James Lupski participated in the 1986 Molecular Biology of Homo sapiens meeting at Cold Spring Harbor Laboratory, during which the initial discussions arose over whether researchers should sequence the entire human genome. Twenty-two years later, he was part of the team that deciphered the first personal genome sequence, that of the CSHL meeting organizer — and co-discoverer of the structure of DNA — James Watson. And now Lupski is the lead author on the first study ever to use next-generation whole-genome sequencing to identify the cause of a Mendelian disease: his own.
Lupski, a geneticist and pediatrician at Baylor College of Medicine, and his colleagues opted to use a whole-genome sequencing approach — rather than a more directed -method, like exome sequencing — in their examination of the molecular basis of Charcot-Marie-Tooth neuropathy.
"When we're dealing with a discovery situation, what we need to do is capture all variation," he says. "That includes not just single-nucleotide variation — a lot of which the genetic code can help us determine — but also copy-number variation."
Using the SOLiD platform, the team sequenced Lupski's genome to 30-fold coverage for around $50,000; they identified compound, heterozygous, causative alleles in SH3TC2, which they validated by genotyping nine family members.
"For 24 years we've tried to find my cause of CMT disease, and [we] have discovered the first copy number variant in this way," Lupski says. "The remarkable feat here [is] that the sequencing technology is clearly robust enough that, from the 3.5 million single nucleotide variants each one of us has ... one could actually dissect out the signal from the noise and find the alterations that appear to be responsible for the disease."
Lupski's team suggests that, with sequencing costs on a rapid decline, whole-genome sequencing could revolutionize diagnostics and eventually become a cost-effective way to screen for mutant alleles. "We'll be seeing this applied as a research tool more and more, and probably in cases that are clinical conundrums," Lupski says. "Certainly if [whole-genome sequencing costs] get down to about $1,000, which is probably the cost of your average MRI or CT scan."
Lupski says that his training as a pediatrician has, in a sense, distinguished his patient care mentality from that of those trained in internal medicine. "All adults are treated the same way — they even use the same doses for all medications in adults — whereas with children, we base [dosages] on their weight, age, and other things; we individualize," he says. "Well, here you can individualize things right down to having some real knowledge of what your patient could be susceptible to."
Lupski concedes that it will take a lot of work to get to that point — "It's not going to happen overnight," he says — but suggests that a whole-genome sequencing approach could bring researchers closer to realizing the potential of personalized medicine. Though he doesn't think whole-genome sequencing will ever replace traditional diagnostics entirely, Lupski says that traditional and next-gen methodologies could be most effectively used in concert.
He adds that this study, published in the New England Journal of Medicine, represents "the first time that whole-genome sequencing was used to really find the cause of a disease" and that "hopefully, we will see someday [that] we [can] go the other way around; we use whole-genome sequencing to see what you may be susceptible to ... to enable personalized genomic medicine to happen."