Human Molecular Genetics, 2003, Vol. 12, No. 5 509-515
© 2003 Oxford University Press
A major locus on mouse chromosome 18 controls XX sex reversal in Odd Sex (Ods) mice
1Department of Obstetrics and Gynecology, and 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Received October 27, 2002; Revised December 13, 2002; Accepted December 20, 2002
We have previously reported a dominant mouse mutant, Odd sex (Ods), in which XX Ods/+ mice on the FVB/N background show complete sex reversal, associated with expression of Sox9 in the fetal gonads. Remarkably, when crossed to the A/J strain 
95% of the (AXFVB) F1 XX Ods/+ mice developed as fully fertile, phenotypic females, the remainder developing as males or hermaphrodites. Using a (AXFVB) F2 population, we conducted a genome-wide linkage scan to identify the number and chromosomal location of potential Ods modifier genes. A single major locus termed Odsm1 was mapped to chromosome 18, tightly linked to D18Mit189 and D18Mit210. Segregation at this locus could account for the presence of sex reversal in 100% of XX Ods/+ mice which develop as males, for the absence of sex reversal in 92% of XX Ods/+ mice which develop as females, and for the mixed sexual phenotype in 72% of XX Ods/+ mice that develop with ambiguous genitalia. We propose that homozygosity for the FVB-derived allele strongly favors Ods sex reversal, whereas homozygosity for the A/J-derived allele inhibits it. In mice heterozygous at Odsm1, the phenotypic outcome, male, female or hermaphrodite, is determined by a complex interaction of several minor modifying loci. The close proximity of Smad2, Smad7 and Smad4 to D18Mit189/210 provides a potential mechanism through which Odsm1 might act.
* To whom correspondence should be addressed: Department of Obstetrics and Gynecology, Baylor College of Medicine, 6550 Fannin Street, Houston, TX 77030, USA. Tel: +1 7137988221; Fax: +1 7137985074(1); Email: bishop{at}bcm.tmc.edu
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