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XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy
1Laboratory of Eukaryotic Molecular Genetics, National Institute of Medical Research, The Ridgeway, Mill Hill, London.
Abstract:
Chimeric mice constructed with XY embryonic stem (ES) cells that had been multiply infected with a retroviral vector were used in a genetic screen to look for mutations affecting the sex determination pathway in mice. From a small number of chimeras screened one was identified that gave rise to a low proportion of XY females amongst his offspring. Analysis of the segregating patterns of retroviral insertions demonstrated that the mutation was found in a subset of the offspring derived from one originally infected ES cell. However, the mutation appeared to have occurred subsequent to the infection. Some of the XY females proved to be fertile, and the mutant phenotype was found to segregate exclusively with the Y chromosome. Analysis of the offspring also confirmed the absence of any retroviral insertion that could be correlated with the mutation. Further characterisation of the Y chromosome carrying the mutation by karyotypic analysis, and by Southern blotting with a range of Y-specific DNA probes suggested that there has been no gross deletion or rearrangement of the Y carrying the mutation. There also appeared to be no loss of Y-specific gene functions apart from that of testis determination. Moreover, the mutation is complemented by Sxr', the minimum portion of the mouse Y known to carry Tdy. From the phenotype and deduced location of the mutation, we conclude that it is within the Tdy locus. This is the first such mutation to be described in mice.
Insights
Researchers identified a novel mutation affecting mouse sex determination. This mutation, located in the Tdy locus on the Y chromosome, results in XY females and is the first of its kind described in mice.
Area of Science:
- Developmental Biology
- Genetics
- Mammalian Reproduction
Background:
- The sex determination pathway in mammals is complex and precisely regulated.
- Mutations affecting this pathway can lead to developmental abnormalities, such as sex reversal.
- Genetic screens are crucial for identifying novel genes and mutations involved in fundamental biological processes.
Purpose of the Study:
- To identify mutations affecting the mouse sex determination pathway using a genetic screen.
- To characterize a novel mutation leading to XY female offspring.
- To determine the genetic locus and nature of the identified mutation.
Main Methods:
- Construction of chimeric mice from XY embryonic stem (ES) cells infected with a retroviral vector.
- Genetic screening of offspring from chimeric mice to identify sex determination mutations.
- Analysis of retroviral insertion patterns and segregation of the mutation.
- Karyotypic analysis and Southern blotting of the Y chromosome.
- Complementation studies using Sxr' to assess the Tdy locus.
Main Results:
- A mutation causing a low proportion of XY female offspring was identified in one chimera.
- The mutation arose spontaneously after retroviral infection and segregated exclusively with the Y chromosome.
- Karyotypic and molecular analyses revealed no gross Y chromosome deletions or rearrangements, with normal Y-specific gene function except for testis determination.
- The mutation was complemented by Sxr', indicating it resides within the Tdy locus.
Conclusions:
- A novel mutation within the Tdy locus affecting mouse sex determination has been identified.
- This mutation leads to XY females and represents the first described mutation at this locus in mice.
- The findings provide new insights into the genetic regulation of mammalian sex determination.