Research

As a graduate student in Katie Peichel's lab (2002-2008), my dissertation research comprised genetic, sequence, and cytogenetic characterizations of the young sex chromosome systems and sex determination mechanisms found in several species of stickleback fish, particularly the threespine stickleback, Gasterosteus aculeatus. My experiences in Katie's lab solidified my interest in continuing to use a comparative method to understand the genetic basis of developmental change.



As a post-doctoral scientist, I chose to move from stickleback fish to a model species, the nematode Caenorhabditis briggsae. This relative of the more famous C. elegans is useful to biologists for a number of reasons. In particular, although it is a globally distributed species like C. elegans, C. briggsae wild isolates exhibit much more genetic and phenotypic diversity. This natural variation makes C. briggsae ideal for the study of evolutionary genetics and development. In addition, C. briggsae shares many of the characteristics that makes C. elegans a model species for genetics:
  • small, sequenced genome (100 Mbp; 6 chromosomes)
  • physically small (~ 1 mm adults)
  • short generation time (~4 days)
  • self-fertile hermaphrodite
  • large brood sizes (200+)
  • males facilitate crosses
  • transgenesis (microinjection; biolistic transformation)
  • gene knockdown (RNAi)
My research has revolved around analyzing the genotypes of a collection of hybrids of two divergent wild strains of C. briggsae. Initially, I used these genotypes to create high-resolution genetic maps and then to reassemble the genome sequence. The same genotype data set was also useful for identifying novel intra-species genetic divergence in C. briggsae.





Genetic Incompatibilities

Background

The genetic breakdown of fitness in hybrids can be simply described as a result of outbreeding depression. Organisms like C. briggsae, which reproduce by self-fertilization, are typically found to be homozygous at all loci. This contrasts with the situation of obligate outbreeders, like humans. We know to avoid inbreeding because of the deleterious consequences of inbreeding depression (making recessive mutations homozygous, thus producing mutant phenotypes). However, C. briggsae individuals are completely inbred, yet fit. Thus, as opposed to the case of humans, it is the offspring from an inter-strain cross (outbred hybrids) that will experience a decrease in fitness. If population-specific alleles of genes optimally interact with each other, then combining the alleles from two populations in a single outbred hybrid individual might elicit organismal dysfunction by breaking up co-adapted complexes of genes. Such a loss of fitness in hybrids is often ascribed to a "genetic incompatibility" between alleles that arose in different populations.

An absolute loss of hybrid fitness (hybrid inviability or infertility) defines biological species: populations that are unable to produce viable or fertile hybrid offspring. Undoubtedly, a continuum of such hybrid dysfunction phenotypes parallels the continuum of genetic divergence that can exist between populations. Fitness effects might range from inviability and infertility to an almost imperceptible loss of fitness in hybrids between populations that have only barely begun to genetically diverge. A key challenge in understanding how speciation is initiated is the empirical identification of naturally occurring inter-population genetic incompatibilities that have a minor effect on hybrid fitness.

Results and Interpretation

We have identified the genetic signatures of inter-population genetic incompatibilities in AF16-HK104 hybrids. In one case, hybrids with the HK104 mitochondrial haplotype are significantly more likely also to have HK104 alleles in one region of one autosome. This correlation of nuclear and mitochondrial genotypes suggests that certain combinations of mitochondrial and nuclear alleles are unfit and selected against.

The rationale for the interdependence of mitochondrial and nuclear genomes is clear: both genomes encode proteins that physically interact to form mitochondrial electron transport complexes. Thus, sequence variation in a mitochondrial gene might demand that a compensatory nuclear mutation exist in order to maintain electron transport efficiency. Indeed, the separation of co-adapted mito-nuclear gene complexes during the formation of hybrids has been suggested to result in mitochondrial dysfunction in a handful of taxa. The fitness effects of such hybrid genetic incompatibilities likely result from decreased ATP production.

Future

These hypotheses suggest a specific experimental approach: establishing genetic crosses to assess the effect of mitochondrial genotype on hybrid fitness. Phenotyping such hybrids for mitochondrial and life history traits should reveal whether genotype influences phenotype, facilitating a mapping approach to identify the specific nuclear and mitochondrial loci involved. Crosses between additional pairs of wild isolates are being undertaken to identify the extent of incompatibilities between strains of the species.

It is rare to discover cases representing the early stages of an evolutionary process, and I am capitalizing on my empirical identification of a hybrid mito-nuclear incompatibility between two wild strains of the same species. My proximal research goal is to use C. briggsae to understand the mechanisms and genetic architecture of incompatibilities arising between two populations. Investigations of mito-nuclear incompatibility in the C. briggsae model system promise to inform us about how nuclear and mitochondrial genomes co-evolve to maintain fitness and how disrupting those co-adapted gene complexes might lead to hybrid dysfunction.

The research goals for the study of intra-species hybrid incompatibilities are to:
  • survey other C. briggsae temperate-tropical strain hybrids for incompatibilities
  • assess the effect of the mito-nuclear incompatibility on organismal fitness
  • identify the nuclear loci involved