When Lupski was first diagnosed with Charcot-Marie-Tooth as an adolescent in New York in the 1960s, the tools of human genetics were still rudimentary, and no disease genes had yet been identified. Physicians relied on particular symptoms and patterns of family inheritance to diagnose genetic disorders. In Lupski’s case, three of his seven siblings developed muscular symptoms similar to his own, suggesting that they were suffering from a recessive genetic disease. The affected siblings had apparently inherited two mutant copies of an unknown gene, one from their mother and one from their father.
In 1983, while studying for both a medical degree and a PhD at New York University, Lupski picked up a copy of the journal Nature in which geneticists reported for the first time that they had identified the approximate location of a gene responsible for a human disease, in this case the neurological disorder Huntington’s disease. (It would take another decade to find the gene within the target region.) Lupski decided that he could follow the example of the Huntington’s researchers, who had studied large families in which the disease was prevalent, to search for the genetic cause of his own disorder. That decision, which he now laughs off as naïve, would trigger a decades-long quest.
The strategy that Lupski and other gene hunters used in the 1980s was to build large family trees of relatives afflicted with a disorder. The scientists would then screen family members’ DNA for genetic markers–specific sequences, found at spots on the genome known to vary from person to person–present only in those with the disease. If all the affected family members carried a particular marker and none of the unaffected family members did, the researchers hypothesized that the disease-causing variation was somewhere near that marker. Scientists needed to study large families in order to rule out markers that were inherited in this pattern by chance; the more subjects in a sample, the easier it is to distinguish a relevant signal from genetic noise. Large families were especially important in studying diseases like Charcot-Marie-Tooth, which has such variable symptoms that individual cases can be misdiagnosed. Once they had identified a likely marker, scientists would laboriously sift through the DNA in that area of the genome, looking for candidate genes and mutations in them.
Lupski’s efforts paid off in 1991, when he and his coworkers discovered the first genetic variation linked to Charcot-Marie-Tooth. A gene on chromosome 17, at a spot involved in producing the fatty insulation that covers nerve fibers, turned out to be duplicated in some people with the disorder. It was the first time a disease had been linked to a variation in the structure of DNA, rather than to a change in a single letter or some other simple alteration in sequence. (These mutations, now known as copy-number variations, have since been implicated in a wide array of diseases, including schizophrenia and autism.)
Over the next 17 years, Lupski’s lab would identify a number of other genetic variations tied to the disease. Yet Lupski never found any of the newly discovered mutations in his own DNA. Then in 2008 came Gibbs’s offer–an opportunity to examine every gene simultaneously. After Lupski and his team sifted through the roughly 90 gigabases of raw data generated by sequencing his genome, they identified approximately three million spots where his DNA differed from the reference sequence created by the Human Genome Project. They homed in on those variations found only in genes previously linked to Charcot-Marie-Tooth or other nerve disorders.
Finally, they found two mutations in a gene called SH3TC2, one inherited from each parent. With that anomaly in sight, the researchers defrosted a set of DNA samples that Lupski had collected 25 years earlier and sequenced the gene in his siblings, his parents, and his late grandparents. He and all of his affected siblings turned out to carry both mutations, while the