Scientists are proposing new method of researching genetic disease, which was discussed at the recent American Society of Human Genetics annual meeting. The method is similar to the “gene knockout” model, in which a target gene is inactivated to study its function, except that instead of mice the subjects will be humans.
The procedure, which science writer Ewen Callaway described in Nature, does not involve actively knocking out genes in humans. Using enormous databases, researchers can look for mutations that inactivate a gene. Everyone carries some such mutations, though they are rare in particular genes. The large sample size of the databases will increase the likelihood of finding multiple cases of the same mutations.
Not all knockout mutations are deleterious. Some are harmless, or even beneficial. The method is especially useful for identifying harmful mutations that might contribute to a certain disease. Already, a new kind of drug has been developed based on human knockout research on a gene called PCSK9, which was found to be linked with high cholesterol. People with natural knockout mutations that block PCSK9 have been found to possess low cholesterol. The drugs work by mimicking the knockout gene to block the activity of PCSK9.
Studying knockout mutations in human databases has enormous potential to improve diagnosis and treatment of a host of diseases. It can also reveal how our genes change function as we age. Bioinformatician Mark Gerstein of Yale University explains in Nature: “You could imagine there’s a gene that is beneficial to you as a 25-year-old, but the thing is not doing a good job for you when you’re 75.”
