Myotonic dystrophy is a degenerative muscle disorder whose victims can grip but can’t let go. They may also suffer from such bewildering and seemingly disparate symptoms as cataracts, abnormal heartbeat, diabetes, and mental retardation. But what has most puzzled doctors about this inherited condition is that the disease gets worse with each generation: children tend to be more afflicted than their parents; grandchildren suffer even more.
This pattern of escalation has been an utter enigma to physicians. The genetic rules they learned in medical school simply can’t explain a disorder that gets more severe from parent to child. According to these rules children inherit two of every gene, one copy from each parent. More to the point, each of those individual genes (even an abnormal one) should pass from parent to child unchanged, barring the odd spontaneous mutation. But last February, when investigators discovered the gene that causes myotonic dystrophy, they found that it didn’t obey this pattern at all.
A gene, you’ll recall, is made up of a long sequence of chemical bases designated by the letters A, C, G, and T (for adenine, cytosine, guanine, and thymine). Now, in the normal counterpart of the gene that causes myotonic dystrophy, there’s a section that includes several repeats of the combination of letters CTG. But in people with the disease, these copies multiply. It’s as if some internal Xerox machine goes wild when the gene replicates, spewing out at least 50 CTG sequences in the first afflicted generation and as many as 2,000 repeats in their children and grandchildren. The more repeats there are, the longer the gene becomes and the worse the symptoms tend to get. We might call genes like this accordion genes because of their propensity to stretch with each new generation.
Although they received a good deal less attention, two other examples of accordion genes emerged last year as well: one is responsible for a form of retardation called fragile X syndrome; the other inflicts a wasting illness known as Kennedy’s disease. In fragile X the disastrously repeated triplet is CGG. In Kennedy’s it’s CAG. Fired-up geneticists are now looking for more diseases that might be explained by gene expansion, and they are pretty sure they’re going to find them. In short, the phenomenon has given them a whole new way of thinking about genes, inheritance patterns, and human disease.
We have known that genes were the units of inheritance since 1900, when Gregor Mendel’s famous breeding experiments on peas were rediscovered. (The Austrian monk actually worked out the fundamental principles of heredity in the 1860s, but he died before his ideas were accepted.) Mendel was the first to show that inherited traits such as color, size, and shape are controlled by discrete factors (genes), with each individual inheriting two forms of a gene (alleles), one from each parent. Since each parent in turn has two alleles, the offspring has a 50 percent chance of getting any particular allele and a 25 percent chance of getting any particular combination of alleles. And as Mendel’s pea-breeding experiments revealed, these alleles don’t blend or change--they retain their distinct identity from generation to generation.