The polyglutamine motif is highly conserved at the Clock locus in various organisms and is not polymorphic in humans

Circadian rhythms play a central role in diverse physiological phenomena an d the recent years have witnessed the identification of a number of genes r esponsible for the maintenance of these rhythms. One of these is the Clock gene, which was first identified in mouse and subsequently in a large numbe r of organisms, including humans. The human Clock gene has been proposed as a possible candidate for disorders affected by alterations of circadian rh ythm, including bipolar disorder and schizophrenia. This gene contains a hi ghly conserved polyglutamine motif, that in humans is coded for by CAG repe ats. In view of the involvement of CAG repeat expansion in a number of neur o-psychiatric disorders, we have sought to determine the polymorphism statu s of CAG repeats at the Clock locus in humans. Our analysis of 190 unrelate d individuals, who included patients suffering from bipolar disorder and sc hizophrenia, indicated that the repeat, which consisted of 6 CAG triplets, was not polymorphic in humans. An analysis of the repeat in non-human prima tes and other organisms revealed that the glutamine stretch is shortest in humans and baboons, and longest in Drosophila and zebrafish. A study of var ious Drosophila species revealed that the repeat number is highly polymorph ic, ranging from 25 to 33 pure glutamine repeats. Unlike most other microsa tellites, the CAG repeat stretch at the Clock locus in humans is smaller th an its homologues in non-human primates. We propose that glutamine repeat s ize is functionally important in this gene and thus tightly regulated. The variation in repeat number is probably deleterious to the individual, resul ting in the maintenance of a short and invariable repeat structure in the h uman population.