Bickering Genes Shape Evolution

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Science  26 Sep 2003:
Vol. 301, Issue 5641, pp. 1837-1839
DOI: 10.1126/science.301.5641.1837

Not all genes follow the rules of inheritance; now researchers are discovering how organisms adapt to the troublemakers

Reproduction is supposed to be an equal opportunity event. Consider humans: In developing sperm, the sex chromosomes sort 50:50 such that half the sperm carry the male-defining Y chromosome and the rest sport an X. Only the randomness of fertilization leads to families of nine girls and no boys, for example. The same supposedly holds true for the rest of the genome.

But in humans, flies, mice, and perhaps many other organisms, guerrilla warfare within the genome sometimes pits one element against another. This often takes on the appearance of a battle between the sexes, but it is really a fight between genes. In this struggle, typically one or more of the X chromosome's genes strike out against the Y's genes. Genes on other chromosomes also can get caught up in this struggle, causing an escalating arms race.

Researchers have caught glimpses of these so-called intragenomic conflicts ever since the 1920s. They dubbed the phenomenon “meiotic drive.” But only in the past decade have they come to appreciate just how devious and pervasive the aggressive genes—called drivers—are, and how dogged the counterattacks can be. This interplay “may markedly affect the evolution of the whole genome,” says Catherine Montchamp-Moreau, an evolutionary biologist at CNRS, the French basic research agency, in Gif-Sur-Yvette. As such, the work is leading evolutionary biologists to see patterns in what once was considered a fluke of nature.

Emblem of excellence.

Female stalk-eyed flies judge males (above) by the length of their stalks, which reveal whether the male carries selfish genes.


Genes usually work together. Their survival depends on their collective ability to make an individual run fast, eat well, reproduce efficiently, and ward off infections. Still, as biologists are increasingly coming to realize, not all versions—called alleles—of each gene are alike. Some appear to look out for themselves. Somehow, they are more adept at passing copies of themselves on, sometimes even crowding other alleles out. It's a game of numbers, and the more prolific the DNA, the greater its evolutionary success.

In recent years, researchers have discovered a few mechanisms by which one gene can thwart a rival. During meiosis, chromosomes copy themselves, line up with their matching partners, and then split up. First the partners head into different halves of the dividing cell; then the duplicates—so-called sister chromatids—separate as that new cell splits in two. In 2000, Montchamp-Moreau and her group unraveled one cellular mechanism behind meiotic drive, a technique that seems to be particularly widespread among insects. They found that certain fruit fly driver genes caused a misstep when Y chromosome chromatids parted ways. “As a result, the corresponding [precursor sperm] did not develop into functional Y-bearing sperm,” she says. But in mice and possibly humans, other researchers have since determined that the action takes place in the egg rather than the sperm.

To counter a selfish driver gene, one or more genes often evolve the ability to gang up against it to keep it from proliferating more than it should. The defensive behavior appears by chance, but if effective, it is selected for through time. In other cases, new research is showing, meiotic drive can spur the evolution of sexual selection or other adaptations to quell selfish genes.

Hidden intrigue

Thomas Hunt Morgan of Columbia University in New York City first observed skewed genetic inheritance patterns in the fruit fly Drosophila melanogaster. Some populations had more females than males, and through breeding experiments he linked this bias to the sex chromosome. In the 1950s, Yuichiro Hiraizumi and James Crow of the University of Wisconsin, Madison, observed biased inheritance wherein certain crosses between white-eyed and red-eyed flies yielded only red-eyed offspring, rather than a mix of the two. Thirty years later, Mary Lyon, a geneticist at the Medical Research Council's Mammalian Genetics Unit in Harwell, U.K., discovered a similar phenomenon wherein a chromosome bearing the “T” version of a group of immune system genes called the T locus was transmitted more often than the “t” version, another example of what Hiraizumi and Crow called segregation distortion. Now researchers know that meiotic drive exists in more than 20 species of flies, two species of mosquito, an arachnid, a lemming, mice, humans, and some plants and fungi.

In the early 1990s, researchers began to uncover just how complex this jockeying during reproduction could be and glimpse its potential consequences. Some who never intended to look at meiotic drive became the most avid researchers. Montchamp-Moreau stumbled across female-biased progeny in Drosophila simulans while looking into how mobile elements, short stretches of DNA that hop from one part of a genome to another, might interfere with mating. At about the same time, Gerald Wilkinson, an evolutionary biologist at the University of Maryland, College Park, discovered something strange about tiny stalk-eyed flies that he and his colleagues had collected in Malaysia. “Some males were producing all daughters,” he explains. And Jeanne and David Zeh, evolutionary biologists at the University of Nevada, Reno, unsuspectingly headed in this direction with Jeanne's work on a pseudoscorpion found in Central and South America. Still others were drawn to mammals that demonstrated unequal inheritance of certain genes and chromosomes.

Montchamp-Moreau and her colleagues were the first to discover meiotic drive in D. simulans. Typically, reproduction in these fruit flies yields about equal numbers of males and females. But her experiments upset the détente that maintained a balanced sex ratio. To look at mobile elements, she had begun to breed flies from isolated populations. Sometimes offspring of males and females from different places had skewed sex ratios.

Driver genes were at fault, she discovered. These genes were normally undetectable because other genes—the suppressors—had evolved ways to keep the driver in check. But in these experiments, the second-generation flies often inherited suppressors from one population and drivers from another. The suppressors were unequipped to neutralize new aggressors— uncloaking meiotic drive.

Suppressors had been found in other species. However, “for the first time, we described a complete suppression of drive, which restored an equal sex ratio in the populations even though the drivers were at high frequency,” says Montchamp-Moreau. The cloaking had fooled her and others into thinking that this species was free of drivers, and so were most others.

The discovery helped explain why drivers persist. Uncontrolled, drivers can be their own worst enemy. Theoretical work indicates that aggressive alleles can cause a population—and the driver it hosts—to go extinct. Each generation would have fewer males, until none would be left to mate with females. A suppressor diverts a driver from its destructive path. Montchamp-Moreau's discovery prompted others to search for this hidden antagonism. And, according to David Hall, an evolutionary biologist at the University of Texas, Austin, “a lot of cryptic drivers are now showing up.”

The evolution of meiotic drive can take different trajectories, Montchamp-Moreau has found. In some D. simulans populations, the drivers seem to be spreading; in others, drivers show signs of becoming ineffective; and in a few, drivers are completely disarmed and are probably breaking down within the genome.

Driving evolution

Laboratory breeding studies also alerted the University of Maryland's Wilkinson to meiotic drive. He became curious about why some male stalk-eyed flies produce only female young. He ruled out infections with Wolbachia, a bacterium that distorts sex ratios in its hosts. More breeding experiments traced the cause of the skewed sex ratio to the X chromosome. Then, in 1998, he and his colleagues discovered a connection between meiotic drive and a male ornament: the eye stalk. But suppressor genes weren't keeping the drivers in check, the team found—sexual selection was.

Males have longer eye stalks than females, and females often prefer males with particularly long stalks. This favoritism allows females to avoid driver genes, which are associated with short stalks, Wilkinson and colleagues found. Stalk length is determined largely by a gene on the X chromosome. That gene is close to the driver gene—so close that the two are inherited as a unit, Wilkinson's postdoctoral fellow Philip Johns reported in June at the Evolution 2003 meeting in Chico, California. The allele for a shorter stalk is hooked up to the allele causing meiotic drive, whereas that for a longer stalk is joined to the nondriving allele.

“Our results surprisingly implicate meiotic drive as a potent evolutionary agent that can catalyze sexual selection,” Wilkinson points out. Before, researchers thought that females evaluate ornamental male traits as a way to tell which males are the healthiest. In this case, general health seems to be secondary. Instead, this preference seems to have evolved in reaction to a selfish gene. Meiotic drive “might have a fairly significant input on behavior,” concludes Laurence Hurst, a genetic evolutionary biologist at the University of Bath, U.K.

In addition to luring more females, stalk-eyed males without the driver genes have a second defense, Wilkinson's graduate student Catherine Fry reported at the Evolution meeting. She mated the same female with males that carried the driver and other males that didn't. When sperm from both are in the female reproductive tract, “less than 10% of the offspring are fathered by the [male with the] driver,” says Wilkinson. Fry's work indicates that seminal fluid from the nondriver male is toxic to the driver male's sperm.

Meiotic drive can affect another behavioral aspect of mating behavior, says Jeanne Zeh. During the 1990s, she and her colleagues began studying paternity patterns in a strange arachnid—a pseudoscorpion—that hitches rides on the abdomens of harlequin beetles. “The results were quite unexpected,” she recalls. Females, which brood their young in translucent sacs carried under their abdomens, mated with an unusually large number of males. In one case, there were four fathers for seven young. Moreover, females that had just one or two mates tended to abort their embryos.

Zeh's group studied the literature and found that spontaneous abortion is common soon after fertilization, particularly in mammals and live-bearing arachnids. She blames incompatibility between the male and female contributions to the offspring's genome, some of which may be caused by driver or suppressor genes. To hedge against losing her embryos, the female has evolved to take sperm from multiple males into her reproductive tract. There the immune system weeds out unsuitable sperm, Zeh speculates.

Turf war.

Pseudoscorpions, here dueling on a harlequin beetle, extend their rivalry to within the female reproductive tract. Multiple matings by females may counteract driver or suppressor genes.


Although studies such as these follow the effects of meiotic drive on the natural history of organisms, geneticists Fernando Pardo-Manuel de Villena of the University of North Carolina, Chapel Hill, and Carmen Sapienza of Temple University in Philadelphia have been homing in on how meiotic drive affects evolution within the genome. Meiotic drive in mammals, they're finding, seems to shape the genome in a different setting and through a different mechanism. Mammalian drivers bias inheritance patterns by exerting their effects in the egg; in insects, sperm bear the brunt of a driver's power.

Pardo-Manuel de Villena, Sapienza, and colleagues have begun to focus on a chromosomal rearrangement called a Robertsonian translocation, common in both humans and mice. In some individuals, two chromosomes merge to form a single long one—causing the total number in humans to drop to 45 from 46. In 1991, Sapienza and Pardo-Manuel de Villena reported that such translocations could foster meiotic drive in females. The Siamese-twin chromosome, with its sole working centromere, somehow gets the jump on the two individual chromosomes during meiosis and is more likely to survive.

The reduced chromosome number thus becomes ever more common: In humans, for example, “a female with 45 chromosomes has more offspring with 45 than with 46,” Pardo-Manuel de Villena points out. Males with this reduced number of chromosomes father equal numbers of offspring with 45 and 46 chromosomes, indicating that the chromosomal competition is being played out in eggs rather than sperm. He thinks that meiotic drive at Robertsonian translocations might explain why humans have two fewer chromosomes than chimps. And it might help explain why in some European mice, as other geneticists have shown, the chromosome number has dropped from 40 chromosomes 5000 years ago to 22 today.

Sometimes the opposite process can also fuel meiotic drive. When a chromosome breaks apart, causing an uneven distribution of centromeres, offspring may be more likely to inherit the newly enlarged set. Here again meiotic drive seems to have influenced speciation. For example, on Madeira Island off Portugal, where mice landed less than 500 years ago, mouse chromosome numbers now range from 22 to 28. When those with 22 breed with mice carrying 28, the offspring are infertile. “This is really evolution working fast,” says Pardo-Manuel de Villena.

Genetic weaponry

Gradually researchers are homing in on the identity of drivers and the strategies that let them proliferate more than other DNA. Pardo-Manuel de Villena's lab is now busy searching for genes involved in meiotic drive in mammals. In one case, “we have mapped the first gene to a region of 200,000 bases,” he says. They must check out the functions of the half-dozen genes in that region to pinpoint the right one. Driver strategies vary from species to species, but usually a malfunctioning protein is involved.

It doesn't take much to mess up chromosomal inheritance, Barry Ganetzky, a geneticist at the University of Wisconsin, Madison, and his colleagues reported in the 14 May 2002 issue of the Proceedings of the National Academy of Sciences. A signaling molecule called ranGAP helps transport molecules into and out of the nucleus. His team had already shown that mutated forms of this protein spell trouble for developing Drosophila sperm. But recently the researchers found that even the normal protein distorts the inheritance of certain chromosomes if it is present in excess. In this case, a driver gene—possibly just a second copy of the fruit fly's ranGAP gene—increases the amount of ranGAP in competitor sperm, which is enough to cause problems.

Prions, too, get caught up in intragenomic conflict, Henk Dalstra of Wageningen University, the Netherlands, and his colleagues reported earlier this year. Spores produced during the sexual phase of reproduction in the filamentous fungus Podospora anserina contain either an allele that prompts prion formation or one that codes for a normal protein. Spores containing the prion-forming allele somehow get rid of spores with the other allele, they reported in the 27 May 2003 issue of the Proceedings of the National Academy of Sciences.

The accumulation of examples of meiotic drive suggests that deep inside every individual—and in more species than researchers realize—there's a lot of conflict going on. “It's like kids at dinner,” Hurst explains. “Underneath that lovely perfection of the 50:50 sex ratio, there's a lot of kicking under the table.”

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