Discovery overturns long-held genetic belief

January 3, 2002

A classic belief found in genetics and evolution textbooks since the 1930s has been overturned by powerful new techniques combined with the willingness to question dogma.

Researchers from the University of Chicago report in the January 4, 2002, issue of Science that, contrary to expectations, the tiny fourth chromosome of the fruit fly, believed to be identical in every member of the species, actually has several regions that vary.

"This classic conviction of genetics and evolution, this rock-bottom-solid conclusion, which has become a textbook example of natural selection's propensity to eliminate variation from closely linked genes, just doesn't hold up," said Manyuan Long, PhD, assistant professor of ecology and evolution at the University of Chicago and director of the study.

Since 1906, Drosophila melanogaster, the common fruit fly, has been at the center of genetic research. The proof that genes exist on chromosomes like beads on a string, that they are linked together, that they can be mapped, even the method of naming genes, comes from early research on fruit flies.

The synthesis of Darwin's theories about evolution and Mendel's discoveries about genetics was made using fruit flies. And the discovery of recombination, in which paired chromosomes can exchange genes as they form egg or sperm cells and thus increase genetic diversity, derived from early work on the four chromosomes of the fruit fly.

Despite the fly's century in the laboratory limelight, its tiny fourth chromosome--which contains only one percent of the insect's coding DNA--has been comparatively neglected. Based on limited evidence available at the time, the pioneers, including Calvin Bridges and Nobel Prize winner Hermann Muller, determined that there were no genetic crossovers--meaning no exchange of hereditary information--on this tiny chromosome.

This belief helped to inspire elaborate theories about the consequences of a nonrecombinant chromosome, introducing the concepts of "selective sweeps" and "genetic hitchhiking." If a mutated gene on Chromosome 4 conferred a sufficient survival advantage, the experts posited, the entire advantageous chromosome, rather than the single gene, would sweep through a population, carrying along the founder's version of every gene on that chromosome, thus eliminating all variation.

In 1991, as a graduate student in Martin Kreitman's laboratory at the University of Chicago, one of the authors of the current Science paper tested the theory. Andrew Berry (now a researcher at Harvard's Museum of Comparative Zoology) sequenced the cubitus interruptus gene, on Chromosome 4, from 10 natural lines of Drosophila melanogaster. All ten were identical.

Long's research team, including postdoctoral fellow Wen Wang, PhD, and genetics graduate student Kevin Thornton, became suspicious, however, when Wang identified sphinx, a new gene with several variations. Sphinx was on Chromosome 4. So they analyzed the sphinx gene from Drosophila melanogaster populations from all over the world.

They found high levels of variation within this gene and in other scattered sites on Chromosome 4. The level of variation was similar to genes in regions on other chromosomes with normal levels of recombination. They also found recombination at at least six sites on the chromosome.

After looking at multiple sites from many populations, Long and colleagues determined that Chromosome 4 could be divided into three discrete domains: a proximal region (near the centromere, and including the cubitus interruptus gene) with no variation, the central region around sphinx (nearly 20 percent of the chromosome) with normal levels of variation, and a region farther out with low variation.

"This indicates that the fourth chromosome is not evolving as a single unit," note the authors; "different regions appear to have different evolutionary histories."

Another surprise was an unusual distribution pattern for the highly variable region. The researchers found two very different versions of this region. The ratio between the two versions was consistent for fly populations from all over the world: evidence that fruit flies "must embrace diversity, even on Chromosome 4, to survive," said Long.

"This should lay to rest the 70-year-old notion that the fourth chromosome is non-recombining," added Long. "We have long thought of Chromosome 4 as the 'black hole' of genetics because we thought no variation could escape the relentless purging effect of natural selection on a non-recombining chromosome, but when we peered long enough and hard enough into this void it began to emit light."

The research was supported by grants from the National Science Foundation and by a Packard Fellowship awarded to Long.

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