Writing today (Oct. 11, 2007) in the journal Nature, Howard Hughes Medical Institute investigator Sean B. Carroll and former UW-Madison graduate student Chris Todd Hittinger document how, over many generations, a single yeast gene divides in two and parses its responsibilities to be a more efficient denizen of its environment. The work illustrates, at the most basic level, the driving force of evolution.

"This is how new capabilities arise and new functions evolve," says Carroll, one of the world's leading evolutionary biologists. "This is what goes on in butterflies and elephants and humans. It is evolution in action."

The work is important because it provides the most fundamental view of how organisms change to better adapt to their environments. It documents the workings of natural selection, the critical idea first posited by Charles Darwin where organisms accumulate random variations, and changes that enhance survival are "selected" by being genetically transmitted to future generations.

The new study replayed a set of genetic changes that occurred in a yeast 100 million or so years ago when a critical gene was duplicated and then divided its nutrient processing responsibilities to better utilize the sugars it depends on for food.

"One source of newness is gene duplication," says Carroll. "When you have two copies of a gene, useful mutations can arise that allow one or both genes to explore new functions while preserving the old function. This phenomenon is going on all the time in every living thing. Many of us are walking around with duplicate genes we're not aware of. They come and go."

In short, says Carroll, two genes can be better than one because redundancy promotes a division of labor. Genes may do more than one thing, and duplication adds a new genetic resource that can share the workload or add new functions. For example, in humans the ability to see color requires different molecular receptors to discriminate between red and green, but both arose from the same vision gene.

The difficulty, he says, in seeing the steps of evolution is that in nature genetic change typically occurs at a snail's pace, with very small increments of change among the chemical base pairs that make up genes accumulating over thousands to millions of years.

To measure such small change requires a model organism like simple brewer's yeast that produces a lot of offspring in a relatively short period of time. Yeast, Carroll argues, are perfect because their reproductive qualities enable study of genetic change at the deepest level and greatest resolution because researchers can produce and quickly count a large number of organisms. The same work in fruit flies, one of biology's most powerful models, would require "a football stadium full of flies" and years of additional work, Carroll explains.

"The process of becoming better occurs in very small steps. When compounded over time, these very small changes make one group of organisms successful and they out-compete others," according to Carroll.

The new study involved swapping out different regions of the yeast genome to assess their effects on the performance of the twin genes, as well as engineering in the gene from another species of yeast that had retained only a single copy.

"We retraced the steps of evolution," the Wisconsin biologist explains.

The work shows in great detail how the ancestral gene gained efficiency through duplication and division of labor.

"They became optimally connected in that job. They're working in cahoots, but together they are better at the job the ancestral gene held," Carroll says. "Natural selection has taken one gene with two functions and sculpted an assembly line with two specialized genes."

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Next, Lengner stressed the tissue in several ways, forcing the adult stem cells within to regenerate the tissue. All regenerated normally. Lengner and his fellow researchers then tested to confirm that Oct4 had indeed been deleted from these cells. Finally, the researchers set out to validate the previously published reports claiming Oct4 was expressed in these adult stem cell types. Using highly sensitive assays that could detect Oct4 at the single cell level, they were unable to confirm the earlier reports.

This is a cautionary tale of believing what you read in the literature, says Lengner, who suggests that earlier studies may have misapplied tricky analytical techniques or worked with cell cultures that had spent too much time in an incubator.

We now know that adult stem cells regulate their pluripotency, or stemness', using different mechanisms from embryonic stem cells, and we're studying these mechanisms, he says. Is there a common pathway that governs stemness in different adult stem cells, or does each stem cell have its own pathway" We don't yet know.

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