Locomotion is an integral component of most animal behaviors: movement is required for localization of food and mates, escape from predators, defense of territory, and response to stress. Many human neurological diseases (e.g., Parkinson's Disease and Huntington's Disease) are associated with locomotor deficits. Locomotion is a complex behavior, with variation in nature attributable to the joint segregation of multiple interacting quantitative trait loci (QTLs), with effects that are sensitive to the environment. Thus, understanding the genetic architecture of locomotor behavior is important from the dual perspectives of evolutionary biology and human health. However, our current knowledge falls short of the level of detail with which we ultimately seek to describe variation in locomotor behavior. We used complementary approaches in the model system Drosophila melanogaster to identify genes affecting locomotion: QTL mapping, followed by linkage disequilbrium mapping and association testing; artificial selection to derive lines for transcriptome analysis using microarrays; and P-element insertional mutagenesis to confirm the microarray results.; QTL mapping uncovered four regions that contribute to variation in locomotor reactivity (a component of locomotor behavior) between two lab stocks. Deficiency complementation mapping refined our large QTL into 12 smaller QTL, then complementation tests to mutations identified 13 positional candidate genes affecting locomotor reactivity, including Dopa decarboxylase (Ddc) and Catecholamines Up (Catsup). Linkage disequilibrium mapping in a natural population of 164 second chromosome substitution lines suggested polymorphisms at Ddc and Catsup were associated with naturally occurring genetic variation in locomotion.; Another strategy to discover genes affecting complex behaviors is to combine artificial selection for divergent phenotypes with whole genome expression profiling. Artificial selection lines created from a genetically heterogeneous background were selected for 25 generations to derive replicate lines with divergent levels of locomotor reactivity. Transcription profiling identified nearly 1,800 probe sets that were differentially expressed between the selection lines. Functional tests of P-element mutations in ten differentially expressed genes confirmed seven novel candidate genes affecting locomotion. Many of the genes identified in this study have other functions in metabolism, nervous system development, and response to different stimuli, suggesting extensive pleiotropy among the genes affecting locomotor behavior.
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