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Echoes of Ancient Genes
By Lee Siegel
The Salt Lake Tribune
In embryos of humans and other mammals, a gene named Hoxa3 helps control development of the voice box and certain neck and chest glands that fight infection and
produce hormones essential for life.
So when University of Utah geneticists bred mice without Hoxa3 genes, each newborn mouse could not squeak, lacked thymus and parathyroid glands and had an
abnormally small thyroid gland. The newborn mice died within minutes of birth.
Another gene, named Hoxd3, helps form the ball-and-socket joint between the first two vertebrae in people and other mammals. When the geneticists bred mice without Hoxd3
genes, the connection between the head and neck did not form, and the baby mice died from severed spinal cords as soon as their mothers lifted them by the scruffs of their
necks.
In an experiment that sheds new light on how genes evolved, U. genetics professor Mario Capecchi and colleagues then bred mice in which key parts of the two gene were swapped.
Newborn mice without Hoxa3 genes survived and had normal voice boxes and glands if the main components of Hoxd3 genes replaced the missing genes.
And baby mice without Hoxd3 genes were healthy and had normal head-neck connections if Hoxa3 genes were substituted for the absent genes.
"That was a big surprise," Capecchi said. "Normally if you didn't have a Hoxa3 gene you'd be dead. Normally if you didn't have Hoxd3 genes, you would be crippled with
respect to the connection between your head and neck. But these mice are perfectly happy and healthy."
Hoxa3 and Hoxd3 evolved into separate genes 530 million years ago as part of a multiplication of genes that allowed spineless animals to evolve and diversify
into animals with backbones.
Yet Capecchi's new study shows that despite major chemical changes in the two genes that led them to perform different jobs in developing embryos, each gene still retains
the ancient ability to do the other gene's job.
That suggests that during 530 million years of evolution of life on Earth, genes crucial to embryo development haven't changed as much as once thought, Capecchi
said.
Each gene contains orders for production of a protein, and those proteins make up various body parts and perform various tasks in the body. So the study suggests that
while the genes have not changed much, what has changed is the amount of protein a gene makes in one kind of embryonic cell vs. how much it makes in another kind
of cell.
"What differentiates man from mouse isn't different genes, but the control of those genes" by other pieces of DNA in chromosomes, Capecchi explained. "That
is, the genes that are important for making us distinct are the same, but what is important is control of these genes and subtle changes in where and how much proteins
are made by those genes."
"This is an important study," said Ray Gesteland, the U.'s human-genetics chairman. "It radically changes how we think about how the body is formed. The evolution of
complex organisms is all about networks of genes. The complexity of organisms comes from increasing the complexity of the networks instead of changing the genes."
The Utah study was published last month in the journal Nature. Capecchi conducted it with doctoral student Joy Greer, geneticist Kirk Thomas and former U. postdoctoral
fellow John Puetz, now a physician at Washington University in St. Louis.
Denis Duboule, a geneticist at the University of Geneva in Swi tzerland, said the study was "elegant."
ΚΚ Hox3a and Hox3d belong to a group of genes called "hox" or "homeobox" genes. Like a maestro conducting a symphony, hox genes orchestrate many other
genes to make an embryo develop into an animal. Hox genes thus determine why some cells become muscle or skin, while others become nerve, liver or bone.
Until 530 million years ago, Earth was inhabited by spineless creatures that had only 13 hox genes to guide development of their embryos. But as invertebrates evolved
into fish and other animals with backbones, the genetic blueprint in animals quadrupled into four identical sets of genes. So vertebrate animals initially had 52 hox
genes.
The extra genes let them evolve new features lacking in their spineless ancestors, such as teeth and facial bones and muscles. Without the extra genes, higher animals could
not have evolved, Capecchi said.
Some of the 52 hox genes in early vertebrates gradually vanished because they were unnecessary. So humans and all other mammals now have 39 hox genes that guide
embryo development.
One set of quadrupled hox genes evolved from the ancient Hox3 gene. One of the four new genes later disappeared, leaving Hoxa3, Hoxb3 and Hoxd3. Capecchi's study compared Hoxa3 and Hoxd3 to show their similarities and differences after a half-billion years of evolution.
The discovery that the two genes could be swapped and perform each other's jobs in mouse embryos suggests the different jobs all hox genes perform are not strongly
related to how the genes changed during evolution. Instead, the genes play different roles because they make different amounts of protein in different embryo cells.
"This tells us how a small number of [hox] genes can control the vast number of genes involved in making a complex organism," Gesteland said.
Capecchi said: "It says that if you want to make new body forms -- new animals -- through evolution, it's easier to do that by changing where, how much and when certain
proteins are made by genes rather than by changing the genes themselves."
He said an analogy is that "if you want to make a more complicated computer, you don't have to change the transistors and diodes. You change how you connect them together
and how many you use."
Capecchi said one provocative implication relates to the human genome project -- the massive effort to decipher the human genetic blueprint. Some scientists argue it is important
only to decode or "sequence" the key parts of genes that make proteins. But the new study suggests that to truly learn how human genes work, researchers also must
decode so-called "junk DNA" because of its role in controlling the protein-making portions of genes, he said.
He said the study also suggests that if we are to learn why humans are more intelligent than chimpanzees, comparing differences in their genes will not be adequate. Instead,
it will be necessary to learn how genes control formation of nervous-system proteins that influence intelligence.
Originally published March 16, 2000, in The Salt Lake Tribune.
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