unaffected family members carried either one or none.
The variant of Charcot-Marie-Tooth disease that Lupski suffers from is a Mendelian disorder, meaning that it is caused by mutations in a single gene. (Many other diseases–typically more common ones, such as diabetes and heart disease–are triggered by a combination of complex genetic and environmental factors.) Some Mendelian diseases, known as dominant disorders, affect people who inherit just one copy of the mutant gene. For so-called recessive diseases, such as Lupski’s, it takes two defective copies to do the damage. This concept has dominated the study of human genetics for decades. But as more people have their genomes sequenced, and researchers and physicians begin to look more closely at the genes linked to specific disorders, it’s becoming clear that Mendelian genetics isn’t black and white. Genetic variations once thought to follow Mendelian rules may in fact behave in a more subtle and complicated way.
A catalogue of genetic mistakes: James Lupski has spent the last 25 years searching for the genetic basis of a number of inherited disorders. The bookshelves of his Baylor office are filled with data on different mutations.
For instance, analysis has revealed that Lupski carries two copies of mutations in each of four genes linked to other Mendelian disorders. According to traditional thinking, he should suffer from all four. But he does not. The findings may turn out to be an error in sequencing, but more likely, they suggest that these mutations don’t work the way researchers have assumed. Now the researchers are being forced to conclude that mutations in genes linked to Mendelian diseases don’t always guarantee those disorders.
It’s also turning out that carriers of recessive diseases–those who have inherited a single copy of the disease-linked mutation–may not be wholly unscathed, as Mendelian theory says they should be. Previous studies have shown that people with a single copy of the defective gene that causes cystic fibrosis are more likely than people with two copies of the normal gene to suffer from chronic sinusitis and pancreatitis. The DNA from Lupski’s family fits a similar pattern.
Twenty years ago, when he was collecting the family DNA samples, Lupski had his relatives undergo a common test for neurological disease in which physicians attach electrodes to the upper arm and measure the speed of an electrical signal sent down to the wrist. Thanks to his new genetic insights, Lupski now realizes that this test revealed nerve impairment in siblings who did not have Charcot-Marie-Tooth but had inherited a single defective gene from their mother. This type of dysfunction is linked to carpal tunnel syndrome, a common disorder often caused by repetitive hand movements. The findings hint that a single mutant copy of this gene makes people more susceptible.
If the variant is indeed linked to carpal tunnel syndrome, it probably explains only a tiny percentage of cases; the genetic defect involved in the Lupskis’ disease is rare. But the finding illustrates how studies of rare genetic diseases may also shed light on more common ones. Perhaps a number of different mutations, each one rare on its own, can all give rise to the set of relatively common symptoms that characterize carpal tunnel syndrome.
This notion falls in line with a shift in thinking among geneticists. Until recently, the role of genes in common diseases like Alzheimer’s and type 2 diabetes was thought to be very different from the one they play in Mendelian diseases. The predominant theory was that these disorders were triggered by a number of common genetic variations, each individually exerting a relatively minor effect. Over the last five years, scientists have used microarray chips designed to quickly and cheaply detect a million or more of the most common genetic variations in hundreds of thousands of people with a variety of diseases.
But the effort has failed to identify most of the genetic basis for many diseases. So scientists are increasingly concluding that the common-variant hypothesis is wrong, and that rare variants play an important role in common diseases. If so, the best way for scientists to understand the genetics of common diseases will be to take the same approach they are now using to study rare