Evolution of gene regulation

Using experimental and computational approaches and C. elegans and other nematodes as primary model systems we are addressing the following questions:

1) What are the "rules" governing cis-regulatory evolution? How distant can two species be for their orthologous cis-elements still to retain similar functions? (Drosophila and C. elegans appear to be too distant − Ruvinsky and Ruvkun, 2003) How much sequence conservation is required for functional conservation? We are exploring these questions using a number of orthologous cis-elements from various nematode species.

2) Are indistinguishable patterns of orthologous gene expression between closely related species caused by conservation of cis-regulatory elements? Our results suggest that the situation may be more complicated. Specifically, we identified a case in which a conserved gene, unc-47, is expressed in indistinguishable patterns in C. elegans and a close relative C. briggsae, yet the orthologous cis-elements are functionally distinct. What mechanisms mediate conserved patterns of expression given divergent promoter functions? Taking advantage of the detailed knowledge of C. elegans development, we identified a transcription factor that mediates the functional difference between C. elegans and C. briggsae. We are currently identifying specific molecular changes responsible for the divergent functions of cis-elements and transcription factors regulating expression of this gene. We are testing a hypothesis that compensatory changes in cis- and trans-regulators have contributed to the conservation of the expression pattern, despite divergence in the underlying regulatory architecture.

Evolution of nested gene arrangements

A substantial fraction of genes in complex eukaryotic genomes is contained within introns of protein-coding genes. In C. elegans only ~2.5% of protein-coding genes are so nested, whereas nearly 50% of non-protein-coding RNA genes found in introns. We are investigating how these gene arrangements have arisen and are continuing to evolve. In addition, we developed a rules-and-Bayesian classifier that allows accurate predictions of previously undetected snoRNAs based on the properties of their host genes (Wang and Ruvinsky, 2010). We suggest that similar approaches can be developed for computational discovery of other classes of rapidly evolving genes which are therefore recalcitrant to discovery via conventional homology-based methods.

Heterozygosity in whole-genome shotgun assemblies

In collaboration with Eric Haag's group, we demonstrated that substantial fractions of genes in the genome assemblies of C. remanei, C. brenneri, and C. japonica are represented by two alleles (Barrière et al., 2009). This finding has significant implications for comparative genome analysis. For example, we showed that in these three genomes most pairs of closely related sequences (these could be interpreted as recently arisen paralogs) are in fact alleles. This suggests that gene complements are quite similar between all five currently sequenced Caenorhabditis species and offers an improved annotation of the whole-genome assemblies.