Host management of the mitochondrial genome the small genome of the mitochondria has an influence out of proportion to its size. It is not just tha its few gene products are extremely important in energy metabolism. The apparent independence of the mitochondrial genome has required a complex administrative arrangement: the nucleus creates developmental programs that ensure the continued contribution of the mitochondrial genome to the host's needs. If the mitochondrial genome had free reign, it would evolve selfishly, enhance its replication to out compete its neighbors, and abandon production of electron transport functions, which do not naturally contribute to the replication or transmission of this genome. Nuclear management largely but not completely contains such unruly behaviors. This proposal explores the poorly understood regulatory interactions underlying the intergenomic relationship. For example, we found that mitochondrial DNA (mtDNA) is eliminated from mitochondria during spermatogenesis. This elimination enforces maternal-only inheritance, an inheritance pattern that limits mitochondrial genomes to a lineage. This limitation caps the evolutionary advantages of selfish behavior: for example, a super replicating genome might succeed within a lineage but it cannot spread to infect the whole breeding population. This proposal will examine the mechanism of this DNA elimination program and test the use of this DNA elimination pathway to control and limit mitochondrial genomes in somatic development. We will also use a bevy of new tools to study how different mitochondrial genomes within an organism compete for transmission, and how the nucleus oversees this competition. A specialized competition among mitochondrial genomes to populate the egg is important to the host. During this process, genomes functional in electron-transport out-replicate less functional genomes. This competition provides the purifying selection that eliminates mutations detrimental to the host. However, competition among mitochondrial genomes during growth and development is not based on function. During this stage, selfish interests dominate, and each mitochondrial genome strives to out-compete its neighbor, selecting for super replicating genomes. We created heteroplasmic lines with two mitochondrial genomes, one with a replicative advantage but functional deficit, and one with a functional edge but a replicative disadvantage. Retention of these two genomes depends on the strength of the selection in oogenesis versus selection during zygotic growth. We will examine the genetic changes in the mitochondrial genome and in the nuclear genome that influence this balance. This will identify the nuclear genes that modify competition to oversee the evolutionary directions taken by the mitochondrial genome, and the sites of their action on the mitochondrial genome. This approach will give us a molecular and genetic foothold on the mysterious processes controlling a central axis of regulation influencing metabolic disease, aging, metabolism and evolution.
The energy that supports our life relies on the mitochondrion, an energy producing organelle derived from an ancient bacterial infection. This study examines how the developmental programs of an organism manipulate the independent genome of this organelle so that it follows an evolutionary trajectory that benefits us. The processes maintaining the mitochondrial genome are relevant to metabolic disease, aging, and fertility.
| Yu, Zhongsheng; O'Farrell, Patrick H; Yakubovich, Nikita et al. (2017) The Mitochondrial DNA Polymerase Promotes Elimination of Paternal Mitochondrial Genomes. Curr Biol 27:1033-1039 |
| Duronio, Robert J; O'Farrell, Patrick H; Sluder, Greenfield et al. (2017) Sophisticated lessons from simple organisms: appreciating the value of curiosity-driven research. Dis Model Mech 10:1381-1389 |
| Ma, Hansong; O'Farrell, Patrick H (2016) Selfish drive can trump function when animal mitochondrial genomes compete. Nat Genet 48:798-802 |
| Ma, Hansong; O'Farrell, Patrick H (2015) Selections that isolate recombinant mitochondrial genomes in animals. Elife 4: |
| Ma, Hansong; Xu, Hong; O'Farrell, Patrick H (2014) Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster. Nat Genet 46:393-7 |
| DeLuca, Steven Z; O'Farrell, Patrick H (2012) Barriers to male transmission of mitochondrial DNA in sperm development. Dev Cell 22:660-8 |
