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Natural Science

Study supports 'balancing selection' as an explanation for genetic variation within a species

Why is it that we can find so many genetic variations within a single species?

One theory in this longstanding debate among evolutionary biologists is that most of this genetic variation is 'junk,' caused by mutations that are of no value or could actually harm a species, and tend to be eliminated over the long term because they make it less likely for individuals with those mutations to reproduce. Much of the variation we see, in other words, is simply the result of mutations occurring faster than they can be eliminated from a population.

Another theory is that at least some of this genetic variation is maintained because it is beneficial. For example, a novel trait resulting from a mutation may help one subset of a population survive better in one type of environment, while other members of the same species that lack the trait thrive better in other environments. This and other mechanisms that can maintain variation go under the general term of balancing selection.

A new study by James Fry, Associate Professor of Biology, and Mahul Chakraborty, now a postdoctoral fellow at the University of California at Irvine, offers strong support for the balancing selection theory by examining how different strains of Drosophila melanogaster handle alcohol. The study appeared in the Jan. 25 issue of Current Biology.

"This model fruit fly species, used widely in the study of genetics, also lives outside of the lab," Fry said. "If you go to the orchards around Rochester in late August or September when the fruit is on the ground, you can find clouds of them breeding."

Previous studies have shown that some strains of D. melanogaster in the wild can feed and reproduce on fruit with high levels of ethanol — as much as five or six percent — which would kill other strains.

Acting on an educated hunch, Fry and Chakraborty decided to examine to what extent this differing ability to tolerate alcohol involves aldehyde dehydrogenase, an enzyme known to help detoxify ethanol in both flies and humans by converting a toxic ethanol byproduct called acetaldehyde into acetate, which is less toxic.

Fry and Chakraborty used DNA sequencing on D. melanogaster strains from around the world and found that different strains have different forms of the enzyme. Moreover, for this study, they pinpointed how variation in a single amino acid — among the 500 or so amino acids that constitute the enzyme's protein chain — helps determine to what extent a strain of fruit flies can, or cannot, tolerate high levels of ethanol.

The mutation in this "alcohol tolerance" gene, Fry noted, has been around for "thousands of generations of fruit flies, perhaps for 10,000 or 20,000 generations. That would be incompatible with the idea that it is a recent mutation on its way to being eliminated."

The mutation clearly gives certain strains of fruit flies a competitive edge over other strains in environments with high levels of dietary alcohol. But it places those strains at a disadvantage in environments where alcohol levels are lower. Why? The mutation reduces the ability of aldehyde dehydrogenase to carry out its other important function, namely eliminating toxic byproducts of oxidative damage that are produced in the fly's own cells. In low alcohol environments, this gives other strains the edge.

"Basically what we found is a classic hypothesized tradeoff in fitness between environments, which is the central assumption for any theory for maintenance of genetic variation by environmental differences," Fry said. "It doesn't prove the difference is maintained by balancing selection, but everything points to that as the explanation for this variant being there."

The study's "elegant findings provide concrete, elusive evidence supporting a foundational and controversial theory about the maintenance of genetic variation," write Andrew D. Gloss and Noah K. Whiteman, evolutionary biologists at the University of Arizona, in their discussion of the paper.

While studies of entire genomes now suggest balancing selection might be widespread, they note, few studies have identified variations in specific genes to support the theory, as Fry and Chakraborty do in this study.

"Leveraging modern genetic tools, including insertion of alternative alleles of this enzyme into the genomes of isogenic flies, coupled with enzymology and laboratory fitness studies, their study sets a new bar in the field."

Balancing selection may be at work in human populations as well, Fry said.

For example, classic studies in the 1950s showed that the trait responsible for sickle cell anemia also confers partial resistance to a virulent form of malaria in Africa. As a result, carriers and actual victims of sickle cell anemia "are much more common than you would expect based on the mutation rate alone," Fry said.

"Maybe that's the tip of the iceberg; maybe there are quite a few human traits that are affected by genes that have variation maintained by balancing selection. Possibly some traits that seem bad actually are there because, at least in the past, they conferred some advantage under certain circumstances, as opposed to being deleterious mutations that haven't been eliminated yet."

Click here to read the study by Fry and Chakraborty, entitled "Evidence that Environmental Heterogeneity Maintains a Detoxifying Enzyme Polymorphism in Drosophila melanogaster."