UC Riverside

ABSTRACT OF THE DISSERTATION

The Genetic Architecture of High Voluntary Wheel Running in House Mice

by

Robert Michael Hannon

Doctor of Philosophy, Graduate Program in Genetics, Genomics, and Bioinformatics

University of California, Riverside, December 2010

Dr. Theodore Garland, Jr., Chairperson

The voluntary wheel running phenotype is a complex trait. Its components include motivation and ability, both likely controlled by multi-allelic systems. This dissertation focuses on crosses of mice from lines selectively bred for high voluntary wheel running (HR lines). Cross 1 examined how a gene of major effect (GOME) known as the "mini muscle" (MM) would operate in a genetic background different from HR lines. Cross 2 tested for heterosis in a cross of two HR lines. Cross three investigated dominance and parental effects in a cross between one HR line and one control line. Finally, cross 3 mice were bred to produce F2 and backcross generations to estimate the minimum number of genes that contribute to the HR phenotype.

When one HR line fixed for MM was crossed with inbred strain (C57BL/6J), effects were similar to those seen in the HR and control lines that possess the allele (e.g., homozygotes exhibit ~50% reduction in mass of the triceps surae muscle complex, but enlarged hearts). A 50:50 ratio of normal/MM was observed in the backcross generation, confirming Mendelian recessive inheritance. Cross 2 hybrid males ran more revolutions/day than purebred males, but hybrid females ran intermediate distances compared with purebred females. This result demonstrates differential and sex-specific responses to selection in two HR lines, implying divergent genetic architectures. Cross 3 found dominance for the HR phenotype in both sexes. Positive maternal influences were observed for all wheel measures, wherein F1 mice from HR dams ran more than those from C dams. Estimates of the minimum number of genes that account for the difference between an HR and control line were 10 for females and 11 for males, showing that high voluntary wheel running has a polygenic basis, as expected.

In conclusion, this research supports ideas that the HR trait has a complex genetic architecture, consisting of multiple genes, dominance, maternal effects, and at least one GOME on traits related to wheel running. It also shows that during the artificial selection protocol, changes to the genetic architecture have occurred and that high levels of running can be achieved through different genetic pathways.