Hermaphrodism and sex reversal associated with the dominant hemimelia mutation in XY mice

Abstract

After two generations of backcrossing six different Y-consomic strains onto a C57BL/6J inbred mouse strain with a dominant hemimelia (Dh) mutation, a small percentage of Dh/+ males containing a Y chromosome from the AKR/J or RF/J strain showed hermaphrodism; they lacked the right testis and had an ovary and a uterus instead. Approximately 15% of Dh/+ females considered to be phenotypically normal had the Sry gene from the AKR/J or RF/J strain; they were actually sex-reversed XY females. Backcrossing of Y chromosomes from BALB/cA, C3H/HeJ, C57BL/6J, DH/Sgn, and DDD/Sgn onto the C57BL/6J strain with Dh did not result in hermaphrodism or sex reversal in adult mice. Subsequent linkage mapping analysis revealed that at least one C57BL/6J-derived homozygous allele at a locus on chromosome 13 was required for hermaphrodism and sex reversal. This condition was genetically distinct from known inherited sex-reversal conditions. It therefore offers a novel opportunity to investigate the genetic basis of sex determination in mammals.

Fig. 1

Incidence of hermaphrodism in B6-Chr Y^AKR-Dh/+ N(2) males. Arrowheads indicate left testis and arrows indicate uterus and/or ovary formed on the right side. Mouse numbers: (A) AKP22, (B) AK604, and (C) AKAM79.

Fig. 2

(A–C): Ovarian histology of B6-Chr Y^AKR-Dh/+ N(2) hermaphrodites at 80 days of age. Mouse numbers: (A) AKP22, (B) AK219, and (C) AK280. Hyperplasia of luteinized cells was common to all. Atrophy of the ovary was noted in AK219 (B) and AK280 (C). A corpus luteum cyst was identified in AKP22 (A) and AK219 (B). (D–F): Ovarian histology of younger B6-Chr Y^AKR-Dh/+ N(2) and B6-Chr Y^RF-Dh/+ N(2) hermaphrodites. Mouse numbers: (D) AKAM59 at 31 days old; (E) AKAM79 at 35 days old, and (F) RFRM211 at 37 days old. Atrophy of the ovary was common to all. Atretic follicles degenerated at various stages. Primordial follicles were absent in all ovaries. (G and H): Ovarian histology of B6-Chr Y^AKR-Dh/+ N(2) normal-appearing females. At (G) 32 days old and (H) 45 days old. No marked were changes observed.

Fig. 3

Ovarian histology of two sex-reversed XY females [B6-Chr Y^AKR-Dh/+ N(2)] at 80 days of age. As a rule, ovaries were severely atrophied and primordial follicles were absent. (A) Sclerotic changes of the cortex were noted and developing follicles were absent. This ovary was considered to be anovualatory. (B) Cortex was markedly luteinized (plural corpora lutea); therefore, this ovary was considered to have ovulated once.

Fig. 4

Plot of percentages of mice homozygous for B6 alleles at each microsatellite marker locus in the initial genome-wide scan of 85 microsatellite marker loci.