DNA-SEQUENCE ANALYSIS OF SRY ALLELES (SUBGENUS MUS) IMPLICATES MISREGULATION AS THE CAUSE OF C57BL 6J-Y-POS SEX REVERSAL AND DEFINES THE SRY FUNCTIONAL UNIT/

The Sry (Sex determining region, Y chromosome) open reading frame from mice representing four species of the genus Mus was sequenced in an e ffort to understand the conditional dysfunction of some M. domesticus Sry alleles when present on the C57BL/6J inbred strain genetic backgro und and to delimit the functionally important protein regions. Twenty- two Sry alleles were sequenced, most from wild-derived Y chromosomes, including 11 M. domesticus alleles, seven M. musculus alleles and two alleles each from the related species M. spicilegus and M. spretus. We found that the HMG domain (high mobility group DNA binding domain) an d the unique regions are well conserved, while the glutamine repeat cl uster (GRC) region is quite variable. No correlation was found between the predicted protein isoforms and the ability of a Sry allele to all ow differentiation of ovarian tissue when on the C57BL/6J genetic back ground, strongly suggesting that the cause of this sex reversal is not the Sry protein itself, bur rather the regulation of SRY expression. Furthermore, our interspecies sequence analysis provides compelling ev idence that the M. musculus and M. domesticus SRY functional domain is contained in the first 143 amino acids, which includes the HMG domain and adjacent unique region (UR-2).