Von Baer watched embryos develop, compared one species to another, and saw fundamental patterns in bodies. Mangold and Spemann physically distorted embryos to learn how their tissues build bodies. In the DNA age, we can ask questions about our own genetic makeup. How do our genes control the development of our tissues and our bodies? If you ever thought that flies are unimportant, consider this: mutations in flies gave us important clues to the major body plan genes active in human embryos. We put this kind of thinking to use in the discovery of genes that build fingers and toes. Now we'll see how it tells us about the ways entire bodies are built.
Flies have a body plan. They have a front and a back, a top and a bottom, and so on. Their antennae, wings, and other appendages pop out of the body in the right place. Except when they don't. Some mutant flies have limbs growing out of their heads. Others have duplicate wings and extra body segments. These are among the fly mutants that tell us why our vertebrae change shape from the head end to the anal end of the body.
People have been studying abnormal flies for over a hundred years. Mutants with one particular kind of abnormality got special attention. These flies had organs in the wrong places—a leg where an antenna should have been; an extra set of wings—or were missing body segments. Something was messing with their fundamental body plan. Ultimately, these mutants arise from some sort of error in the DNA. Remember that genes are stretches of DNA that lie on the chromosome. Using a variety of techniques that allow us to visualize the chromosome, we can identify the patch of the chromosome responsible for the mutant effect. Essentially, we breed mutants to make a whole population where every individual has the genetic error. Then, using a variety of molecular markers, we compare the genes of individuals with the mutation to those without. This allows us to pinpoint the region and the likely stretch of chromosome responsible for the mutant effect. It turns out that a fly has eight genes that make such mutants. These genes lie next to one another on one of the long DNA strands of the fly. The genes that affect the head segments lie next to those that affect the segments in the middle of the fly, the part of the body that contains the wings. These bits of DNA, in turn, lie adjacent to the ones that control the development of the rear part of the fly. There is a wonderful order to the way the genes are organized: their position along the DNA strand parallels the structure of the body from front to back.
Now the challenge was to identify the structure of the DNA actually responsible for the mutation. Mike Levine and Bill McGinnis, in Walter Gehring's lab in Switzerland, and Matt Scott, in Tom Kauffman's lab in Indiana, noticed that in the middle of each gene was a short DNA sequence that was virtually identical in each species they looked at. This little sequence is called a homeobox. The eight genes that contain the homeobox are called Hox genes. When the scientists fished around for this gene sequence in other species, they found something so uniform that it came as a true surprise: versions of the Hox genes appear in every animal with a body.
Hox genes in flies and people. The head-to-tail organization of the body is under the control of different Hox genes. Flies have one set of eight hox genes, each represented as a little box in the diagram. Humans have four sets of these genes. In flies and people, the activity of a gene matches its position on the DNA: genes active in the head lie at one end, those in the tail at another, with genes affecting the middle of the body lying in between.
Versions of the same genes sculpt the front-to-back organization of the bodies of creatures as different as flies and mice. Mess with the Hox genes and you mess with the body plan in predictable ways. If you make a fly that lacks a gene active in a middle segment, the midsection of the fly is missing or altered. Make a mouse that lacks one of the genes that specifies thoracic segments, and you transform parts of the back.
Hox genes also establish the proportions of our bodies—the sizes of the different regions of our head, chest, and lower back. They are involved in the development of individual organs, limbs, genitalia, and guts. Changes in them bring about changes in the ways our bodies are put together.
Different kinds of creatures have different numbers of Hox genes. Flies and other insects have eight, mice and other mammals thirty-nine. The thirty-nine Hox genes in mice are all versions of the ones that are found in flies. This similarity has led to the idea that the large number of mammalian Hox genes arose from a duplication of the smaller complement of genes in the fly. Despite these differences in number, the mouse genes are active from front to back in a very precise order just as the fly genes are.
Can we go even deeper in our family tree, finding similar stretches of DNA involved in making even more fundamental parts of our bodies? The answer, surprisingly, is yes. And it links us to animals even simpler than flies.
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