Top-down approaches to the study of natural variation in complex physiological pathways using the white-footed mouse...

Variation in complex physiological pathways has important effects on human function and medical treatment. Complex pathways involve cells at multiple locations, which serve different functions regulated by many genes and include complex neuroendocrine pathways that regulate physiological function. One of two competing hypotheses regarding the effects of selection on complex pathways predicts that variability should be common within complex pathways. If this hypothesis is correct, then we should expect wide variation in neuroendocrine function to be typical within natural populations. To test this hypothesis, a complex neuroendocrine pathway that regulates photoperiod-dependent changes in fertility in a natural population of white-footed mice (Peromyscus leucopus) was used to test for natural genetic variability in multiple components of the pathway. After testing only six elements in the photoperiod pathway in P. leucopus, genetic variation in the following four of these elements was evident: the circadian clock, melatonin receptor abundance or affinity, sensitivity of the reproductive axis to steroid negative feedback, and gonadotropin-releasing hormone neuronal activity. If this result can be extended to humans, the prediction would be that significant variation at multiple loci in complex neuroendocrine pathways is common among humans, and that variation would exist even in human populations from a common genetic background. This finding could only be drawn from an "exotic" animal model derived from a natural source population, confirming the continuing importance of nontraditional models alongside the standard laboratory species.