Genetic variation in the MHC II promoter: lessons for regulation and for comparative genomics

Sequence data have been accumulating that reveal variation in gene promoters of the immune system, notably in MHC class II, cytokines and chemokines. The variation is non-random: it occurs most often in proximity to and within certain regulatory elements such as CRE and NFY (in MHC class II these are respectively the X2 and Y boxes). These are elements that are widely used elsewhere in the genome, and appear to act as rheostats (modulators of expression) in contrast to the type of on-off switch operated by the RFX element that is unique to a single family of promoters such as MHC class II. It is proposed that a complex mouse phenotype described in Prague and elsewhere may reflect this pattern of variation in/around CRE. Such rheostats are expected to operate in other promoters. Their identification will be facilitated by short-range comparisons (e.g. human-chimp), and indeed this is a motive for extending comparative genomics.