Genetics of complex traits, Genome biology, Drosophila quantitative genetics.
Complex phenotypes are influenced by a number of genetic loci and environmental factors. Examples of complex traits include susceptibility to a variety of human diseases, such as heart disease and many forms of mental illness, as well as numerous ecologically- and evolutionarily-relevant traits. Even though complex traits are tremendously important with regard to human health and organismal diversity, they have proven difficult to molecularly characterize. Indeed, we have only limited information on a broad range of key questions:
- What types of loci contribute to variation in complex traits? Are they generally structural (protein-coding) or regulatory in nature?
- How many loci contribute to genetic variation in complex traits? What are the effects of these causative sites?
- Do causative loci interact epistatically with each other?
- Do variants show different phenotypic effects in different environments (genotype-by-environment interaction)?
Only by identifying the precise DNA variants that contribute to variation in complex traits can we begin to answer these questions. Such understanding is vital both for human health (Can we assess whether a patient carries alleles at certain genes that may predispose them to develop disease? Is it possible to predict which individuals may have adverse reactions to drug regimes?) and evolutionary biology (How is genetic variation in complex traits maintained in the face of selection which should erode this variation?).
In our lab we use the elite model genetic organism Drosophila melanogaster to answer fundamental questions about the molecular genetics of complex traits. Drosophila is an excellent model system because, (1) complete genome sequences are available for D. melanogaster and several closely-related species, (2) sophisticated genetic tools are available for Drosophila, and (3) flies can be easily/rapidly cultured in the laboratory, allowing us to carry out powerful experiments on a massive scale. We also implement empirical high-throughput technologies to allow us to collect vast genetic polymorphism (SNP - Single Nucleotide Polymorphism) datasets, and use computationally intensive analytical approaches to examine the relationship between phenotype and genotype.
Current projects in the lab include association mapping of Drosophila bristle number (a model quantitative trait), developing novel methodologies for genetic mapping, and QTL (Quantitative Trait Locus) mapping of morphological traits distinguishing Drosophila species.
- Macdonald SJ, Long AD. Joint estimates of quantitative trait locus effect and frequency using synthetic recombinant populations of Drosophila melanogaster. Genetics 2007; 176(2):1261–81.
- Macdonald SJ, Long AD. Fine scale structural variants distinguish the genomes of Drosophila melanogaster and D. pseudoobscura. Genome Biol. 2006; 7(7):R67.
- Macdonald SJ, Pastinen T, Genissel A, Cornforth TW, Long AD. A low-cost open-source SNP genotyping platform for association mapping applications. Genome Biol. 2005; 6(12):R105.
- Macdonald SJ, Pastinen T, Long AD. The effect of polymorphisms in the Enhancer of split gene complex on bristle number variation in a large wild-caught cohort of Drosophila melanogaster. Genetics 2005; 171(4):1741–56.
- Macdonald SJ, Long AD. Prospects for identifying functional variation across the genome. Proc. Natl. Acad. Sci. USA 2005; 102(Suppl):6614–21.
- Macdonald SJ, Long AD. Identifying signatures of selection at the Enhancer of split neurogenic gene complex in Drosophila. Mol. Biol. Evol. 2005; 22(3):607–19.
- Macdonald SJ, Long AD. A potential regulatory polymorphism upstream of hairy is not associated with bristle number variation in wild-caught Drosophila. Genetics 2004; 167(4):2127–31.
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