species become two, and what keeps them that way? Why isn't there just one good, all-purpose fruit fly? Despite the promise of his masterwork's title, On the Origin of Species, Charles Darwin really didn't know the details. To him, and to the several generations of biologists who followed, the forces that create species and keep them distinct were just a fascinating black box—crucial, but unknown.

Only in the last decade has a handful of scientists finally pried the lid off the true origin of species and begun to glimpse what's inside. Mohamed Noor, thirty-eight, an ebullient, fast-talking geneticist inclined to wear T-shirts at any occasion and just as happy with McDonald's at every meal, is one of them. Noor has discovered a process at the chromosomal level whereby one species of fruit fly can become two and stay that way, even when they aren't physically separated by geography. It involves the reversal of a portion of the fly's DNA that governs behavior and subtly influences its choice of mate.

In February, Noor traveled to London to stand beside a dozen evolutionary biologists from around the world honored with the prestigious Darwin-Wallace Medal. The medal, given by the august Linnean Society, is awarded to scientists who have done the most to advance Darwin's thinking over the last fifty years. They are, in essence, his direct descendants. In a singular honor, Noor was asked by the society to speak on behalf of all of the medal recipients.

It was the Linnean Society that first took delivery on Darwin's Big Idea—on July 1, 1858, when the group heard a synopsis of what became On the Origin of Species. Presented along with Darwin's thesis that day was a paper by Alfred Wallace, whose parallel epiphany impelled Darwin to hand over what he considered unfinished work. The Darwin-Wallace Medal has only been given twice before, on the fiftieth and 100th anniversaries of that momentous meeting.

Biology professor Mohamed Noor. Credit: Chris Hildreth

The last batch of scientists was recognized thirteen years before Mohamed Noor was born in Australia to Egyptian parents. He grew up in Virginia, where his dad taught mechanical engineering at various universities and did research with NASA at the Langley Research Center. As an undergraduate, Noor was less than a stellar student, until he took a course on genetics his junior year at the College of William & Mary. "Then I thought, 'Why not take every course that has genetics in the title?'" Many of this year's Darwin-Wallace honorees became familiar fixtures in his textbooks: household names like the late Stephen Jay Gould, and others, like Lynn Margulis and John Maynard-Smith (Richard Dawkins' mentor), best known in scientific circles.

Darwin didn't know anything about the mechanics of genetics that Noor was taught: Gregor Mendel's principles of inheritance, the gene-shuffling rules of recombination, the structure and function of DNA.

But he didn't need to because he based many of his ideas on a near-perfect laboratory of evolution, the isolated Galapagos Islands. He correctly deduced that geographic isolation allowed populations to slowly drift apart in their appearance and habits, eventually becoming two species that would have nothing to do with one another, and indeed be unable to produce viable offspring.

But that can only be one of possibly several ways to make species. "To explain the diversity of life, you'd have to posit a geographic barrier every time," says Carlos Machado, a biologist at the University of Maryland and close collaborator with Noor. The process of making a new species isn't sudden and irreversible, so how do we end up with similar species coexisting in a single habitat, like the eleven variations of a basic woodpecker that we see in eastern North America or the two fruit flies—the spurned lover and the object of his desire—living side by side in the Pacific Northwest? Clearly, there's another way to separate two species and allow them to progress in their own ways.

Noor is credited with helping to solve that riddle, but like most good science, it's not what he initially set out to do. As a University of Chicago graduate student, he shaped his thesis to test a theoretical notion called "reinforcement," in which two species in the process of separating experience some kind of subtle pressure to discriminate between mating partners. It was theoretical because no one had actually seen it operate in species that were not already irreversibly set.

Having identified two species of fruit flies that appear to share a large area of the western United States, Noor spent a month tramping around the mountains of Utah, Arizona, and California, setting out buckets of mashed bananas and yeast—an irresistible banquet for fruit flies—and then netting and jarring the flies he wanted. He hauled them back to the lab in Chicago and watched them having sex, keeping track of who danced with whom and how their kids turned out. "It was really 1930s science," Noor says, referring to the pioneering work by Thomas Hunt Morgan, who discovered much of what we know about chromosomes and heritable traits through a series of very clever experiments with the fruit fly Drosophila melanogaster.

Old school, maybe, but still full of power. Morgan was a geneticist and embryologist and, like many of his colleagues at the time, thought that Darwin could be proved wrong in the details of species formation. In fact, Morgan wasn't so sure that species were even real distinctions. He set out to prove his point by tracking how a mutation is handed down through generations, discovering along the way that chromosomes, those squiggly X-shaped things at the center of every cell, are the carriers of inheritance. Morgan established Drosophila melanogaster as the tiny workhorse of biology, a species we understand better than any other; he spawned a generation of great geneticists; and in the end, he showed that Darwin had been more correct about species than anyone had a right to expect.

Noor chose to study Drosophila pseudoobscura and Drosophila persimilis instead of the obsessively studied melanogaster. Some colleagues tried to warn him away from working on what they felt would be dead-end species. But unlike the lab flies, these two species had a natural history. They shared a geographic area and are related closely enough to produce hybrid offspring. That's what he needed.

Under controlled conditions in the lab, a female pseudoobscura from an area where persimilis flies are not found will mate with a persimilis male, even though he sings, dances, and smells funny. Her hybrid offspring will be a mixed success: the males sterile; the females fertile. By contrast, a pseudoobscura female from any area where these kinds of matings might actually occur is not the least bit interested in allowing a persimilis to mate: If she's from an area where her ancestors had the opportunity to accept this kind of pairing, the cues that the persimilis proffers are a powerful deterrent.

This is reinforcement, the concept Noor was testing for. There is a factor—mating selectivity—that keeps the two species moving apart, even though they are still genetically similar enough to produce viable offspring. The selectivity isn't something the pseudoobscura females think about, but it has been incorporated into their behavior genes by the subtle accumulation of reduced odds of reproductive success. Where the two species might have been able to interbreed, countless generations of trial-and-error matings created untold numbers of sterile male hybrids. And those, in turn, have slightly reduced the odds of success for pseudoobscura females who are willing to cross species boundaries. The ones who tried it had fewer offspring in the aggregate than the females who stuck to their kind, and so the entire population, slowly and inexorably, shifted toward pickiness. "Sterility is the ultimate barrier to blending species," Noor says, adding a booming laugh all out of proportion to his slim, wiry body.

This part of Noor's dissertation work was published in Nature, and immediately set him on the fast track. "This is pretty classical work," says Allen Orr, the Shirley Cox Kearns Professor of biology at the University of Rochester, who also received the Darwin-Wallace Medal in February. "Now it pays for them to stop mating with everyone because it produces sterile hybrids," says Orr, who shared both his undergraduate and graduate mentors with Noor. The behavioral barrier between them enables their genes to adapt on separate trajectories, just as if they were on separate islands.

Biology lab photos. Credit: Chris Hildreth.

In addition to conceiving of geologic time, this is perhaps the hardest part of getting one's mind around evolution. There isn't a flash and boom that makes one species into two; it's a subtle, interminable process. "It takes hundreds, thousands, maybe tens of thousands of generations for speciation to happen," says Greg Wray Ph.D. '87, professor of biology and director of the center for evolutionary genomics in the Duke Institute for Genome Sciences & Policy. "So how do you study that?"

So far, a big part of the answer has been fruit flies. They multiply geometrically, producing a new generation every three weeks, and can live by the tens of thousands in a space the size of a suburban walk-in closet. Thanks to Noor and a few others, complete genetic sequences for a dozen different species of flies are now just a mouse click away. Starting with Morgan, biologists have learned how to make genetic mutations at will by exposing flies to toxic gases and radiation, resulting in flies without eyes, flies with legs on their heads, and myriad other perversions. Thousands of dissertations have sacrificed millions of flies. And nobody has ever complained.

In the fly room on the fourth floor of Duke's gleaming new French Family Science Center, a single one-inch-diameter glass tube with a teaspoon of yeasty glop at the bottom can sustain fifty adult flies. The tube is in a carefully labeled rack with fifty more tubes on a shelf with a dozen racks, on a wall with twenty-five shelves. There are something like 50,000 flies over graduate student Audrey Chang's shoulder as she sits down to one of a dozen microscopes to sort flies. Through the doors, a room chilled to 64 degrees holds at least another 50,000 flies that do everything a bit slower, including dying. In a bank of freezers lining a nearby hallway, another 50,000 lie in permanent repose.

Chang, the Noor lab's lead grad student, pulls the stopper from a vial, inverts it over a three-by-five white block, and gives it a sharp rap. The fly that tumbles out is a male D. pseudoobscura bogotana, descendant of a rare subspecies of pseudoobscura from the mountains of Colombia that are still members of the species, despite a separation of 4,000 miles and perhaps 10,000 years. This guy's a lab mutant, with two select chunks of D. persimilis DNA inserted into his genome. Landing upright, he takes a couple of halting steps and then freezes in his tracks, stunned by the pure carbon dioxide wafting up from the stage beneath his feet. Chang scoops the fly up deftly on a small white paintbrush and pops him unharmed into a new vial where a virgin bogotana female with one chunk of D. persimilis genes waits.

The mutant pair will mate, having little else to do in there, producing eggs and larvae in their tube. For her dissertation, Chang, who grew up in Taiwan, is making thousands of these careful crosses to narrow down the genetic factors that make some hybrid males sterile. She is a meticulous, steady-handed, and long-suffering scientist who previously ripped the testicles from 4,500 male fruitflies, smashed them under 4,500 cover slips on 4,500 slides, and then eyeballed each one under a microscope to see whether any sperm were wiggling, a sign of fertility. She saw fruit-fly sperm when she closed her eyes at night. "I realized that I needed a certain sample size, and there wasn't any other way to do it," Chang says. "I really want to know the answer." Twenty days per generation for four years yields more than seventy generations of fruit flies, a number Chang doesn't even want to think about.

It would be easy to get lost in the details and the mechanical tedium required by this search for anomalous needles in the haystack. But the goal looms large: understanding the exact schism that starts a new species. What she's doing is really an outgrowth of Morgan's methodical work but rendered at a much finer scale by today's ability to read individual letters of genetic code.

This is where Noor's energetic pursuit of species formation has led them. Soon after publishing his landmark paper on reinforcement in Nature, he turned his attention to learning the then new-fangled tools of gene sequencing. By mapping specifically where on the fruit fly's four chromosomes various traits seemed to lie, he hoped to find the signature of divergence, the split of species. What he found is so elegant that it's a wonder it wasn't more obvious: Chunks of pseudoobscura's chromosomes are upside-down in relation to their counterparts in persimilis. Noor had looked for the genes that govern fruit-fly sex selection—dancing, scent, and song—and found that all of them lay within these inverted sections of chromosome.

By way of analogy, imagine going to a shelf in a library and pulling out an armload of books, say a dozen or so. Each book represents a single gene. Flip that stack of books 180 degrees and re-shelve them. That's sort of what an inversion looks like. Chromosomes, the bookshelves, are a packaging device for moving bulk amounts of DNA around in a cell and facilitating the orderly shuffling of genes that makes your children a blend not only of you, but of your parents as well.

In the process that forms an egg or sperm, the floppy arms of those X-shaped chromosomes will sometimes cross over each other, break, and swap segments. This is known as recombination. Then, when the cell divides to make two sperm, the X splits at the center, and each arm goes its own way. That new hybrid arm becomes the genetic cargo of a single sperm carrying, say, your mother's eyes and your father's ears. This blending of traits from grandpa and grandma is part of the process by which nature continually shuffles the deck of genetic traits. Conception is another. Over and over, the deck is shuffled, creating endless variations on a theme and making life more robust. Over time, variation can also make new species, further enhancing life's hold. Variety isn't just the spice of life, it's the secret ingredient.

Biology professor Mohamed Noor. Credit: Chris Hildreth

But an inversion, a chunk of the chromosome that comes out completely and is then reinstalled upside down, prevents recombination. The genes within the inversion can no longer be shuffled with the like sequence on the other arm of the X because they're in an unrecognizable order. Consequently, they will travel together through the generations in a block. And while segregated from shuffling with their counterparts, the genes within the inversion will also begin to change, becoming subtly different.

Here was a mechanistic process that could account for two species ratcheting apart, but never back together.

"The moment of the inversion is one step in divergence, but the inversion by itself does not necessarily cause a new species," Noor is quick to add. For one thing, it occurs in only one fly at first; her progeny then have to conquer the population.

"This piece of inversion propagates from one generation to another, either through random events or maybe if it harbors a favorable gene form," Noor explains. "It may be be-bopping around at very low frequency and then get lucky with a favorable mutation." Over many generations, this kind of stepwise change, coupled with the inability to recombine, leads to divergence, the separation of one species into two. "Divergence is not a moment, but a process," Noor says.

In the case of the two western flies, the block of genes that became segregated by inversion happened to carry the genes for mating discrimination. Otherwise, Noor never would have found it.

With some degree of scientific understatement, the Linnean Society calls chromosome inversions that support reinforcement "a likely important first phase in speciation."

"There is a pattern there," Allen Orr says. "He's onto something pretty big."

"Important is always a tricky word," says Noor, who appears baffled to have been included among the Darwin-Wallace Medal recipients. "Does 'important' mean it happened, or does 'important' mean 95 percent of the time this is how it works? We always come back to that with almost every evolutionary question. You can find a single example of just about anything you toss out there. A bigger question will be frequency, which unfortunately is much tougher to get."

But that's what he's going after now, pulled by thousands of tiny beasts of burden.

— Bates is director of research communications in Duke's Office of News & Communications and editor of Duke Research, an online magazine.

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