The Congenic Footprint

Backcrossing knockout alleles into inbred mouse strains is common procedure, but unintended consequences can occur. Leonard C. Schalkwyk of the Institute of Psychiatry at Kings College London and collaborators at the University of Tartu in Estonia backcrossed cholecystokynin 2 knockouts with C57BL/6 mice and demonstrated a "congenic footprint," a remaining fragment of the flanking stem cell-derived chromosome that causes differences in gene expression.¹

"What you have here is shot across the bow," says Stephen Schwartz, professor of pathology at the University of Washington and a member of Faculty of 1000. "Even in knockout studies you have to pay attention to the content, because you're going to be transferring a hunk of genome along with whatever you've targeted. You have to be aware you're not just cutting and pasting a tiny part of the genome.

"In two mouse strains you have two different phenotypes. This [paper] says in addition to thinking about genes signaling some difference, you have to think about what else you're transferring into a local genome."

As a result, phenotypes could be mistaken for a direct result of target-gene manipulation. Schwartz notes, "Since most knockouts as disease models are crossed into reporter strains, this paper needs to always be considered as a caution in interpretation of phenotypes attributed to either knockouts or knockins."

These papers were selected from multiple disciplines from the Faculty of 1000, a web-based literature awareness tool (www.f1000biology.com).