A radical revision of human genetics

Erika Check Hayden in Nature:

Nature_genomic_resource_400dpiLurking in the genes of the average person are about 54 mutations that look as if they should sicken or even kill their bearer. But they don't. Sonia Vallabh hoped that D178N was one such mutation. In 2010, Vallabh had watched her mother die from a mysterious illness called fatal familial insomnia, in which misfolded prion proteins cluster together and destroy the brain. The following year, Sonia was tested and found that she had a copy of the prion-protein gene, PRNP, with the same genetic glitch — D178N — that had probably caused her mother's illness. It was a veritable death sentence: the average age of onset is 50, and the disease progresses quickly. But it was not a sentence that Vallabh, then 26, was going to accept without a fight. So she and her husband, Eric Minikel, quit their respective careers in law and transportation consulting to become graduate students in biology. They aimed to learn everything they could about fatal familial insomnia and what, if anything, might be done to stop it. One of the most important tasks was to determine whether or not the D178N mutation definitively caused the disease.

Few would have thought to ask such a question in years past, but medical genetics has been going through a bit of soul-searching. The fast pace of genomic research since the start of the twenty-first century has packed the literature with thousands of gene mutations associated with disease and disability. Many such associations are solid, but scores of mutations once suggested to be dangerous or even lethal are turning out to be innocuous. These sheep in wolves' clothing are being unmasked thanks to one of the largest genetics studies ever conducted: the Exome Aggregation Consortium, or ExAC.

More here.