Simultaneously studying all the mutations in BBS led to some notable discoveries. Contrary to popular scientific belief, some mutations in BBS not only cause the loss of function of a protein, they actually influence the "good" remaining copies of the protein. In addition, the researchers saw that a subset of commonly occurring versions of some genes (called alleles) can be detrimental to protein function. The common alleles also can interact with strong, rare alleles to determine a trait.
"We speculate that such interactions are probably widespread across genetic disorders," Katsanis said. "Indeed, this might help settle a 100-year-old argument about common versus rare mutations and how they might underlie human genetic disorders. Perhaps not surprisingly, the answer is both, in a context-dependent fashion."
Katsanis is a world expert in ciliopathies such as BBS, in which the primary cilium (protrusion) of cells is abnormal and leads to a host of problems. About one child in 1,000 live births will have a ciliopathy, an incidence that is in the range of Down's syndrome, said Katsanis.
Katsanis said that the complex architecture of BBS probably is not unique to this disorder so the approach used by these researchers could improve understanding of a wide variety of human traits.
The researchers did in vivo tests in fish to learn whether they would develop defects if they had specific mutations and then validated their results with in vitro tests on cells in a lab dish to learn whether the aberrant activity in zebrafish embryos could be explained by defective behavior in mammalian cells.
Importantly, by comparing their data with previous clinical studies, they found their tools to be both highly sensitive and highly accurate, correctly predicting the effect of mutations at 98 percent, with a false-positive rate of less than 10 percent. "These numbers are quite critical, becaus
|Contact: Mary Jane Gore|
Duke University Medical Center