At the MOHB today, Alaine Keebaugh of Emory University presented work that helps to explain a 20-year old puzzle in mouse and human genetics. In the late 1980s Mario Cappechi and Oliver Smithies disrupted the first gene in mouse embryonic stem cells, a mouse homologue of the human gene, HPRT1. The gene was a useful target because it was on the X chromosome, meaning that they only had to knock out one copy in a male embryonic cell line to completely abolish production of the protein. And they had a way to test that the protein had been eradicated. The knockout mice that resulted from this work transformed genetics and earned Cappechi and Smithies a Nobel Prize. But surprisingly, aside from the verifiable lack of the protein, the mouse was unremarkable, not very different from wild type.