First complete look at families’ genes

Genome sequences of parents and children pinpoint disease-causing mutations

Gene sequencing has become a family affair. Two independent teams of researchers have found DNA changes underlying rare diseases by comparing the complete genetic material of parents and one or more of their children.

The studies, appearing online March 10 in the New England Journal of Medicine and March 11 in Science, highlight how powerful family sequencing techniques can be for understanding genetic diseases, comments geneticist Stacey Gabriel of the Broad Institute, a joint research center of MIT and Harvard University. “It’s great to see rare disease genes being identified by sequence-based approaches,” she says. In these early days of using gene sequencing as a discovery tool, “family-based studies are a really interesting place to start.”

Reading all of the 3 billion base pairs in the human genome and identifying the differences between people is daunting. Sequencing techniques can misread some of the base pairs, calling a particular base an A instead of a G, for example. Such reading errors occur roughly 1,000 times more frequently than the expected mutation rate, says Science study coauthor David Galas of the Institute for Systems Biology in Seattle.

“The chance that you’re identifying something [as a mutation] that is actually an error is pretty high,” Galas says. “The major advantage of sequencing in a family is you can reduce the error rate dramatically.”

Galas and his colleagues sequenced the complete genomes of a family including two parents, a son and a daughter. By comparing DNA sequences in the parents to those of their children, the researchers narrowed down the pool of base pairs that could be mutations to those that differed between generations. Resequencing those differing regions eliminated about 70 percent of reading errors, they report.

The team estimates that the spontaneous mutation rate from parent to child is a little slower than previous, indirect estimates suggested, Galas says. The newly determined rate might be different in other families and could be influenced by other variables such as the parents’ age when they conceived and environmental factors, he says.

The two children sequenced in the Science study both had rare genetic diseases — Miller syndrome, characterized by craniofacial abnormalities, and primary ciliary dyskinesia, which affects the respiratory tract. By comparing the parents’ genomes to the children’s, researchers were able to pinpoint two likely gene culprits. Knowing exactly which genes trigger a disease could help researchers tailor treatments, for example by prescribing drugs that work on the relevant disease pathway or providing genetic counseling to families.

Galas says that family sequencing techniques can be applied to other diseases, too. “I think this will be a powerful way of getting at those questions,” he says.

The NEJM study focused on a different inherited disease — Charcot-Marie-Tooth neuropathy. The lead author of the study, James Lupski, has the disease, which is characterized by improperly functioning nerves and progressive muscle atrophy. Lupski, a clinical geneticist at Baylor College of Medicine in Houston, had his genome fully sequenced — a “quite exciting” event, he says. He and his colleagues then compared select regions of his DNA to sequences in his parents and seven siblings, three of whom also have Charcot-Marie-Tooth disease.

This targeted approach pinpointed two mutations in a gene called SH3TC2 that caused Lupski’s form of the disease. “We’ve worked on studying this disease close to 25 years,” he says. “We’ve never been able to identify the cause of my specific disease in my family. We now know the exact thing going on.”

Laura Sanders is the neuroscience writer. She holds a Ph.D. in molecular biology from the University of Southern California.

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