|
|
RESEARCH INTERESTS
Relating Genotypic and Phenotypic Variation
PUBLICATIONS
RELATING GENOTYPIC AND PHENOTYPIC VARIATION
Genetic variation is ubiquitous in most populations. In humans and other animals, such variation distinguishes individuals and their attendant susceptibility to a broad spectrum of diseases. In plants, genetic variation underlies diverse morphological and life history traits. We seek a comprehensive, molecular-genetic understanding of the causes and consequences of such variation. We work at the interface between molecular biology, population and quantitative genetics, and computational biology.
A HapMap for a Tractable Reference Organism
Arabidopsis thaliana, the reference plant, has become an important model for the study of complex traits. Thousands of diverse wild strains are available, and both gain- and loss-of-function studies can be easily performed in essentially any genetic background. In my postdoctoral research, we both used and extended these exceptional resources. By employing whole-genome, high-density oligonucleotide microarrays, we identified over 1 million single nucleotide polymorphisms (SNPs), as well as over 13,000 regions of extreme polymorphism or deletion, in a global A. thaliana population sample (Clark et al., 2007). This dense polymorphism data has become the basis for establishing a permanent haplotype map (HapMap) resource for the species. Toward this end, 250,000 of the SNPs we identified, or about 1 every 500 bp on average, will be genotyped in 1,000 wild strains (Kim et al., 2007).
Relating Variation to Selection and Adaptive Phenotypes
Our HapMap data is providing tantalizing insights into the distribution of genetic variation across the genome. Non-neutral sequence evolution is strikingly apparent. Positive selection has almost certainly contributed to observed patterns (Clark et al. , 2007), with dynamic forces shaping diversity at specific loci (e.g., Tang et al. , 2007).
Nevertheless, the observed patterns are complex, and understanding this diversity ultimately requires whole-genome resequencing data. Consequently, we have recently initiated ultra-high throughput resequencing of entire A. thaliana genomes. With one method, Illumina/Solexa sequencing by synthesis, we have identified the majority of all sequence variation in 3 strains (manuscript in preparation). Extending this work to population samples will allow us to understand, with unprecedented resolution, the range of forces shaping genetic diversity in this moderately-sized plant genome.
Beyond these broad patterns, we are also keenly interested in the molecular and mechanistic basis of functional polymorphisms. With their sessile life history, plants are ideal for understanding gene-by-environment interactions-a particular interest for the lab. By combining linkage disequilibrium mapping using the HapMap panel with the resequencing data, we aim to characterize the sequences and genes that mediate variation in response to varying environments. Particular interests are responses to temperature and biotic pests, known factors that change with climate. What types of sequence changes underlie variation in environmental responses? What is the relative contribution of regulatory variation? Finally, how does such variation in turn affect patterns of local and regional sequence diversity in the genome? At the mechanistic level, we wish to understand which nodes in regulatory networks can and cannot harbor cis and trans variation.
Extending Methods and Knowledge to Other Species
As we address fundamental questions about the relationships between sequence variation, complex traits, and adaptive evolution, our work generalizes well to other species. A long-term goal is the transfer of detailed methodology and biological insights from A. thaliana to plant or animal species of environmental and economic importance for which extensive genetic and genomic resources are absent.
SELECTED RECENT PUBLICATIONS
Clark, R.M., et al. 2007. Common sequence polymorphisms shaping genetic diversity in Arabidopsis thaliana. Science 317(5836): 338-342.
Kim, S., V. Plagnol, T.T. Hu, C. Toomajian, R.M. Clark, S. Ossowski, J.R. Ecker, D. Weigel, and M. Nordborg. 2007. Recombination and linkage disequilibrium in Arabidopsis thaliana. Nature Genetics 39(9): 1151-1155.
Tang, C., C. Toomajian, S. Sherman-Broyles, V. Plagnol, Y.L. Guo, T.T. Hu, R.M. Clark, J.B. Nasrallah, D. Weigel, and M. Nordborg. 2007. The evolution of selfing in Arabidopsis thaliana. Science 317(5841): 1070-1072.
Clark, R.M., T.N. Wagler, P. Quijada, and J. Doebley. 2006. A distant upstream enhancer at the maize domestication gene tb1 has pleiotropic effects on plant and inflorescent architecture. Nature Genetics 38(5): 594-597.
Clark, R.M., E. Linton, J. Messing, and J. Doebley. 2004. Pattern of diversity in the genomic region near the maize domestication gene tb1. PNAS 101(3):700-707.
| |
|
|
