Organisms differ in many important anatomical, physiological, and behavioral traits. Despite rapid progress in genome sequencing, we know remarkably little about the detailed genetic mechanisms that produce these differences between naturally occurring species. We have been developing threespine stickleback fish as a new model system for rigorous, unbiased, forward genetic analysis of the molecular basis of vertebrate evolution. Sticklebacks have undergone a remarkable adaptive radiation in different freshwater streams and lakes created since widespread melting of glaciers only 15,000 years ago. Recently derived freshwater populations with dramatic differences in morphology, physiology, and behavior can still be crossed using artificial fertilization in the laboratory. F1 hybrids are viable and fertile, making it possible to use genome-wide linkage mapping to determine the number, location, and type of genetic changes that create evolutionary adaptations in naturally occurring organisms.

     Thousands of papers and several full-length textbooks have been written on the ecology, morphology, paleontology, and adaptive significance of stickleback traits. We have developed a complete set of genetic and genomic resources for this classic system, including the first genome-wide linkage maps, transgenic methods, expressed sequence tag (EST) collections, large-insert BAC (bacterial artificial chromosome) libraries, and physical maps useful for positional cloning (genetic work done in collaboration with Dolph Schluter [University of British Columbia–Vancouver]; molecular work done in collaboration with Jane Grimwood, Jeremy Schmutz, and Richard Myers [Stanford University]; Chris Amemiya [Benaroya Research Institute at Virginia Mason, Seattle]; Pieter de Jong [BACPAC Resources, Oakland, California]; and Marco Marra and Jacqueline Schein [University of British Columbia]). We also nominated threespine sticklebacks for complete genome sequencing to the National Institute of Human Genome Research. We have worked with the Broad Institute and Ensembl on development, assembly, and annotation of the first whole-genome sequence for Gasterosteus aculeatus, which was released in 2006.

     We are using these new tools to identify the number, location, and type of genes and mutations that control differences in body size and color, skeletal armor, feeding modifications, fin development, behavioral characteristics, and physiological traits such as temperature preference and salinity tolerance. Our studies have focused on a number of populations that have been particularly well studied from a morphological and ecological perspective, including fish from lakes near Vancouver (in collaboration with Dolph Schluter); in Alaska (with Michael Bell, New York University–Stony Brook); the Queen Charlotte Islands (with Thomas Reimchen, University of British Columbia–Victoria); Iceland (with Bjarni Jónsson, Institute of Freshwater Fisheries, Iceland); and other populations in California, Washington State, Nova Scotia, and Scotland.

     Our linkage studies have shown that major morphological differences in different stickleback populations can be mapped to particular chromosome regions. Using positional cloning methods, we have recently identified the genes responsible for some of the dramatic morphological changes between populations. For example, loss of the entire pelvic apparatus in some populations is controlled by changes in a master regulatory transcription factor that is normally expressed in hindlimbs but not forelimbs of most vertebrates. Similarly, differences in armor plate patterning and pigmentation patterning are controlled by changes in two different major secreted signaling molecules that normally guide the formation of multiple ectoderm-, mesoderm-, and neural crest–derived tissues. In each of these cases, null mutations of the corresponding genes in mice or humans cause major developmental defects or lethality. However, evolution has been able to use these genes to induce major morphological changes in wild animals, using regulatory changes rather than coding region mutations to confine dramatic differences to particular body regions.

     The widespread evolution of sticklebacks offers a unique opportunity to test whether the same or different genes are used when the same traits evolve in widely separated locations. Genetic mapping, complementation tests, and gene expression studies suggest that similar genetic mechanisms are used when the same traits are selected in multiple populations around the world. How far might such reuse of particular genes extend? Our recent studies suggest that the genes underlying major morphological change in sticklebacks are also reused when similar morphological changes evolve even in distantly related animals, including loss of hindlimbs in marine mammals and recent adaptation of humans to different environments around the world. Further studies of sticklebacks may thus reveal general features of evolutionary change, with broad implications for our understanding of evolution in many other vertebrates, including humans.

Projects:

1) Genes Controlling Formation of Bones and Joints in Mice

2) Skeletal Disease

3) Genetic Control of Vertebrate Evolution