One gene mutation, centuries later

Minuscule event, far-reaching consequences. During the time of the Ottoman Empire, one person experienced a single mutation in a certain gene. Centuries later, children descended from that unknown individual still suffer the consequences: a deadly form of degeneration of the brain that is called pontocerebellar hypoplasia (PCH).

The mutation was discovered by Yale genetics, neurosurgery, and neurobiology professor Murat Günel ’94Grd, working with researchers in Turkey and several other countries. PCH is a collection of disorders caused by various genetic mishaps. But this mutation and the surrounding genomic areas were identical in the affected patients, who came from four families with a history of intermarriage. The researchers deduced, from the nature of the mutation, that all of the children share a common ancestor who lived roughly 16 generations ago. The findings appeared in the April 24 issue of Cell.

Specific mutations can tell us a lot about normal function; this one, the researchers learned, leads to a defective form of the enzyme CLP1—an ancient and fundamental enzyme found all over the human body. They also discovered that CLP1 assembles transfer RNA—the molecule that transfers the building blocks of proteins to a cell’s protein factories. The faulty CLP1 can’t do the job, so the cells can’t build the proteins they need; meanwhile, they fill with useless, and toxic, fragments of transfer RNA. Children wind up with shrunken brains and lose motor and cognitive skills. They usually die young.

Exome sequencing, which searches only the 1 percent of the human genome that actually codes for proteins, sped up the discovery. Through a grant from the National Human Genome Research Institute, the Yale Center for Mendelian Genomics is deploying the technique on a massive scale. “The idea is to solve as many Mendelian human disorders as possible,” says Günel.