In the late 1990s, a surprised radiologist in Connecticut came across a real-life version of Bruce Willis’s character in the movie Unbreakable. The patient came to the hospital after a motor vehicle accident. But rather than revealing broken bones, the x-rays revealed an extremely high bone density. (Bone-density testing later confirmed it to be the highest ever recorded.) In 2002, Richard Lifton, a geneticist at Yale who specializes in genetic analysis of human outliers–people with extreme phenotypes–discovered that a mutation in a gene called LDL-related receptor protein 5 was responsible for the man’s high bone density, a condition shared by about half of his family. (While mutations in this gene can sometimes lead to health problems, Lifton says that this family’s only complaint was that they couldn’t float in water because their bones are so dense.)
Lifton’s team went on to study the molecular pathway affected by this mutation–and just seven years later, drugs targeting one of these molecules is in late-stage clinical testing for osteoporosis, a progressive disease of brittle bones that leads to fracture and a substantially increased risk of disability and death among the elderly.
While the unbreakable man’s case is unusual, Lifton’s approach isn’t. Anyone familiar with the history of human genetics knows that many of the field’s most significant early discoveries came from studies of families afflicted with rare diseases. Uncovering the genes involved in those diseases has in turn shed light on more common medical problems, such as high cholesterol, Parkinson’s disease, and autism.
As genetic technologies have improved, so has the scope of these investigations. While researchers once had to undertake painstaking pedigree studies to pinpoint the region of the genome affected in a particular family and then sift through the most likely genetic candidates in that region, rapid advances in DNA sequencing in the past few years have significantly broadened the number of genes that can be searched. Scientists are now beginning to sequence individuals’ entire exome–the gene coding region of the genome–searching for mutations in genes never suspected to play a role in particular diseases. Lifton, whose research has focused in large part on the genetics of hypertension, is now sequencing the exomes of a number of people referred to his clinic with severe early hypertension. Expect to see a growing number of studies along these lines.