Genetic Mismatches Between Nuclei and Mitochondria Make Yeast Hybrids Sterile

When one species mates with another, the resulting hybrids typically die or fail to reproduce. Hybrids can form between similar species from microorganisms to mammals, with the mule being a classic example. Sterile offspring of horses and donkeys, mules are prized for being more agile than the former, less obstinate than the latter, and smarter than both. But researchers prize hybrids for an additional reason: these reproductive dead ends could help explain how new species begin to form. A critical mechanism on the path to speciation is known as genetic incompatibility, in which genes from diverging species no longer interact properly. These improper interactions prevent these species from producing fertile offspring, leading to reproductive isolation. Understanding the basis of genetic incompatibility is key to identifying the driving forces of speciation. In a new study in this issue of PLoS Biology, Jun-Yi Leu and colleagues address the role of incompatibility between genomes in the nucleus and mitochondria in generating reproductive isolation in yeast. Mitochondria have a limited genome that produces a mere eight of the 1,000some proteins this organelle needs to function, leaving the overwhelming majority to be encoded in the nucleus. Nuclear-mitochondrial genetic incompatibility occurs broadly amongst organisms including plants, insects, amphibians, and primates, yet this intracellular conflict is not well understood at the molecular level. Although Baker’s yeast (Saccharomyces cerevisiae) mates readily with several close relatives, nearly all the gametes (spores) from these hybrids die. The researchers reported in 2008 that hybrids of S. cerevisiae and Saccharomyces bayanus exhibited a nuclear-mitochondrial mismatch (known as cytonuclear incompatibility): an S. bayanus nuclear gene (AEP2) blocked translation of an S. cerevisiae mitochondrial mRNA. In this study, Leu and colleagues set out to determine whether cytonuclear incompatibility is a common cause of reproductive isolation in yeast by investigating hybrids of S. cerevisiae (Sc) crossed with either S. bayanus (Sb) or Saccharomyces paradoxus (Sp). One parent in each cross was a mutant that effectively lacks mitochondria, thus allowing the researchers to track which species contributed these organelles to the hybrids. Mitochondria are key players in respiration, the process whereby cells produce energy, and growth assays revealed that most of the hybrid spores were respiration-deficient, indicating cytonuclear incompatibility. The worst cytonuclear mismatch was between Sc nuclei and Sb mitochondria, where about two-thirds of the spores failed to respire. Next, the researchers identified the genes causing this mismatch by screening for those that rescued respiration in the hybrid spores. In Sc nucleus-Sb mitochondria hybrids, respiration was restored by two Sb nuclear genes required for mitochondrial function, showing that the corresponding Sc nuclear genes were incompatible with Sb mitochondria. The genes were AIM22, which encodes a ligase required for mitochondrial protein lipoy-