Projects
Evo-devo studies in the 1990s demonstrated a remarkable commonality in the developmental regulatory genes of diverse animals. The resolution of this “Hox Paradox” most likely involves evolutionary changes in interactions between developmental regulatory genes and their downstream targets. We are currently investigating the evolution of developmental gene networks, focusing on changes in transcriptional regulation.
Some of our ongoing projects are listed below. References can be found on the publications page.
Evolution of transcriptional regulation and gene networks in sea urchins
During embryonic development, a fertilized egg containing a few simple spatial cues is transformed into an intricately patterned, functioning organism consisting of thousands of differentiated cells. This remarkable process is accomplished through the operation of a complex gene regulatory network that activates specific sets of genes in different cells, endowing them with distinct functional properties. This gene regulatory network is particularly well understood in the purple sea urchin (Strongylocentrotus purpuratus), where just a few direct regulatory linkages connect maternal gene expression with fully differentiated cells in the larva. A subnet of this gene regulatory network that produces the larval skeleton is shown below.
We are interested in understanding the evolution of this gene network, both within populations and among species. Our evolutionary analyses cover several levels of biological organization: the genomic regions that encode network connections, the biochemistry of protein:DNA interactions, the molecular biology of transcriptional regulation, and the anatomical consequences of network function. We use a combination of computational, genetic, and experimental approaches to understand the consequences of genetic variation on network function, as well as the evolutionary mechanisms that operate on this variation.
Evolution of the Endo16 cis-regulatory system
The cis-regulatory region of Endo16 is one of the most thoroughly characterized of all eukaryotic transcriptional regulatory systems, making it an ideal subject for a detailed evolutionary analysis. We are currently studying this ~2 kb regulatory region across multiple evolutionary time scales: within populations, between closely related species, and between more distantly related ones. Our approach involves comparisons of complete cis-regulatory haplotypes, transcription profiles, protein-DNA interactions, and expression assays of natural and artificial promoter sequences.
We are using these analyses to ask a variety of questions about the evolutionary mechanisms that shape regulatory sequences. We have found that different levels and modes of natural selection operate on the seven functional modules of this cis-regulatory region. Surprisingly, genetic variation is elevated within transcription factor binding sites, perhaps due to balancing selection. We are also interested in identifying the genetic basis for evolutionary changes in the transcription profile of Endo16 among species and for the conservation of transcription profile among other species despite large differences in the promoter sequence.
The genetic basis for human evolution
Thirty years ago, Allan Wilson and Mary-Claire King proposed that the genetic basis for the traits that distinguish humans from the other great apes are due in large part to regulatory mutations, rather than changes in protein sequences. With the recent release of the chimpanzee genome and the explosion of genomic information about humans, it is possible to test this hypothesis explicitly. We have begun to identify some of the specific mutations that are responsible for uniquely human traits in cognition, anatomy, and physiology.
We are analyzing the evolution of the cis-regulatory sequences of several genes that are functionally associated with uniquely humans traits. One of these genes, PDYN, serves as an example. This locus encodes dynorphin, a peptide with functions in memory, perception of pain, and emotional affect. We found that mutations within the cis-regulatory regions of this gene experienced positive selection during human origins, while the coding sequence of dynorphin has remained constant throughout the great apes. Using cell culture assays, we found that the positively-selected mutations result in higher levels of PDYN transcription specifically in neuronal cells. Our analyses of genetic variation within PDYN cis-regulatory regions of modern humans indicate that balancing selection has maintained functional variants at different frequencies among populations, suggesting that natural selection on gene expression is ongoing at this locus. These results suggest that regulatory mutations in PDYN contributed to the evolution of human cognition.
The evolution of gene expression in a wild baboon population
Despite widespread interest in primate evolution, very little information exists about the genetics of wild primate populations, nor about the phenotypic consequences of genetic variation. We are collaborating with Drs Susan Alberts (Duke) and Jeanne Altmann (Princeton) to characterize genetic, functional, and phenotypic variation in gene expression in a well-studied population of wild savannah baboons (Papio cynocephalus) from the Amboseli Basin of Kenya. Although this species is genetically farther from humans than are the great apes, it is more similar ecologically, making it an excellent model for understanding the evolutionary genetics of early hominids.
We are currently analyzing levels of genetic variation at a number of genes with roles in behavior, immune function, and reproductive biology. The few hundred Amboseli baboons harbor more genetic variation than the entire human race, a result consistent with the hypothesis that humans went through a major bottleneck and then expanded explosively. Comparisons of 1) functional variation in transcription and 2) genetic variation in cis-regulatory sequences for the same locus in humans and baboons are allowing us to contrast the evolutionary mechanisms that operate on the same locus in different species. These analyses provide a unique window into the population and evolutionary genetics of cis-regulatory sequences in a wild primate population.
Genetic and functional variation in gene expression in wild yeast
Baker's yeast (Saccharomyces cerevisiae) provides an outstanding opportunity to study the evolution of gene networks and gene expression: its genome is the most thoroughly understood of any eukaryote in terms of both structure and function, and the genomes of several related species have been characterized. We are interested in understanding the evolution of gene expression in natural populations of yeast, using approaches that capitalize on this wealth of knowledge.
We have isolated several dozen strains of S. cerevisiae from a variety of habitats on three continents and are in the process of characterizing genetic and functional variation in gene expression. Of particular interest are ecologically relevant genes that might play a role in adaptation, including genes involved in carbohydrate metabolism.
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