November 15, 2005
Development Genes Evolve New Functions
For an animal to acquire a new form during evolution, the proteins
that control its physical development sometimes take on new or altered
functions through changes to the genes that encode them. But these
proteins often carry out many essential roles that must be preserved
for the animal to survive, and the function of most developmental
proteins has been conserved throughout evolution. Now HHMI researchers
have shown how those proteins can evolve new functions while retaining
their old ones—enabling new animal forms to arise.
HHMI investigator Sean Carroll and HHMI predoctoral fellow Chris
Todd Hittinger report their findings in the December 1, 2005, issue of
the journal Development, published early online in November.
Hittinger is first author on the paper. Carroll, his mentor at the
University of Wisconsin-Madison, is the senior author.
“The most interesting questions remaining for evolutionary geneticists are whether certain evolutionary paths are favored and what conditions cause them to be favored.”
Chris Hittinger
Findings from the growing field of evolutionary developmental
biology, sometimes called “evo-devo,” have been surprising
because the genetic sequences controlling development are not as
diverse as expected, given the diversity of the organisms themselves.
In fact, the ability to conserve function is almost frightening in its
precision, Carroll observed. Previous studies have shown that
Hox genes swapped between species with seemingly little in
common are able to maintain their function. Having long focused on the
surprising genetic similarities between organisms, scientists such as
Hittinger and Carroll are now tackling the underlying mechanisms that
cause the differences.
Among the most highly conserved of the developmental genes are the
Hox genes—a large family of genes best known for their
role in controlling the pattern of body development. Like many
developmental regulators, the proteins produced by Hox genes
control the activity of a diverse assortment of target genes. Due to
their broad range of cellular responsibilities, even subtle changes to
these proteins' functions may be detrimental to the organism, limiting
the opportunity for evolution. Indeed, the function of Hox
proteins—which are found in all higher animals—has remained
virtually unchanged through time.
Nevertheless, there are rare examples of Hox proteins that have
adopted new functions through evolution. To better understand what it
takes for these highly conserved genes to evolve, the researchers
analyzed a specific segment within a Hox protein known as Ultrabithorax
(Ubx). In insects, Ubx prevents the development of limbs along the
abdomen—but the same protein in other organisms lacks this
function.
Fossil records show that insects' forebears had many legs, much like
a centipede. Over time, however, insects lost their abdominal legs,
retaining only the six located on the thorax. In modern insects, the
repression of abdominal legs is partially attributed to a specific
segment of the Ubx protein that scientists refer to as QA.
Using the fruit fly (Drosophila melanogaster), Hittinger,
Carroll, and co-author David Stern at Princeton University deleted the
portion of the Ubx gene that encodes QA—effectively
reversing evolution by deleting this developmentally important protein
sequence. “By physically altering the genome and removing a small
part of Ubx implicated in limb repression, we've created the first
insects in 300 million years that don't have this piece of
protein,” said Hittinger.
Simply deleting QA did not cause the flies to grow abdominal legs.
However, when the scientists further manipulated the flies' genes to
reduce the expression of both the QA-deleted version of Ubx and another
Hox protein, rudimentary abdominal limbs did form. This demonstrated
that QA is no longer strictly required for leg repression in modern
insects but is one of many regions of Ubx and the other Hox proteins
now involved in leg repression.
The study showed that subtle changes in some of the proteins
produced by the genes that regulate development, such as Hox, enable
other proteins to evolve new functions.
“Hox proteins are central to the evolution of animal form, and
this work offers us insights into how small changes in these proteins
are used to fine-tune their activities in different kinds of
animals,” said Carroll. His research has shown that the evolution
of body parts more commonly occurs through changes in how development
genes are regulated than through the evolution of new genes.
Deleting or “knocking out” a gene is more
straightforward and such mutants have long been known for Ubx, but
researchers are taking the next step to understanding evolutionary
pathways. “It's much easier to knock out a gene, but here we
actually remove and study the part of the gene that is insect-specific
and arose during evolution,” Hittinger said.
The redundancy found in the protein sequences that contribute to leg
repression makes evolutionary sense, he added. “Backup systems
may prevent catastrophic developmental failures from occurring when the
embryo is stressed,” Hittinger explained. In fact, redundancy may
provide development with a robustness that matters more in the wild,
where conditions vary more than they do in laboratory-controlled
conditions.
“The most interesting questions remaining for evolutionary
geneticists are whether certain evolutionary paths are favored and what
conditions cause them to be favored,” said Hittinger. He noted
that their work shows that many small peptide sequences exist whose
functions are poorly understood.
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Cindy Fox Aisen
