AN OLD genetic trick could allow biologists to explore what Leland Hartwell
says is emerging as an important evolutionary property of organisms—the
ability to accumulate a huge amount of genetic variation.
Natural populations, including humans, contain lots of genetic variation.
This includes obvious differences, such as height, as well as hidden ones. The
ability of human cells to repair DNA damage, for example, varies as much as a
hundredfold between individuals. What’s remarkable, says Hartwell, a geneticist
at the Fred Hutchinson Cancer Research Center in Seattle, is that such
tremendous variation isn’t harmful.
Hartwell and Stanislas Leibler of Princeton University think that cells
contain “biological circuits” of molecules that buffer the potentially harmful
effects of genetic variation. When one part of a circuit changes by mutation,
another part can balance the effect—a property that Leibler dubbed
robustness. “It permits the accumulation of variation by limiting its impact on
expression,” says Hartwell.
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He proposes a way to find these robust circuits by turning a familiar genetic
phenomenon on its head. Certain pairs of genes are innocuous when one mutates,
but when both mutate they kill the cell. Geneticists frequently use such
combinations when hunting for proteins that interact with each other. They begin
with a mutation in one gene and hunt for mutations in another that will kill a
cell.
Hartwell realised that these lethal combinations are a form of robustness. If
mutations in gene A don’t become apparent until gene B is mutated, and vice
versa, each is buffering defects in the other. His lab recently found an example
while looking for lethal genes that compensate for deletion of a yeast gene
MEC1. This gene encodes a protein that helps to halt chromosome replication when
DNA is damaged. The deletion isn’t deadly by itself.
Most of the genes they found were involved in synthesising nucleotides, the
building blocks of DNA. Hartwell believes these genes might form a circuit that
balances the availability of nucleotides when DNA replication is interrupted. A
cell that tries to replicate in the absence of nucleotides—because they
aren’t being created fast enough—is certain to die.