The ability to detect a relevant mutation or variation is dependent on the sensitivity of the phenotypic screen. Mutations in protein-coding sequences usually give severely compromised (i.e., obvious) phenotypes, whereas those in regulatory sequences often do not. Proteins are the key structural and functional analogue components of cells, and the loss of their function is often disastrous, leading in many cases to obvious defects, and in some cases to embryonic lethality. Mutations in generic transcription factors and other “regulatory” proteins are included, and their loss causes pleiotropic effects on gene expression at many loci and plays an important role in the molecular etiology of cancer [71],[90],[91]. This is in contrast to regulatory sequences, which, when damaged, may only affect a small part of the network, with more restricted and subtle consequences, often referred to as quantitative trait variations. Indeed the use of the word “mutation”, as opposed to “variation”, reflects an inherent bias in the identification of genetic factors that influence phenotype in animals, with those exhibiting strong effects understandably having taken precedence over those that do not, both perceptually
