Big Genes Are Back

One more genomewide linkage map, this for a fish called the three-spined stickleback, was announced late last year to not much fanfare.1 But rather than just another stride in the march of genomics, the accomplishment heralded a new way to approach a question that has stumped evolutionary biologists for decades: What is the architecture of genetic change? The model organisms for which linkage maps have been created are often bred in the laboratory to express certain phenotypes, and they can reve

By | March 18, 2002

One more genomewide linkage map, this for a fish called the three-spined stickleback, was announced late last year to not much fanfare.1 But rather than just another stride in the march of genomics, the accomplishment heralded a new way to approach a question that has stumped evolutionary biologists for decades: What is the architecture of genetic change? The model organisms for which linkage maps have been created are often bred in the laboratory to express certain phenotypes, and they can reveal only so much about the structures that give rise to phenotypic diversity. What has been lacking is a system for studying the genetics of adaptation in the wild.

"The whole notion of the stickleback work was to get out of the mode or trap of betting on a candidate gene, and then doing a lot of work to see if you're right," notes the team's leader, Stanford University developmental biologist David M. Kingsley. Instead, he devised a top-down method that starts with the organism and the genome. This approach facilitates investigation into a central question of genetic architecture: do genes of large phenotypic effect exist, or does evolution proceed solely via micromutation, cumulative changes to multiple genes of small effect?

The question goes back to Charles Darwin, who favored continual accrual of small variations. But after him, early geneticists held that adaptation involves macromutations. Then, in the second half of the 20th century, the Modern Synthesis of Darwinism and genetics pushed the pendulum back to micromutations. However, a recent accumulation of both experimental and genetic evidence has returned major genes to the limelight, indicating that they do play a role in adaptation, although their frequency remains undetermined. The stickleback work supports this thinking.

The pugnacious little teleost has a remarkable natural history. After the end of the last ice age a mere 15,000 years ago, sticklebacks rapidly radiated into coastal streams and lakes around the world. The species differ dramatically in behavior, body size, shape, color, and skeletal and fin development. They don't crossbreed in the wild, but here's the catch: They can still be productively mated in the lab, and the offspring are fertile. The morphological differences between the parents quickly intermingle in successive generations. Add a linkage map, and what you have is a speeded-up version of evolutionary development that can be genetically traced.

For example, it turns out that the length of the first and second dorsal spines of the fish are controlled by regions on two different chromosomes. This suggests that, like the lab mouse that Kingsley studied for years, development of the stickleback's skeletal structure is modular. Although he and colleagues now must do larger crosses to narrow the location of genes contributing to morphological change, they already know that a greater than tenfold increase in the size of the first dorsal spine is probably influenced by a major gene. "There isn't going to be a single answer to the way traits evolve, but I think the genetics of some traits are going to be simple enough to drag all the way down to the molecular level," Kingsley says.

An important point is that the stickleback's ecology has been well studied. That often isn't the case with model organisms, whose ways of adapting to the natural environment can be overlooked in favor of genetic experimentation and analysis. Model animals generally are chosen for ease of handling, breeding, and manipulating various characters, rather than for their natural history or traits that influence evolution. Indeed, a longstanding criticism of the Modern Synthesis is that it has focused on micromutations at the expense of adequately considering the role of ecological pressures.

"Model organism research asks fundamental questions about how the animal works," comments David N. Reznick, a biology professor at University of California, Riverside. "It isn't done with regard to how the animal functions in nature."

Reznick works with Trinidadian guppies, which have been studied on the island for decades. When the guppies are moved between high-predation or low-predation habitats, successive generations rapidly change morphology. Reznick is working on ways to fund the expensive accumulation of genetic markers necessary to compile a linkage map. "What you really want to know is if the genes you identify are the same as those the people in the lab identify," he comments. The cost to fitness could make large gene effects less likely in natural conditions than in the lab, he adds.

Loss of Footing

A salamander called the Mexican axolotl exemplifies the genetic differences that can arise between laboratory and natural populations. Unlike some salamanders, the axolotl does not develop feet to move out of its water habitat. This evolutionary dead end, called paedomorphosis, has made the axolotl a favorite of developmental biologists since its introduction to the laboratory in the 1800s. For decades, a major gene was thought to be responsible. In 1997, Colorado State University evolutionary geneticist S. Randal Voss crossed axolotls with another salamander species that does develop feet. He then looked for a region of genetic change called a quantitative trait locus (QTL) that could be linked to paedomorphosis. His findings supported the major gene hypothesis. But three years later, Voss repeated the experiment, this time with wild-caught rather than laboratory-bred salamanders. Voss found no major gene locus,2 a result confirmed recently when one of his students crossbred hundreds of wild salamanders.

"What this suggests to me is that the major gene effect was probably generated in captivity," Voss explains. "In cases of domestication, quite often these major genes are selected for." But Voss hasn't lost faith in the major gene effect. "We should see a spectrum of genetic architectures underlying traits," he believes. In the salamander, he's pursuing that spectrum by creating a high-density linkage map, funded by about $2 million (US) from the National Institutes of Health and the National Science Foundation.

Despite the false start with the axolotl, in recent years genes have been shown to exert large phenotypic effects within some species, and when species are crossed. Examples within species include the bill size of the Arabian finch, the floral symmetry of toadflax, and resistance to Bacillus thuringiensis (Bt) insecticide of the tobacco budworm. Artificial crosses between species have demonstrated major gene effects in tomato size and in the morphology of the monkeyflower. In February, evidence was revealed that mutations to a homeotic or Hox regulatory gene is a major contributor to differences in leg development between crustaceans and six-legged insects, helping to explain an evolutionary leap from water to land about 400 million years ago.3

Such findings, which emphasize comparisons within and between species in their embryonic development, constitute a relatively new combination of developmental biology and evolutionary studies. Evolutionary developmental biology, or evo-devo, was only officially sanctioned by the Society for Integrative and Comparative Biology in 1999, although it had been functioning as a field of research for about a decade. One of its central hypotheses is that modular alterations in discrete genomic regions of embryos are what spark adaptive change.4

Large Genes and Complexity

"I don't think the answer is in yet as to how modular organisms are, but I think it's an important question," says evolutionary geneticist H. Allen Orr of Rochester University, an experimentalist with fruit flies and a leading theorist of the large gene-small gene problem. He explains that the more complex an organism is, the less likely fixation of a major gene becomes, because functions elsewhere in the organism are likely to be affected. Modularity makes the organism less effectively complex.

Until recently, Orr's theoretical work focused on a geometric model of adaptation proposed in 1930 by statistician Sir Ronald Fisher, in which populations attempt to evolve to a phenotypic optimum via a step-wise substitution of favorable mutations. Fisher's conclusion, which influenced the field for decades, was that genes of major effect don't play a role in evolution. Orr claims that Fisher got the math right but the interpretation wrong. Using Fisher's model, he determined that phenotypic effects are distributed among genes in an almost exponential fashion, extending in proportion from many factors of small effect to few of major effect.5 "Are there rules that characterize how genes approach a phenotypic optimum? The nice thing is, there do appear to be rules," Orr summarizes. He's taking the theory to its next logical phase, abandoning Fisher's model in favor of constructing population models based explicitly on DNA sequences.

Orr warns that the meaning of the term "major gene" can be ambiguous. Although QTLs, the primary measurements used, can gauge either genetic gaps between species or variations within species, Orr charges that the field overemphasizes the more glamorous species gap in seeking major genes. He labels this "silly," because when two species differ dramatically in a trait, the major gene might account for, say, 20% or 30% of that phenotypic gap. On the other hand, it might have a huge effect on variation within the species, which is the "bigness" that natural selection recognizes. Accordingly, Orr applauds the study of intraspecific morphs, "to calibrate what you see between species by what you see within species."

Barry Sinervo, an ecology and evolutionary biology professor at University of California, Santa Cruz, has discovered fascinating differences among three male morphs of the side-blotched lizard. He recognized that the morphs—distinguished by a genetic-based coloration on their throats that appears with maturity—employ different mating strategies that he likened to the children's game of rock-paper-scissors.6 In the game, rock smashes scissors, scissors cut paper, and paper covers rock. Among the lizards, the highly aggressive orange-throated male ("rock") increases at the expense of the less aggressive blue-throat ("scissors"). This makes more orange females available to the furtively mating, nonterritorial yellow-throated male ("paper"), eventually causing an orange decline due to cuckoldry. Meanwhile, the smaller territory of the blues makes it easier for them to defend against yellow incursions. As orange declines, blue increases, causing yellow to decrease. The circle closes when increased blue frequency allows orange to regain dominance.

A major endocrine locus related to gonadal steroid metabolism in the lizards drives these effects, Sinervo's work has shown. A dramatic illustration of this is the change in throat color some yellow males undergo when the orange decline begins, after the first clutch of the season is laid. These yellows develop a blue patch on their throats and begin to take territory, behaving like blues. Sinervo explains that these individuals are heterozygous for throat color, and thus capable of this plasticity through natural selection in the presence of the other morphs.

Such studies raise a question concerning the fossil record, which suggests bursts of speciation interspersed with long periods of relative stasis, the phenomenon of punctuated equilibrium. If major genes can cause rapid phenotypic change, could they be instrumental in these speciation bursts? Sinervo thinks that large and small genes are part of a broad continuum that includes speciation processes. "Microevolution tells you just about everything you need to know about macroevolution," he declares. "The problem is the time scale."

Steve Bunk ( is a contributing editor.

1. C.L. Peichel et al., "The genetic architecture of divergence between threespine stickleback species," Nature, 414:901-5, Dec. 20, 2001.

2. S.R. Voss, H.B. Shaffer, "Evolutionary genetics of metamorphic failure using wild-caught vs. laboratory axolotls (Ambystoma mexicanum)," Molecular Ecology, 9:1401-7, 2000.

3. M. Ronshaugen et al., "Hox protein mutation and macroevolution of the insect body plan," Nature, advance online publication Feb. 6, 2002.

4. S.F. Gilbert et al., "Resynthesizing evolutionary and developmental biology," Developmental Biology, 177:616-9, 1996.

5. H.A. Orr, "The population genetics of adaptation: the distribution of factors fixed during adaptive evolution," Evolution, 52:935-49, 1998.

6. B. Sinervo, C. Lively, "The rock-paper-scissors game and the evolution of alternative male strategies," Nature, 380:240-3, 1996.

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