Searching for genes underlying behavior: lessons from circadian rhythms

Abstract

The success of forward genetic (from phenotype to gene) approaches to uncover genes that drive the molecular mechanism of circadian clocks and control circadian behavior has been unprecedented. Links among genes, cells, neural circuits, and circadian behavior have been uncovered in the Drosophila and mammalian systems, demonstrating the feasibility of finding single genes that have major effects on behavior. Why was this approach so successful in the elucidation of circadian rhythms? This article explores the answers to this question and describes how the methods used successfully for identifying the molecular basis of circadian rhythms can be applied to other behaviors such as anxiety, addiction, and learning and memory.

Figure 1

(A) The relationship between the precision of the phenotypic assay (relative standard deviation, RSD, %) and the phenotypic effect size (Z score deviation from wild type) for circadian rhythm, fear conditioning and psychostimulant response mutants. The circadian period measurements (circles, squares) have the lowest RSD compared to fear conditioning (FCR-diamonds) and psychostimulant response (PSY - triangles) mutants as well as other circadian measurements such as activity level and circadian amplitude (purple circles). Circadian point mutants (closed circles) discovered in isogenic forward genetic screens have the highest mutant Z scores and the lowest RSD values. The same mutations in hybrid genetic backgrounds have slightly higher RSDs. Circadian knockout (KO) mutations (open squares, hybrid genetic background) have lower mutant Z scores compared to point mutants isolated in forward genetic screens. See Supplemental Table 1 for detailed information and references on mutants. (B, C, D) Phenotypic distribution of Z scores of wild type (blue shading) and mutant animals (red shading) that differ by 6, 3 or 1 standard deviations, respectively, from the mean of wild type. The graphs illustrate the expected 1:1 distribution of wild type and mutant populations for a backcross assuming a dominant mutation. Solid red line indicates the sum of the wild type and mutant populations.