David Kingsley

Research Interests

The skeleton is one of the most highly patterned structures in higher organisms. Although built of only a few tissues, these tissues are molded into beautiful shapes and sizes that illustrate many basic problems in development and vertebrate evolution. The skeleton is also critical to human health, with diseases like osteoarthritis and osteoporosis afflicting a large fraction of the population. To better understand the genetic mechanisms that create, pattern, and repair skeletal tissues, we are using modern genetic approaches to study interesting skeletal traits in humans, mice, and stickleback fish.

We have used high resolution linkage mapping to isolate several classical mouse skeletal mutations. These studies have shown that secreted signaling molecules called bone morphogenetic proteins (BMPs) play a key role in controlling formation of both bones and joints during embryonic development. Each of these genes is expressed in strikingly specific patterns that prefigure the formation of particular bones and joints. We have also developed methods to identify the regulatory elements responsible for patterning the expression of BMPs during vertebrate skeletal development. These studies are revealing how the body creates, shapes, and maintains bones and joints in order to generate a functional skeleton.

We have also used mouse genetics to isolate a completely new gene controlling susceptibility to arthritis after birth. This gene encodes a highly conserved multiple pass transmembrane protein found only in vertebrates. Biochemical experiments show that this molecule acts by stimulating transport of the same small molecule that is used in “tartar control” toothpaste to block unwanted mineral deposition. Mutations in the gene reduce the mineralization inhibitor, leading to ectopic formation of crystals in joints. Similar ectopic mineral deposition is seen in a large fraction of the elderly human population, and may be an important risk factor for human arthritis.

Finally, we are using genetic crosses between recently evolved fish species to study the molecular basis of vertebrate evolution. For this work we have developed a large number of new genetic and genomic resources for threespine sticklebacks, a small teleost fish that has undergone one of the most recent and dramatic evolutionary radiations on earth. Marine sticklebacks colonized countless new streams and lakes at the end of the last Ice Age, and have since evolved dramatic morphological, physiological, and behavioral changes as they adapted to new freshwater environments. Reproductive barriers between the new populations can be overcome using in vitro ferilization, providing a unique opportunity to study the genetic basis of many evolutionary differences. We and collaborators have developed a complete set of genetic and genomic tools for sticklebacks, including genome-wide genetic and physical maps, expression arrays, a reference genome sequence, and efficient methods for transgenic analysis. Using these tools, we have mapped many different traits to particular chromosomes, identified major genes controlling large evolutionary differences, and reversed evolutionary changes using transgenic methods. Using the lessons learned from our initial case studies, we are now re-sequencing many different sticklebacks to identify all the regions that have contributed to repeated evolution of interesting new traits in different populations. Sticklebacks are now recognized as one of the major new model systems for studying the genetic basis of complex traits in natural populations, and one of the only vertebrates where it is possible to determine how many genes are required to evolve a new traits, what kinds of mutations occur in those genes, and whether nature uses similar mechanisms to evolve similar traits in independent locations.