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.
In humans, on the other hand, disruption of HPRT1 results in a devastating disorder known as Lesch-Nyhan disease which has confers gouty arthritis, atrophy of the testicles, developmental delay – they never learn to walk – and they tend to be somewhat aggressive. But most puzzling is the severe self-injurious behaviours, including biting and chewing off of fingers, lips—pretty much anything they can get their mouths on. They don’t want to hurt themselves and many have to be restrained for much of the time. Some can even warn their caregivers that an uncontrollable urge to harm themselves is coming. If you haven’t read a heart-wrenching story from The New Yorker on the topic, (subscription required) I recommend checking it out.
Keebaugh was looking to develop a better mouse model of the disease, so she searched for other similar genes in vertebrate genomes and came across the similarly tongue twisting PRTFDC1, which appears to be an ancestral duplicate of the gene that is active in humans but appears to have been inactivated in the mouse lineage.
Suspecting that the difference in activation might somehow account for why knockout mice don’t show much of a phenotype, she engineered a transgenic line of mouse to express the human version of PRTFDC1. When she crossed this with HPRT1 knockouts she found that the offspring males, containing both the active PRTFCD1 and the inactive HPRT1 display some behaviours similar to Lesch-Nyham males. They’re more aggressive, and while they don’t have the neuromuscular defects, when given amphetamine (a standard way to study stereotypical behaviour, apparently) she observed them doing something she’d never seen mice do before, standing on their haunches and nibbling away at their fingernails.