UC San Diego

Over the course of millions of years, modifications in mammalian genomes have produced an incredible variety of phenotypes, from the antlers of deer, to the breathing capacity of whales, to the dexterous fingers of a human. This remarkable diversity is perhaps nowhere more evident than in the limb of the mammal, which, despite its underlying structural similarities, exhibits specialized morphologies that look strikingly different in different species. Thus the hands typing this abstract are structurally similar but morphologically and functionally divergent from the fins of a manatee, the wings of a bat, or the legs of a horse. Comparing the genetic and regulatory underpinnings of this divergence (and indeed, of the similarities between species) allows us to simultaneously reconstruct genomic evolution and delve into the developmental mechanisms that produce limbs. The lesser Egyptian jerboa, Jaculus jaculus, is genomically similar to the common laboratory mouse, Mus musculus, but has highly divergent derived characteristics in the hindlimb. The hindlimb of the jerboa features a striking elongation of metatarsals and tibia, the loss of two digits, and the fusing of metatarsals into one central bone. By engineering ‘jerboanized’ mouse models, where regions of the mouse genome are replaced with their jerboa homologues to produce animals with jerboa-esque phenotypes, we can elucidate the mechanisms of divergence and development in the jerboa in a well-established and highly manipulable model system. Here, I present work on two genetic engineering techniques that promise to transform interspecies comparisons in rodent systems. First, I introduce a large interspecies conversion that simultaneously deletes a ~26kb region of the mouse genome and replaces it with ~31kb of homologous sequence from the jerboa. Second, I present the first demonstration of active genetics, a technique that makes use of the CRISPR Cas9 system to convert genotypes, in a rodent model. Active genetics in the rodent may be used to increase the rate of inheritance of an allele, which has profound implications the future of genetic engineering in both laboratory and applied settings. Together these tools may be used to develop complex mouse models of jerboanized phenotypes to probe the specific genomic changes responsible for the evolution of the development of the jerboa morphology.